Multiple Myeloma

A growing body of research suggests that clinicians can offer chimeric antigen receptor (CAR) T-cell therapy safely and effectively on an outpatient basis — a positive development as clinicians strive to expand access beyond metropolitan areas.

In one recent study, an industry-funded phase 2 trial, researchers found similar outcomes from outpatient and inpatient CAR T-cell therapy for relapsed/refractory large B-cell lymphoma with lisocabtagene maraleucel (Breyanzi). 

Another recent study reported that outpatient treatment of B cell non-Hodgkin lymphoma with tisagenlecleucel (Kymriah) had similar efficacy to inpatient treatment. Meanwhile, a 2023 review of CAR T-cell therapy in various settings found similar outcomes in outpatient and inpatient treatment. 

“The future of CAR T-cell therapy lies in balancing safety with accessibility,” said Rayne Rouce, MD, a pediatric oncologist at Texas Children’s Cancer Center in Houston, Texas, in an interview. “Expanding CAR T-cell therapy beyond large medical centers is a critical next step.” 
 

Great Outcomes, Low Access

Since 2017, the FDA has approved six CAR T-cell therapies, which target cancer by harnessing the power of a patient’s own T cells. As an Oregon Health & Sciences University/Knight Cancer Center website explains, T cells are removed from the patient’s body, “genetically modified to make the chimeric antigen receptor, or CAR, [which] protein binds to specific proteins on the surface of cancer cells.”

Modified cells are grown and then infused back into the body, where they “multiply and may be able to destroy all the cancer cells.”

As Rouce puts it, “CAR T-cells have revolutionized the treatment of relapsed or refractory blood cancers.” One or more of the therapies have been approved to treat types of lymphoblastic leukemia, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma.

A 2023 review of clinical trial data reported complete response rates of 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B cell lymphoma.

“Commercialization of CAR T-cell therapy brought hope that access would expand beyond the major academic medical centers with the highly specialized infrastructure and advanced laboratories required to manufacture and ultimately treat patients,” Rouce said. “However, it quickly became clear that patients who are underinsured or uninsured — or who live outside the network of the well-resourced institutions that house these therapies — are still unable to access these potentially life-saving therapies.”

A 2024 report estimated the cost of CAR T-cell therapy as $700,000-$1 million and said only a small percentage of those who could benefit from the treatment actually get it. For example, an estimated 10,000 patients with diffuse large B-cell lymphoma alone could benefit from CAR T therapy annually, but a survey of 200 US healthcare centers in 2021 found that 1900 procedures were performed overall for all indications. 
 

Distance to Treatment Is a Major Obstacle

Even if patients have insurance plans willing to cover CAR T-cell therapy, they may not be able get care. While more than 150 US centers are certified to administer the therapy, “distance to major medical centers with CAR T capabilities is a major obstacle,” Yuliya Linhares, MD, chief of lymphoma at Miami Cancer Institute in Miami, Florida, said in an interview. 

“I have had patients who chose to not proceed with CAR T therapy due to inability to travel the distance to the medical center for pre-CAR T appointments and assessments and a lack of caretakers who are available to stay nearby,” Linhares said.

Indeed, the challenges facing patients in rural and underserved urban areas can be overwhelming, Hoda Badr, PhD, professor of medicine at Baylor College of Medicine in Houston, Texas, said in an interview.

“They must take time off work, arrange accommodations near treatment sites, and manage travel costs, all of which strain limited financial resources. The inability to afford these additional expenses can lead to delays in receiving care or patients forgoing the treatment altogether,” Badr said. She added that “the psychological and social burden of being away from family and community support systems during treatment can intensify the stress of an already difficult situation.”

A statistic tells the story of the urban/community divide. CAR T-cell therapy administration at academic centers after leukapheresis — the separation and collection of white blood cells — is reported to be at around 90%, while it’s only 47% in community-based practices that have to refer patients elsewhere, Linhares noted. 
 

Researchers Explore CAR T-Cell Therapy in the Community 

Linhares is lead author of the phase 2 trial that explored administration of lisocabtagene maraleucel in 82 patients with relapsed/refractory large B-cell lymphoma. The findings were published Sept. 30 in Blood Advances.

The OUTREACH trial, funded by Juno/Bristol-Myers Squibb, treated patients in the third line and beyond at community medical centers (outpatient-monitored, 70%; inpatient-monitored, 30%). The trial didn’t require facilities to be certified by the Foundation for the Accreditation of Cellular Therapy (FACT); all had to be non-tertiary cancer centers that weren’t associated with a university. In order to administer therapy on the outpatient basis, the centers had to have phase 1 or hematopoietic stem cell transplant capabilities.

As Linhares explained, 72% of participating centers hadn’t provided CAR T-cell therapy before, and 44% did not have FACT accreditation. “About 32% of patients received CAR T at CAR T naive sites, while 70% of patients received CAR T as outpatients. Investigators had to decide whether patients qualified for the outpatient observation or had to be admitted for the inpatient observation,” she noted.
 

Community Outcomes Were Comparable to Major Trial

As for the results, grade 3 or higher adverse events occurred at a similar frequency among outpatients and inpatients at 74% and 76%, Linhares said. There were no grade 5 adverse events, and 25% of patients treated as outpatients were never hospitalized. 

Response rates were similar to those in the major TRANSCEND trial with the objective response rates rate of 80% and complete response rates of 54%.

“Overall,” Linhares said, “our study demonstrated that with the availability of standard operating procedures, specially trained staff and a multidisciplinary team trained in CAR T toxicity management, inpatient and outpatient CAR T administration is feasible at specialized community medical centers.”

In 2023, another study examined patients with B-cell non-Hodgkin lymphoma who were treated on an outpatient basis with tisagenlecleucel. Researchers reported that outpatient therapy was “feasible and associated with similar efficacy outcomes as inpatient treatment.”

And a 2023 systematic literature review identified 11 studies that reported outpatient vs inpatient outcomes in CAR T-cell therapy and found “comparable response rates (80-82% in outpatient and 72-80% in inpatient).” Costs were cheaper in the outpatient setting. 

Research findings like these are good news, Baylor College of Medicine’s Badr said. “Outpatient administration could help to scale the availability of this therapy to a broader range of healthcare settings, including those serving underserved populations. Findings indicate promising safety profiles, which is encouraging for expanding access.”
 

Not Every Patient Can Tolerate Outpatient Care

Linhares noted that the patients who received outpatient care in the lisocabtagene maraleucel study were in better shape than those in the inpatient group. Those selected for inpatient care had “higher disease risk characteristics, including high grade B cell lymphoma histology, higher disease burden, and having received bridging therapy. This points to the fact that the investigators properly selected patients who were at a higher risk of complications for inpatient observation. Additionally, some patients stayed as inpatient due to social factors, which increases length of stay independently of disease characteristics.”

Specifically, reasons for inpatient monitoring were disease characteristics (48%) including tumor burden and risk of adverse events; psychosocial factors (32%) including lack of caregiver support or transportation; COVID-19 precautions (8%); pre-infusion adverse events (8%) of fever and vasovagal reaction; and principal investigator decision (4%) due to limited hospital experience with CAR T-cell therapy.

Texas Children’s Cancer Center’s Rouce said “certain patients, particularly those with higher risk for complications or those who require intensive monitoring, may not be suited for outpatient CAR T-cell therapy. This may be due to other comorbidities or baseline factors known to predispose to CAR T-related toxicities. However, evidence-based risk mitigation algorithms may still allow closely monitored outpatient treatment, with recognition that hospital admission for incipient side effects may be necessary.”
 

What’s Next for Access to Therapy?

Rouce noted that her institution, like many others, is offering CAR T-cell therapy on an outpatient basis. “Additionally, continued scientific innovation, such as immediately available, off-the-shelf cell therapies and inducible safety switches, will ultimately improve access,” she said. 

Linhares noted a recent advance and highlighted research that’s now in progress. “CAR Ts now have an indication as a second-line therapy in relapsed/refractory large B-cell lymphoma, and there are ongoing clinical trials that will potentially move CAR Ts into the first line,” she said. “Some trials are exploring allogeneic, readily available off-the-shelf CAR T for the treatment of minimal residual disease positive large B-cell lymphoma after completion of first-line therapy.”

These potential advances “are increasing the need for CAR T-capable medical centers,” Linhares noted. “More and more medical centers with expert hematology teams are becoming CAR T-certified, with more patients having access to CAR T.”

Still, she said, “I don’t think access is nearly as good as it should be. Many patients in rural areas are still unable to get this life-saving treatment. “However, “it is very possible that other novel targeted therapies, such as bispecific antibodies, will be used in place of CAR T in areas with poor CAR T access. Bispecific antibody efficacy in various B cell lymphoma histologies are being currently explored.”

Rouce discloses relationships with Novartis and Pfizer. Linhares reports ties with Kyowa Kirin, AbbVie, ADC, BeiGene, Genentech, Gilead, GlaxoSmithKline, Seagen, and TG. Badr has no disclosures. 
 

A version of this article appeared on Medscape.com.

A growing body of research suggests that clinicians can offer chimeric antigen receptor (CAR) T-cell therapy safely and effectively on an outpatient basis — a positive development as clinicians strive to expand access beyond metropolitan areas.

In one recent study, an industry-funded phase 2 trial, researchers found similar outcomes from outpatient and inpatient CAR T-cell therapy for relapsed/refractory large B-cell lymphoma with lisocabtagene maraleucel (Breyanzi). 

Another recent study reported that outpatient treatment of B cell non-Hodgkin lymphoma with tisagenlecleucel (Kymriah) had similar efficacy to inpatient treatment. Meanwhile, a 2023 review of CAR T-cell therapy in various settings found similar outcomes in outpatient and inpatient treatment. 

“The future of CAR T-cell therapy lies in balancing safety with accessibility,” said Rayne Rouce, MD, a pediatric oncologist at Texas Children’s Cancer Center in Houston, Texas, in an interview. “Expanding CAR T-cell therapy beyond large medical centers is a critical next step.” 
 

Great Outcomes, Low Access

Since 2017, the FDA has approved six CAR T-cell therapies, which target cancer by harnessing the power of a patient’s own T cells. As an Oregon Health & Sciences University/Knight Cancer Center website explains, T cells are removed from the patient’s body, “genetically modified to make the chimeric antigen receptor, or CAR, [which] protein binds to specific proteins on the surface of cancer cells.”

Modified cells are grown and then infused back into the body, where they “multiply and may be able to destroy all the cancer cells.”

As Rouce puts it, “CAR T-cells have revolutionized the treatment of relapsed or refractory blood cancers.” One or more of the therapies have been approved to treat types of lymphoblastic leukemia, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma.

A 2023 review of clinical trial data reported complete response rates of 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B cell lymphoma.

“Commercialization of CAR T-cell therapy brought hope that access would expand beyond the major academic medical centers with the highly specialized infrastructure and advanced laboratories required to manufacture and ultimately treat patients,” Rouce said. “However, it quickly became clear that patients who are underinsured or uninsured — or who live outside the network of the well-resourced institutions that house these therapies — are still unable to access these potentially life-saving therapies.”

A 2024 report estimated the cost of CAR T-cell therapy as $700,000-$1 million and said only a small percentage of those who could benefit from the treatment actually get it. For example, an estimated 10,000 patients with diffuse large B-cell lymphoma alone could benefit from CAR T therapy annually, but a survey of 200 US healthcare centers in 2021 found that 1900 procedures were performed overall for all indications. 
 

Distance to Treatment Is a Major Obstacle

Even if patients have insurance plans willing to cover CAR T-cell therapy, they may not be able get care. While more than 150 US centers are certified to administer the therapy, “distance to major medical centers with CAR T capabilities is a major obstacle,” Yuliya Linhares, MD, chief of lymphoma at Miami Cancer Institute in Miami, Florida, said in an interview. 

“I have had patients who chose to not proceed with CAR T therapy due to inability to travel the distance to the medical center for pre-CAR T appointments and assessments and a lack of caretakers who are available to stay nearby,” Linhares said.

Indeed, the challenges facing patients in rural and underserved urban areas can be overwhelming, Hoda Badr, PhD, professor of medicine at Baylor College of Medicine in Houston, Texas, said in an interview.

“They must take time off work, arrange accommodations near treatment sites, and manage travel costs, all of which strain limited financial resources. The inability to afford these additional expenses can lead to delays in receiving care or patients forgoing the treatment altogether,” Badr said. She added that “the psychological and social burden of being away from family and community support systems during treatment can intensify the stress of an already difficult situation.”

A statistic tells the story of the urban/community divide. CAR T-cell therapy administration at academic centers after leukapheresis — the separation and collection of white blood cells — is reported to be at around 90%, while it’s only 47% in community-based practices that have to refer patients elsewhere, Linhares noted. 
 

Researchers Explore CAR T-Cell Therapy in the Community 

Linhares is lead author of the phase 2 trial that explored administration of lisocabtagene maraleucel in 82 patients with relapsed/refractory large B-cell lymphoma. The findings were published Sept. 30 in Blood Advances.

The OUTREACH trial, funded by Juno/Bristol-Myers Squibb, treated patients in the third line and beyond at community medical centers (outpatient-monitored, 70%; inpatient-monitored, 30%). The trial didn’t require facilities to be certified by the Foundation for the Accreditation of Cellular Therapy (FACT); all had to be non-tertiary cancer centers that weren’t associated with a university. In order to administer therapy on the outpatient basis, the centers had to have phase 1 or hematopoietic stem cell transplant capabilities.

As Linhares explained, 72% of participating centers hadn’t provided CAR T-cell therapy before, and 44% did not have FACT accreditation. “About 32% of patients received CAR T at CAR T naive sites, while 70% of patients received CAR T as outpatients. Investigators had to decide whether patients qualified for the outpatient observation or had to be admitted for the inpatient observation,” she noted.
 

Community Outcomes Were Comparable to Major Trial

As for the results, grade 3 or higher adverse events occurred at a similar frequency among outpatients and inpatients at 74% and 76%, Linhares said. There were no grade 5 adverse events, and 25% of patients treated as outpatients were never hospitalized. 

Response rates were similar to those in the major TRANSCEND trial with the objective response rates rate of 80% and complete response rates of 54%.

“Overall,” Linhares said, “our study demonstrated that with the availability of standard operating procedures, specially trained staff and a multidisciplinary team trained in CAR T toxicity management, inpatient and outpatient CAR T administration is feasible at specialized community medical centers.”

In 2023, another study examined patients with B-cell non-Hodgkin lymphoma who were treated on an outpatient basis with tisagenlecleucel. Researchers reported that outpatient therapy was “feasible and associated with similar efficacy outcomes as inpatient treatment.”

And a 2023 systematic literature review identified 11 studies that reported outpatient vs inpatient outcomes in CAR T-cell therapy and found “comparable response rates (80-82% in outpatient and 72-80% in inpatient).” Costs were cheaper in the outpatient setting. 

Research findings like these are good news, Baylor College of Medicine’s Badr said. “Outpatient administration could help to scale the availability of this therapy to a broader range of healthcare settings, including those serving underserved populations. Findings indicate promising safety profiles, which is encouraging for expanding access.”
 

Not Every Patient Can Tolerate Outpatient Care

Linhares noted that the patients who received outpatient care in the lisocabtagene maraleucel study were in better shape than those in the inpatient group. Those selected for inpatient care had “higher disease risk characteristics, including high grade B cell lymphoma histology, higher disease burden, and having received bridging therapy. This points to the fact that the investigators properly selected patients who were at a higher risk of complications for inpatient observation. Additionally, some patients stayed as inpatient due to social factors, which increases length of stay independently of disease characteristics.”

Specifically, reasons for inpatient monitoring were disease characteristics (48%) including tumor burden and risk of adverse events; psychosocial factors (32%) including lack of caregiver support or transportation; COVID-19 precautions (8%); pre-infusion adverse events (8%) of fever and vasovagal reaction; and principal investigator decision (4%) due to limited hospital experience with CAR T-cell therapy.

Texas Children’s Cancer Center’s Rouce said “certain patients, particularly those with higher risk for complications or those who require intensive monitoring, may not be suited for outpatient CAR T-cell therapy. This may be due to other comorbidities or baseline factors known to predispose to CAR T-related toxicities. However, evidence-based risk mitigation algorithms may still allow closely monitored outpatient treatment, with recognition that hospital admission for incipient side effects may be necessary.”
 

What’s Next for Access to Therapy?

Rouce noted that her institution, like many others, is offering CAR T-cell therapy on an outpatient basis. “Additionally, continued scientific innovation, such as immediately available, off-the-shelf cell therapies and inducible safety switches, will ultimately improve access,” she said. 

Linhares noted a recent advance and highlighted research that’s now in progress. “CAR Ts now have an indication as a second-line therapy in relapsed/refractory large B-cell lymphoma, and there are ongoing clinical trials that will potentially move CAR Ts into the first line,” she said. “Some trials are exploring allogeneic, readily available off-the-shelf CAR T for the treatment of minimal residual disease positive large B-cell lymphoma after completion of first-line therapy.”

These potential advances “are increasing the need for CAR T-capable medical centers,” Linhares noted. “More and more medical centers with expert hematology teams are becoming CAR T-certified, with more patients having access to CAR T.”

Still, she said, “I don’t think access is nearly as good as it should be. Many patients in rural areas are still unable to get this life-saving treatment. “However, “it is very possible that other novel targeted therapies, such as bispecific antibodies, will be used in place of CAR T in areas with poor CAR T access. Bispecific antibody efficacy in various B cell lymphoma histologies are being currently explored.”

Rouce discloses relationships with Novartis and Pfizer. Linhares reports ties with Kyowa Kirin, AbbVie, ADC, BeiGene, Genentech, Gilead, GlaxoSmithKline, Seagen, and TG. Badr has no disclosures. 
 

A version of this article appeared on Medscape.com.

A growing body of research suggests that clinicians can offer chimeric antigen receptor (CAR) T-cell therapy safely and effectively on an outpatient basis — a positive development as clinicians strive to expand access beyond metropolitan areas.

In one recent study, an industry-funded phase 2 trial, researchers found similar outcomes from outpatient and inpatient CAR T-cell therapy for relapsed/refractory large B-cell lymphoma with lisocabtagene maraleucel (Breyanzi). 

Another recent study reported that outpatient treatment of B cell non-Hodgkin lymphoma with tisagenlecleucel (Kymriah) had similar efficacy to inpatient treatment. Meanwhile, a 2023 review of CAR T-cell therapy in various settings found similar outcomes in outpatient and inpatient treatment. 

“The future of CAR T-cell therapy lies in balancing safety with accessibility,” said Rayne Rouce, MD, a pediatric oncologist at Texas Children’s Cancer Center in Houston, Texas, in an interview. “Expanding CAR T-cell therapy beyond large medical centers is a critical next step.” 
 

Great Outcomes, Low Access

Since 2017, the FDA has approved six CAR T-cell therapies, which target cancer by harnessing the power of a patient’s own T cells. As an Oregon Health & Sciences University/Knight Cancer Center website explains, T cells are removed from the patient’s body, “genetically modified to make the chimeric antigen receptor, or CAR, [which] protein binds to specific proteins on the surface of cancer cells.”

Modified cells are grown and then infused back into the body, where they “multiply and may be able to destroy all the cancer cells.”

As Rouce puts it, “CAR T-cells have revolutionized the treatment of relapsed or refractory blood cancers.” One or more of the therapies have been approved to treat types of lymphoblastic leukemia, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma.

A 2023 review of clinical trial data reported complete response rates of 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B cell lymphoma.

“Commercialization of CAR T-cell therapy brought hope that access would expand beyond the major academic medical centers with the highly specialized infrastructure and advanced laboratories required to manufacture and ultimately treat patients,” Rouce said. “However, it quickly became clear that patients who are underinsured or uninsured — or who live outside the network of the well-resourced institutions that house these therapies — are still unable to access these potentially life-saving therapies.”

A 2024 report estimated the cost of CAR T-cell therapy as $700,000-$1 million and said only a small percentage of those who could benefit from the treatment actually get it. For example, an estimated 10,000 patients with diffuse large B-cell lymphoma alone could benefit from CAR T therapy annually, but a survey of 200 US healthcare centers in 2021 found that 1900 procedures were performed overall for all indications. 
 

Distance to Treatment Is a Major Obstacle

Even if patients have insurance plans willing to cover CAR T-cell therapy, they may not be able get care. While more than 150 US centers are certified to administer the therapy, “distance to major medical centers with CAR T capabilities is a major obstacle,” Yuliya Linhares, MD, chief of lymphoma at Miami Cancer Institute in Miami, Florida, said in an interview. 

“I have had patients who chose to not proceed with CAR T therapy due to inability to travel the distance to the medical center for pre-CAR T appointments and assessments and a lack of caretakers who are available to stay nearby,” Linhares said.

Indeed, the challenges facing patients in rural and underserved urban areas can be overwhelming, Hoda Badr, PhD, professor of medicine at Baylor College of Medicine in Houston, Texas, said in an interview.

“They must take time off work, arrange accommodations near treatment sites, and manage travel costs, all of which strain limited financial resources. The inability to afford these additional expenses can lead to delays in receiving care or patients forgoing the treatment altogether,” Badr said. She added that “the psychological and social burden of being away from family and community support systems during treatment can intensify the stress of an already difficult situation.”

A statistic tells the story of the urban/community divide. CAR T-cell therapy administration at academic centers after leukapheresis — the separation and collection of white blood cells — is reported to be at around 90%, while it’s only 47% in community-based practices that have to refer patients elsewhere, Linhares noted. 
 

Researchers Explore CAR T-Cell Therapy in the Community 

Linhares is lead author of the phase 2 trial that explored administration of lisocabtagene maraleucel in 82 patients with relapsed/refractory large B-cell lymphoma. The findings were published Sept. 30 in Blood Advances.

The OUTREACH trial, funded by Juno/Bristol-Myers Squibb, treated patients in the third line and beyond at community medical centers (outpatient-monitored, 70%; inpatient-monitored, 30%). The trial didn’t require facilities to be certified by the Foundation for the Accreditation of Cellular Therapy (FACT); all had to be non-tertiary cancer centers that weren’t associated with a university. In order to administer therapy on the outpatient basis, the centers had to have phase 1 or hematopoietic stem cell transplant capabilities.

As Linhares explained, 72% of participating centers hadn’t provided CAR T-cell therapy before, and 44% did not have FACT accreditation. “About 32% of patients received CAR T at CAR T naive sites, while 70% of patients received CAR T as outpatients. Investigators had to decide whether patients qualified for the outpatient observation or had to be admitted for the inpatient observation,” she noted.
 

Community Outcomes Were Comparable to Major Trial

As for the results, grade 3 or higher adverse events occurred at a similar frequency among outpatients and inpatients at 74% and 76%, Linhares said. There were no grade 5 adverse events, and 25% of patients treated as outpatients were never hospitalized. 

Response rates were similar to those in the major TRANSCEND trial with the objective response rates rate of 80% and complete response rates of 54%.

“Overall,” Linhares said, “our study demonstrated that with the availability of standard operating procedures, specially trained staff and a multidisciplinary team trained in CAR T toxicity management, inpatient and outpatient CAR T administration is feasible at specialized community medical centers.”

In 2023, another study examined patients with B-cell non-Hodgkin lymphoma who were treated on an outpatient basis with tisagenlecleucel. Researchers reported that outpatient therapy was “feasible and associated with similar efficacy outcomes as inpatient treatment.”

And a 2023 systematic literature review identified 11 studies that reported outpatient vs inpatient outcomes in CAR T-cell therapy and found “comparable response rates (80-82% in outpatient and 72-80% in inpatient).” Costs were cheaper in the outpatient setting. 

Research findings like these are good news, Baylor College of Medicine’s Badr said. “Outpatient administration could help to scale the availability of this therapy to a broader range of healthcare settings, including those serving underserved populations. Findings indicate promising safety profiles, which is encouraging for expanding access.”
 

Not Every Patient Can Tolerate Outpatient Care

Linhares noted that the patients who received outpatient care in the lisocabtagene maraleucel study were in better shape than those in the inpatient group. Those selected for inpatient care had “higher disease risk characteristics, including high grade B cell lymphoma histology, higher disease burden, and having received bridging therapy. This points to the fact that the investigators properly selected patients who were at a higher risk of complications for inpatient observation. Additionally, some patients stayed as inpatient due to social factors, which increases length of stay independently of disease characteristics.”

Specifically, reasons for inpatient monitoring were disease characteristics (48%) including tumor burden and risk of adverse events; psychosocial factors (32%) including lack of caregiver support or transportation; COVID-19 precautions (8%); pre-infusion adverse events (8%) of fever and vasovagal reaction; and principal investigator decision (4%) due to limited hospital experience with CAR T-cell therapy.

Texas Children’s Cancer Center’s Rouce said “certain patients, particularly those with higher risk for complications or those who require intensive monitoring, may not be suited for outpatient CAR T-cell therapy. This may be due to other comorbidities or baseline factors known to predispose to CAR T-related toxicities. However, evidence-based risk mitigation algorithms may still allow closely monitored outpatient treatment, with recognition that hospital admission for incipient side effects may be necessary.”
 

What’s Next for Access to Therapy?

Rouce noted that her institution, like many others, is offering CAR T-cell therapy on an outpatient basis. “Additionally, continued scientific innovation, such as immediately available, off-the-shelf cell therapies and inducible safety switches, will ultimately improve access,” she said. 

Linhares noted a recent advance and highlighted research that’s now in progress. “CAR Ts now have an indication as a second-line therapy in relapsed/refractory large B-cell lymphoma, and there are ongoing clinical trials that will potentially move CAR Ts into the first line,” she said. “Some trials are exploring allogeneic, readily available off-the-shelf CAR T for the treatment of minimal residual disease positive large B-cell lymphoma after completion of first-line therapy.”

These potential advances “are increasing the need for CAR T-capable medical centers,” Linhares noted. “More and more medical centers with expert hematology teams are becoming CAR T-certified, with more patients having access to CAR T.”

Still, she said, “I don’t think access is nearly as good as it should be. Many patients in rural areas are still unable to get this life-saving treatment. “However, “it is very possible that other novel targeted therapies, such as bispecific antibodies, will be used in place of CAR T in areas with poor CAR T access. Bispecific antibody efficacy in various B cell lymphoma histologies are being currently explored.”

Rouce discloses relationships with Novartis and Pfizer. Linhares reports ties with Kyowa Kirin, AbbVie, ADC, BeiGene, Genentech, Gilead, GlaxoSmithKline, Seagen, and TG. Badr has no disclosures. 
 

A version of this article appeared on Medscape.com.

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

A quadruplet induction regimen of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in the treatment of newly diagnosed multiple myeloma (MM) shows a notably high response, with a favorable safety profile, according to the first findings of the ongoing, novel MIDAS trial.

“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).

“These rates are the highest reported to date regarding MRD negativity,” she said.

The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.

In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.

In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.

The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m² (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.

Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.

Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.

Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.

All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.

The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.

In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.

Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10⁻⁵ and 47% at the threshold of 10⁻⁶, with corresponding rates of 66% and 50%, respectively, in the PP population.

The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.

Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.

However, notable variability was observed in terms of MRD negativity at 10⁻⁵ after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).

“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.

“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
 

Safety

Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.

In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).

Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.

“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10⁻⁵ but also at 10⁻⁶,” Perrot said.

She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.

“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.

“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.

The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.

“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
 

Questions Aplenty Moving Ahead

While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.

“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.

“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”

“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”

Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.

Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”

Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.

Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”

The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.

The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.

A version of this article first appeared on Medscape.com.

A quadruplet induction regimen of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in the treatment of newly diagnosed multiple myeloma (MM) shows a notably high response, with a favorable safety profile, according to the first findings of the ongoing, novel MIDAS trial.

“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).

“These rates are the highest reported to date regarding MRD negativity,” she said.

The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.

In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.

In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.

The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m² (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.

Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.

Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.

Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.

All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.

The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.

In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.

Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10⁻⁵ and 47% at the threshold of 10⁻⁶, with corresponding rates of 66% and 50%, respectively, in the PP population.

The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.

Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.

However, notable variability was observed in terms of MRD negativity at 10⁻⁵ after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).

“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.

“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
 

Safety

Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.

In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).

Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.

“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10⁻⁵ but also at 10⁻⁶,” Perrot said.

She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.

“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.

“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.

The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.

“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
 

Questions Aplenty Moving Ahead

While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.

“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.

“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”

“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”

Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.

Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”

Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.

Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”

The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.

The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.

A version of this article first appeared on Medscape.com.

A quadruplet induction regimen of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in the treatment of newly diagnosed multiple myeloma (MM) shows a notably high response, with a favorable safety profile, according to the first findings of the ongoing, novel MIDAS trial.

“We found that this induction induced exceptionally high response and minimal residual disease (MRD) negativity rates,” said first author Aurore Perrot, MD, PhD, an associate professor of hematology at the University of Toulouse in France, in presenting the findings at the annual meeting of the International Myeloma Society (IMS).

“These rates are the highest reported to date regarding MRD negativity,” she said.

The results from a first interim analysis offer encouraging groundwork in the trial that is investigating the tailoring of subsequent therapeutic choices in patients with newly diagnosed MM based on MRD status after six cycles of induction therapy.

In the standard treatment regimen of induction therapy followed by up-front autologous stem cell transplant (ASCT), the use of ever-improving quadruplet regimens is bolstering prognoses, while the role of up-front ASCT continues to be debated, Perrot explained. She noted that no prospective trials have compared up-front transplant vs no transplant following a quadruplet regimen.

In reporting on the initial findings from the induction phase of the phase 3 IFM 2020-02 MIDAS study, Perrot described results among 791 transplant-eligible patients with newly diagnosed MM and a median age of 59 who were enrolled at 72 centers between December 2021 and July 2023.

The patients were treated with six cycles of 28 days of the Isa-KRd regimen, consisting of isatuximab 10 mg/kg (weekly for 4 weeks then biweekly), carfilzomib 20 mg/m2 on day 1 cycle 1, then 56 mg/m² (days 1, 8, and 15), lenalidomide 25 mg/d (from day 1 to day 21), and dexamethasone at 40 mg/wk.

Overall, MM was classified as International Staging System (ISS) III in 120 patients (15%) and revised-ISS III in 76 (10%) patients.

Of 757 patients undergoing cytogenetics, 8% were considered high risk on the basis of a linear predictor score > 1, while the t(11;14) translocation, a chromosomal abnormality, was present in 26% of patients.

Extramedullary disease was present in five patients, while 53 (7%) had circulating plasma cells.

All 791 patients initiated Isa-KRd induction, and most (766, 97%) had at least one peripheral stem cell mobilization course, with 761 having at least one apheresis. The median number of CD34+ cells collected was 7.106/kg.

The peripheral stem cells collected allowed for potential tandem transplants in 719 patients. In total, 757 patients completed six cycles of Isa-KRd, with an overall response rate of 95%.

In the intent-to-treat (ITT) population, a very good partial response or better was achieved in 92% of patients following induction, with a rate of 99% in the per-protocol [PP] population.

Of 751 patients in the post-induction ITT population, the MRD negativity rates were 63% at the threshold of 10⁻⁵ and 47% at the threshold of 10⁻⁶, with corresponding rates of 66% and 50%, respectively, in the PP population.

The rates of near-complete response and complete response were 64% and 66% in the ITT population, and 69% and 71% in the PP population.

Of note, no significant differences were observed in prognostic subgroups, with a trend for a higher MRD negative rate among poorer prognostic groups, Perrot said.

However, notable variability was observed in terms of MRD negativity at 10⁻⁵ after induction among some cytogenic groups, with an MRD negativity rate as high as 81% among patients with the t(4;14) translocation vs 62% among those without the abnormality (P = .002), while it was only 40% among patients with the t(11;14) translocation vs 64% without (P < .0001).

“This is the first time we have observed this correlation between the MRD negativity and these cytogenetic subgroups,” Perrot noted.

“For the moment, we are not saying that patients with the t(11;14) translocation have a poor prognosis,” she added. “But just that the early assessment of MRD shows the lower negativity rates.”
 

Safety

Seven patients experienced disease progression and five died during induction, with one dying from disease progression, two deaths related to cardiac adverse events (AEs), and two related to other AEs.

In terms of safety, the most common grade 3-4 AEs were neutropenia (25%), thrombocytopenia (5%), and infections (7%).

Peripheral neuropathy was reported among 13% of patients at any grade, and less than 1% grade 3-4.

“Our findings confirm that six cycles of Isa-KRd induce exceptionally high response and MRD negativity rates, not only at a sensitivity of 10⁻⁵ but also at 10⁻⁶,” Perrot said.

She noted that, in comparison, the MRD negativity rate at 10−5 in the related CASSIOPEIA, GRIFFIN, and IsKia trials were 35%, 22%, and 45%, respectively.

“A longer follow-up is needed to better interpret the significance of achieving MRD negativity in patients with different cytogenetic abnormalities,” Perrot added.

“Importantly, the Isa-KRd induction ensures successful stem cell collection, with no new safety signals,” she said.

The Isa-KRd regimen is not yet approved, hence only used in clinical trials, but Perrot told this publication the current evidence should help change that.

“The IsKia trial is comparing KRd and Isa-KRd, and Sanofi should try to approve the combo,” she said. “We hope the Midas data will support this approval.”
 

Questions Aplenty Moving Ahead

While the results are just the first from the ongoing trial, interest in the study and its design is high, Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, told this publication.

“To have a large trial algorithm that is based on response and in particular MRD is novel and reflects the power of MRD in myeloma,” said Mikhael, a professor of applied cancer research and drug discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona.

“Although the results are preliminary, these kinds of trials can inform our approach to MRD testing and may result in more personalized and effective treatments for patients,” he said. “This may include the potential to de-escalate or even stop therapies that have historically been given for longer or provide more intense therapies for patients with inadequate response.”

“We know the biology of myeloma is ‘one size fits all’, so the design of our trials should reflect that heterogeneity.”

Further commenting on the research, the meeting discussant Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at the Winship Cancer Institute of Emory University, Atlanta, Georgia, offered cautious optimism.

Referencing the tale of Midas in Greek mythology as having a “be careful what you wish for” lesson, Lonial pondered that, likewise, a question that may be considered regarding MRD is “whether this is in fact a gift — or could this be a curse that’s going to get us into trouble at some point down the road. I don’t know the answer.”

Some cautionary lessons include prior research indicating that patients with high-risk disease may achieve a complete remission early — but they lose remission earlier down the road, he noted.

Other considerations as the research moves forward: “Recognizing that MRD may in fact be more important than genetics — which is a premise of the current trial,” Lonial pondered. “Does MRD override genetics, or do they travel together?”

The study is ongoing, with future results expected in terms of ASCT vs no ASCT for patients with high and low risk, as well as single vs tandem ASCT.

The trial received financial support from Amgen, Bristol-Myers Squibb, and Sanofi. Perrot reported ties with Amgen, Bristol Myers Squibb, and Sanofi. Mikhael disclosed ties with Amgen, Bristol Myers Squibb, and Sanofi. Lonial reported relationships with Celgene, Bristol-Myers Squibb, Amgen, and Sanofi.

A version of this article first appeared on Medscape.com.

Adding isatuximab, or Isa (Sarclisa, Sanofi-Aventis), to bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of patients with newly diagnosed, transplant-ineligible multiple myeloma reduced the risk for disease progression or death by more than 40% vs VRd alone in the randomized, global, open-label, phase 3 IMROZ trial.

The findings, presented on September 26 at the annual meeting of the International Myeloma Society, support the four-drug combination known as Isa-VRd as a potential new standard of care (SOC) supplanting VRd alone as the SOC in this setting, according to Meletios Dimopoulos, MD, of the University of Athens, Greece.

The IMROZ findings — the first from a phase 3 study of an anti-CD38 monoclonal antibody given in combination with VRd — were also reported in May at the annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in The New England Journal of Medicine. 

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” first author Thierry Facon, MD, told this news organization at ASCO.

Dr. Thierry, of the University of Lille, and the French Academy of Medicine in Paris, France, added that Isa-VRd has the potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients.”

Isatuximab in combination with VRd was subsequently approved by the US Food and Drug Administration (FDA) for this indication, as reported on September 23 by this news organization.

So, what will this quadruplet mean for the treatment of multiple myeloma? IMROZ study coauthors Meral Beksac, MD, of Istinye University, Istanbul, and Liv Hospital Ankara, Turkey, and Mohamad Mohty, MD, of Sorbonne University, Saint-Antoine Hospital, Paris, France, provided some insights in a recent interview, telling the European Medical Journal (EMJ) Hematology that Isa-VRd is a “welcome addition” to the multiple myeloma armamentarium.
 

Should Isa-VRd Be Considered the New First-Choice Frontline Treatment for Transplant-Ineligible Patients?

“The short answer is yes,” Dr. Mohty told EMJ. “Based on this trial, quadruplet should become the preferred regimen in the population of patients represented by these inclusion criteria.”

Dr. Beksac agreed that Isa-VRd will play a role in frontline management for transplant-ineligible patients.

However, both noted that despite having a favorable safety profile similar to VRd, Isa-VRd may not be well tolerated in elderly and frail patients. Demonstrably frail patients were excluded from IMROZ, and this is a factor that should be considered in the practice setting, they agreed.
 

Will Isa-VRd Change How Patients Are Evaluated for Transplant Eligibility?

“The cutoff for transplant eligibility differs from one country to another, and today, we do not have consensus around an agreed-upon age limit,” Dr. Beksac said. “We further rely on frailty and the patient’s performance status, not only at diagnosis but at later stages as well.”

She also noted that “[t]he introduction of very effective systemic regimens with similar efficacy to [hematopoietic stem cell transplant (HSCT)] has seen a shift towards non-transplant regimens, particularly in the USA.”

“In many centers in Europe, these patients [in IMROZ] would be considered transplant eligible. Hence, for this group of patients who are not too old, but not too young, and fit, IMROZ is offering a non-transplant-based treatment with similar efficacy to what can be achieved with HSCT,” Dr. Mohty added.

Patient preference and access are also important considerations, as is cost, he noted.

Younger transplant-eligible patients may prefer transplant over continuous treatment for life, whereas some might prefer long-term treatment over a stem cell protocol that will require months off of work, he and Dr. Beksac explained.

“Based on this trial, we will likely see a decline in the number of transplants,” Dr. Mohty predicted. “With the IMROZ data, we have something valid that we can offer patients without any prejudice to their outcome.”
 

How Will This Combination Be Integrated Into Daily Clinical Practice?

“My interpretation would be that this protocol will be conceived as an applicable protocol that can be adapted to our daily practice,” Dr. Beksac said.

Dr. Mohty added that the multiple myeloma story is changing and evolving.

“It’s not transplant versus no transplant, it’s who is going to receive quadruplet and who’s going to receive less than a quadruplet, who is fit and who is unfit,” he explained, adding that physicians will likely adapt the Isa-VRd regimen for real-world use based on clinical judgment.

For example, the quadruplet may be combined “in a kind of VRd-light version to start with, and maybe we can adapt later depending on the tolerability of the patient,” Dr. Beksac added.

“Until recently, we thought that transplant is the gold standard for everybody whenever possible. Now, we have a more nuanced answer, offering a regimen that actually is as effective, and may even be better, than transplant,” Dr. Mohty said. “So, it’s a most welcome addition to what we do.”

Both the IMROZ study and the EMJ article were funded by Sanofi.

Dr. Dimopoulos reported ties with Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. Dr. Beksac disclosed relationships with Amgen, BMS, GSK, Janssen, Sanofi, and Takeda. Dr. Mohty reported ties with Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, GSK, Janssen-Cilag, Jazz Pharmaceuticals, and others.
 

A version of this article appeared on Medscape.com.

Adding isatuximab, or Isa (Sarclisa, Sanofi-Aventis), to bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of patients with newly diagnosed, transplant-ineligible multiple myeloma reduced the risk for disease progression or death by more than 40% vs VRd alone in the randomized, global, open-label, phase 3 IMROZ trial.

The findings, presented on September 26 at the annual meeting of the International Myeloma Society, support the four-drug combination known as Isa-VRd as a potential new standard of care (SOC) supplanting VRd alone as the SOC in this setting, according to Meletios Dimopoulos, MD, of the University of Athens, Greece.

The IMROZ findings — the first from a phase 3 study of an anti-CD38 monoclonal antibody given in combination with VRd — were also reported in May at the annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in The New England Journal of Medicine. 

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” first author Thierry Facon, MD, told this news organization at ASCO.

Dr. Thierry, of the University of Lille, and the French Academy of Medicine in Paris, France, added that Isa-VRd has the potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients.”

Isatuximab in combination with VRd was subsequently approved by the US Food and Drug Administration (FDA) for this indication, as reported on September 23 by this news organization.

So, what will this quadruplet mean for the treatment of multiple myeloma? IMROZ study coauthors Meral Beksac, MD, of Istinye University, Istanbul, and Liv Hospital Ankara, Turkey, and Mohamad Mohty, MD, of Sorbonne University, Saint-Antoine Hospital, Paris, France, provided some insights in a recent interview, telling the European Medical Journal (EMJ) Hematology that Isa-VRd is a “welcome addition” to the multiple myeloma armamentarium.
 

Should Isa-VRd Be Considered the New First-Choice Frontline Treatment for Transplant-Ineligible Patients?

“The short answer is yes,” Dr. Mohty told EMJ. “Based on this trial, quadruplet should become the preferred regimen in the population of patients represented by these inclusion criteria.”

Dr. Beksac agreed that Isa-VRd will play a role in frontline management for transplant-ineligible patients.

However, both noted that despite having a favorable safety profile similar to VRd, Isa-VRd may not be well tolerated in elderly and frail patients. Demonstrably frail patients were excluded from IMROZ, and this is a factor that should be considered in the practice setting, they agreed.
 

Will Isa-VRd Change How Patients Are Evaluated for Transplant Eligibility?

“The cutoff for transplant eligibility differs from one country to another, and today, we do not have consensus around an agreed-upon age limit,” Dr. Beksac said. “We further rely on frailty and the patient’s performance status, not only at diagnosis but at later stages as well.”

She also noted that “[t]he introduction of very effective systemic regimens with similar efficacy to [hematopoietic stem cell transplant (HSCT)] has seen a shift towards non-transplant regimens, particularly in the USA.”

“In many centers in Europe, these patients [in IMROZ] would be considered transplant eligible. Hence, for this group of patients who are not too old, but not too young, and fit, IMROZ is offering a non-transplant-based treatment with similar efficacy to what can be achieved with HSCT,” Dr. Mohty added.

Patient preference and access are also important considerations, as is cost, he noted.

Younger transplant-eligible patients may prefer transplant over continuous treatment for life, whereas some might prefer long-term treatment over a stem cell protocol that will require months off of work, he and Dr. Beksac explained.

“Based on this trial, we will likely see a decline in the number of transplants,” Dr. Mohty predicted. “With the IMROZ data, we have something valid that we can offer patients without any prejudice to their outcome.”
 

How Will This Combination Be Integrated Into Daily Clinical Practice?

“My interpretation would be that this protocol will be conceived as an applicable protocol that can be adapted to our daily practice,” Dr. Beksac said.

Dr. Mohty added that the multiple myeloma story is changing and evolving.

“It’s not transplant versus no transplant, it’s who is going to receive quadruplet and who’s going to receive less than a quadruplet, who is fit and who is unfit,” he explained, adding that physicians will likely adapt the Isa-VRd regimen for real-world use based on clinical judgment.

For example, the quadruplet may be combined “in a kind of VRd-light version to start with, and maybe we can adapt later depending on the tolerability of the patient,” Dr. Beksac added.

“Until recently, we thought that transplant is the gold standard for everybody whenever possible. Now, we have a more nuanced answer, offering a regimen that actually is as effective, and may even be better, than transplant,” Dr. Mohty said. “So, it’s a most welcome addition to what we do.”

Both the IMROZ study and the EMJ article were funded by Sanofi.

Dr. Dimopoulos reported ties with Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. Dr. Beksac disclosed relationships with Amgen, BMS, GSK, Janssen, Sanofi, and Takeda. Dr. Mohty reported ties with Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, GSK, Janssen-Cilag, Jazz Pharmaceuticals, and others.
 

A version of this article appeared on Medscape.com.

Adding isatuximab, or Isa (Sarclisa, Sanofi-Aventis), to bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of patients with newly diagnosed, transplant-ineligible multiple myeloma reduced the risk for disease progression or death by more than 40% vs VRd alone in the randomized, global, open-label, phase 3 IMROZ trial.

The findings, presented on September 26 at the annual meeting of the International Myeloma Society, support the four-drug combination known as Isa-VRd as a potential new standard of care (SOC) supplanting VRd alone as the SOC in this setting, according to Meletios Dimopoulos, MD, of the University of Athens, Greece.

The IMROZ findings — the first from a phase 3 study of an anti-CD38 monoclonal antibody given in combination with VRd — were also reported in May at the annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in The New England Journal of Medicine. 

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” first author Thierry Facon, MD, told this news organization at ASCO.

Dr. Thierry, of the University of Lille, and the French Academy of Medicine in Paris, France, added that Isa-VRd has the potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients.”

Isatuximab in combination with VRd was subsequently approved by the US Food and Drug Administration (FDA) for this indication, as reported on September 23 by this news organization.

So, what will this quadruplet mean for the treatment of multiple myeloma? IMROZ study coauthors Meral Beksac, MD, of Istinye University, Istanbul, and Liv Hospital Ankara, Turkey, and Mohamad Mohty, MD, of Sorbonne University, Saint-Antoine Hospital, Paris, France, provided some insights in a recent interview, telling the European Medical Journal (EMJ) Hematology that Isa-VRd is a “welcome addition” to the multiple myeloma armamentarium.
 

Should Isa-VRd Be Considered the New First-Choice Frontline Treatment for Transplant-Ineligible Patients?

“The short answer is yes,” Dr. Mohty told EMJ. “Based on this trial, quadruplet should become the preferred regimen in the population of patients represented by these inclusion criteria.”

Dr. Beksac agreed that Isa-VRd will play a role in frontline management for transplant-ineligible patients.

However, both noted that despite having a favorable safety profile similar to VRd, Isa-VRd may not be well tolerated in elderly and frail patients. Demonstrably frail patients were excluded from IMROZ, and this is a factor that should be considered in the practice setting, they agreed.
 

Will Isa-VRd Change How Patients Are Evaluated for Transplant Eligibility?

“The cutoff for transplant eligibility differs from one country to another, and today, we do not have consensus around an agreed-upon age limit,” Dr. Beksac said. “We further rely on frailty and the patient’s performance status, not only at diagnosis but at later stages as well.”

She also noted that “[t]he introduction of very effective systemic regimens with similar efficacy to [hematopoietic stem cell transplant (HSCT)] has seen a shift towards non-transplant regimens, particularly in the USA.”

“In many centers in Europe, these patients [in IMROZ] would be considered transplant eligible. Hence, for this group of patients who are not too old, but not too young, and fit, IMROZ is offering a non-transplant-based treatment with similar efficacy to what can be achieved with HSCT,” Dr. Mohty added.

Patient preference and access are also important considerations, as is cost, he noted.

Younger transplant-eligible patients may prefer transplant over continuous treatment for life, whereas some might prefer long-term treatment over a stem cell protocol that will require months off of work, he and Dr. Beksac explained.

“Based on this trial, we will likely see a decline in the number of transplants,” Dr. Mohty predicted. “With the IMROZ data, we have something valid that we can offer patients without any prejudice to their outcome.”
 

How Will This Combination Be Integrated Into Daily Clinical Practice?

“My interpretation would be that this protocol will be conceived as an applicable protocol that can be adapted to our daily practice,” Dr. Beksac said.

Dr. Mohty added that the multiple myeloma story is changing and evolving.

“It’s not transplant versus no transplant, it’s who is going to receive quadruplet and who’s going to receive less than a quadruplet, who is fit and who is unfit,” he explained, adding that physicians will likely adapt the Isa-VRd regimen for real-world use based on clinical judgment.

For example, the quadruplet may be combined “in a kind of VRd-light version to start with, and maybe we can adapt later depending on the tolerability of the patient,” Dr. Beksac added.

“Until recently, we thought that transplant is the gold standard for everybody whenever possible. Now, we have a more nuanced answer, offering a regimen that actually is as effective, and may even be better, than transplant,” Dr. Mohty said. “So, it’s a most welcome addition to what we do.”

Both the IMROZ study and the EMJ article were funded by Sanofi.

Dr. Dimopoulos reported ties with Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. Dr. Beksac disclosed relationships with Amgen, BMS, GSK, Janssen, Sanofi, and Takeda. Dr. Mohty reported ties with Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, GSK, Janssen-Cilag, Jazz Pharmaceuticals, and others.
 

A version of this article appeared on Medscape.com.

A single infusion of the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel, or cilta-cel (CARVYKTI, Janssen Biotech, Inc.), reduces the risk for death by 45% vs standard-of-care (SoC) therapies in patients with lenalidomide-refractory multiple myeloma, according to the latest data from the phase 3 CARTITUDE-4 study.

“Cilta-cel is the first CAR T-cell therapy to demonstrate an overall survival benefit in multiple myeloma,” María-Victoria Mateos, MD, PhD, said during a presentation of the updated CARTITUDE-4 data at the annual meeting of the International Myeloma Society in late September.

A prespecified overall survival (OS) analysis at a median follow-up of 34 months showed that median OS was not reached in either the cilta-cel or SoC therapy arm (hazard ratio [HR], 0.55). The 30-month OS rates were 76% and 64% in the arms, respectively, said Dr. Mateos, a professor at the University Hospital of Salamanca, Spain.

The significant OS benefit was sustained across all prespecified subgroups, she noted.

The US Food and Drug Administration first approved cilta-cel in 2022 for use after at least four prior lines of therapy in patients with lenalidomide-resistant multiple myeloma based on findings from the CARTITUDE-1 trial. In April 2024, based on progression-free survival (PFS) findings at median follow-up of 16 months in CARTITUDE-4 (HR for progression/death vs SoC, 0.26), that approval was expanded to include patients with lenalidomide-refractory multiple myeloma after one or more prior lines of therapy.

“CARVYKTI demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results,” study coauthor Binod Dhakal, MD, of the Medical College of Wisconsin, in Milwaukee, stated in a press release announcing that expansion. “With this approval, I’m excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease.”

At the latest analysis, PFS was not reached in the cilta-cel arm and was 11.79 months with SoC, Dr. Mateos said.

The 30-month PFS rates were 59% and 26%, respectively (HR, 0.29), and the PFS benefit was observed across prespecified subgroups.

Patients in the cilta-cel arm also had better complete response rates (77% vs 24%), overall response rates (85% vs 67%), and minimal residual disease-negativity rates (62% vs 18%).

Median duration of response was not reached with cilta-cel and was 18.69 months with SoC, and median time to symptom worsening was not reached vs 34.33 months, respectively.

Safety at the latest update was consistent with prior analyses.

The CARTITUDE findings continue to support the overall benefit-risk profile of cilta-cel vs SoC in patients with lenalidomide-refractory multiple myeloma as early as after the first relapse, Dr. Mateos concluded.

Despite the “compelling efficacy” of cilta-cel, there remains a need for “a safer and equally (if not more) effective CAR-T product” in this setting, Manni Mohyuddin, MD, told this news organization.

“The trial does not change my practice,” said Dr. Mohyuddin, an assistant professor in the multiple myeloma program at Huntsman Cancer Institute, University of Utah, Salt Lake City.

“We must recognize that the control arm [in CARTITUDE-4] isn’t the best available standard of care,” he explained, noting that carfilzomib-containing triplets were not allowed. “Furthermore, overall survival is dependent on access to good therapies upon relapse, and patients in the control arm did not cross over to get cilta-cel at the time of relapse.

“We do not know if overall survival benefit would have been present if the control arm was better and if there was access to better post-protocol therapy.”

Toxicity is also a concern, he said.

“I think of it as high risk-high reward. There was a sevenfold increased incidence of secondary hematological malignancies in the cilta-cel arm compared to standard of care — this is a very concerning signal that dampens my enthusiasm to use this drug early for everyone,” he added.

For example, although Parkinsonism was rare, it generally did not resolve and lasted years, resolving in only 13% of affected patients, with a median time to resolution of 523 days.

“These are horrible odds, and for many patients there may be safer options,” he noted, adding that “cilta-cel is an option I would consider for some relapses (very early relapse while still on multi-agent therapy, high-risk disease), but otherwise I think personally it’s too toxic for most first relapses.”

Dr. Mateos reported relationships with AbbVie, Amgen, BMS, GSK, Janssen, Kite, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline Therapeutics, and Takeda. Dr. Mohyuddin had no disclosures.
 

A version of this article first appeared on Medscape.com.

A single infusion of the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel, or cilta-cel (CARVYKTI, Janssen Biotech, Inc.), reduces the risk for death by 45% vs standard-of-care (SoC) therapies in patients with lenalidomide-refractory multiple myeloma, according to the latest data from the phase 3 CARTITUDE-4 study.

“Cilta-cel is the first CAR T-cell therapy to demonstrate an overall survival benefit in multiple myeloma,” María-Victoria Mateos, MD, PhD, said during a presentation of the updated CARTITUDE-4 data at the annual meeting of the International Myeloma Society in late September.

A prespecified overall survival (OS) analysis at a median follow-up of 34 months showed that median OS was not reached in either the cilta-cel or SoC therapy arm (hazard ratio [HR], 0.55). The 30-month OS rates were 76% and 64% in the arms, respectively, said Dr. Mateos, a professor at the University Hospital of Salamanca, Spain.

The significant OS benefit was sustained across all prespecified subgroups, she noted.

The US Food and Drug Administration first approved cilta-cel in 2022 for use after at least four prior lines of therapy in patients with lenalidomide-resistant multiple myeloma based on findings from the CARTITUDE-1 trial. In April 2024, based on progression-free survival (PFS) findings at median follow-up of 16 months in CARTITUDE-4 (HR for progression/death vs SoC, 0.26), that approval was expanded to include patients with lenalidomide-refractory multiple myeloma after one or more prior lines of therapy.

“CARVYKTI demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results,” study coauthor Binod Dhakal, MD, of the Medical College of Wisconsin, in Milwaukee, stated in a press release announcing that expansion. “With this approval, I’m excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease.”

At the latest analysis, PFS was not reached in the cilta-cel arm and was 11.79 months with SoC, Dr. Mateos said.

The 30-month PFS rates were 59% and 26%, respectively (HR, 0.29), and the PFS benefit was observed across prespecified subgroups.

Patients in the cilta-cel arm also had better complete response rates (77% vs 24%), overall response rates (85% vs 67%), and minimal residual disease-negativity rates (62% vs 18%).

Median duration of response was not reached with cilta-cel and was 18.69 months with SoC, and median time to symptom worsening was not reached vs 34.33 months, respectively.

Safety at the latest update was consistent with prior analyses.

The CARTITUDE findings continue to support the overall benefit-risk profile of cilta-cel vs SoC in patients with lenalidomide-refractory multiple myeloma as early as after the first relapse, Dr. Mateos concluded.

Despite the “compelling efficacy” of cilta-cel, there remains a need for “a safer and equally (if not more) effective CAR-T product” in this setting, Manni Mohyuddin, MD, told this news organization.

“The trial does not change my practice,” said Dr. Mohyuddin, an assistant professor in the multiple myeloma program at Huntsman Cancer Institute, University of Utah, Salt Lake City.

“We must recognize that the control arm [in CARTITUDE-4] isn’t the best available standard of care,” he explained, noting that carfilzomib-containing triplets were not allowed. “Furthermore, overall survival is dependent on access to good therapies upon relapse, and patients in the control arm did not cross over to get cilta-cel at the time of relapse.

“We do not know if overall survival benefit would have been present if the control arm was better and if there was access to better post-protocol therapy.”

Toxicity is also a concern, he said.

“I think of it as high risk-high reward. There was a sevenfold increased incidence of secondary hematological malignancies in the cilta-cel arm compared to standard of care — this is a very concerning signal that dampens my enthusiasm to use this drug early for everyone,” he added.

For example, although Parkinsonism was rare, it generally did not resolve and lasted years, resolving in only 13% of affected patients, with a median time to resolution of 523 days.

“These are horrible odds, and for many patients there may be safer options,” he noted, adding that “cilta-cel is an option I would consider for some relapses (very early relapse while still on multi-agent therapy, high-risk disease), but otherwise I think personally it’s too toxic for most first relapses.”

Dr. Mateos reported relationships with AbbVie, Amgen, BMS, GSK, Janssen, Kite, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline Therapeutics, and Takeda. Dr. Mohyuddin had no disclosures.
 

A version of this article first appeared on Medscape.com.

A single infusion of the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel, or cilta-cel (CARVYKTI, Janssen Biotech, Inc.), reduces the risk for death by 45% vs standard-of-care (SoC) therapies in patients with lenalidomide-refractory multiple myeloma, according to the latest data from the phase 3 CARTITUDE-4 study.

“Cilta-cel is the first CAR T-cell therapy to demonstrate an overall survival benefit in multiple myeloma,” María-Victoria Mateos, MD, PhD, said during a presentation of the updated CARTITUDE-4 data at the annual meeting of the International Myeloma Society in late September.

A prespecified overall survival (OS) analysis at a median follow-up of 34 months showed that median OS was not reached in either the cilta-cel or SoC therapy arm (hazard ratio [HR], 0.55). The 30-month OS rates were 76% and 64% in the arms, respectively, said Dr. Mateos, a professor at the University Hospital of Salamanca, Spain.

The significant OS benefit was sustained across all prespecified subgroups, she noted.

The US Food and Drug Administration first approved cilta-cel in 2022 for use after at least four prior lines of therapy in patients with lenalidomide-resistant multiple myeloma based on findings from the CARTITUDE-1 trial. In April 2024, based on progression-free survival (PFS) findings at median follow-up of 16 months in CARTITUDE-4 (HR for progression/death vs SoC, 0.26), that approval was expanded to include patients with lenalidomide-refractory multiple myeloma after one or more prior lines of therapy.

“CARVYKTI demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results,” study coauthor Binod Dhakal, MD, of the Medical College of Wisconsin, in Milwaukee, stated in a press release announcing that expansion. “With this approval, I’m excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease.”

At the latest analysis, PFS was not reached in the cilta-cel arm and was 11.79 months with SoC, Dr. Mateos said.

The 30-month PFS rates were 59% and 26%, respectively (HR, 0.29), and the PFS benefit was observed across prespecified subgroups.

Patients in the cilta-cel arm also had better complete response rates (77% vs 24%), overall response rates (85% vs 67%), and minimal residual disease-negativity rates (62% vs 18%).

Median duration of response was not reached with cilta-cel and was 18.69 months with SoC, and median time to symptom worsening was not reached vs 34.33 months, respectively.

Safety at the latest update was consistent with prior analyses.

The CARTITUDE findings continue to support the overall benefit-risk profile of cilta-cel vs SoC in patients with lenalidomide-refractory multiple myeloma as early as after the first relapse, Dr. Mateos concluded.

Despite the “compelling efficacy” of cilta-cel, there remains a need for “a safer and equally (if not more) effective CAR-T product” in this setting, Manni Mohyuddin, MD, told this news organization.

“The trial does not change my practice,” said Dr. Mohyuddin, an assistant professor in the multiple myeloma program at Huntsman Cancer Institute, University of Utah, Salt Lake City.

“We must recognize that the control arm [in CARTITUDE-4] isn’t the best available standard of care,” he explained, noting that carfilzomib-containing triplets were not allowed. “Furthermore, overall survival is dependent on access to good therapies upon relapse, and patients in the control arm did not cross over to get cilta-cel at the time of relapse.

“We do not know if overall survival benefit would have been present if the control arm was better and if there was access to better post-protocol therapy.”

Toxicity is also a concern, he said.

“I think of it as high risk-high reward. There was a sevenfold increased incidence of secondary hematological malignancies in the cilta-cel arm compared to standard of care — this is a very concerning signal that dampens my enthusiasm to use this drug early for everyone,” he added.

For example, although Parkinsonism was rare, it generally did not resolve and lasted years, resolving in only 13% of affected patients, with a median time to resolution of 523 days.

“These are horrible odds, and for many patients there may be safer options,” he noted, adding that “cilta-cel is an option I would consider for some relapses (very early relapse while still on multi-agent therapy, high-risk disease), but otherwise I think personally it’s too toxic for most first relapses.”

Dr. Mateos reported relationships with AbbVie, Amgen, BMS, GSK, Janssen, Kite, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline Therapeutics, and Takeda. Dr. Mohyuddin had no disclosures.
 

A version of this article first appeared on Medscape.com.

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

RIO DE JANEIRO — The addition of daratumumab to lenalidomide maintenance therapy following autologous stem cell transplant (ASCT) significantly improves rates of achieving minimal residual disease (MRD) negativity and progression-free survival (PFS) among patients newly diagnosed with multiple myeloma (MM), new research showed.

“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.

“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.

Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.

While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.

For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.

The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.

They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.

The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.

Overall, patients received a median of five induction cycles prior to entering the study.

For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).

A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.

The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).

At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)

The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).

Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.

The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.

Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).

Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.

“Overall, there were no new safety concerns for daratumumab,” he said.

The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”

A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.

In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”

Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”

The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.

Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”

Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”

“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.

“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”

The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.

A version of this article first appeared on Medscape.com.

RIO DE JANEIRO — The addition of daratumumab to lenalidomide maintenance therapy following autologous stem cell transplant (ASCT) significantly improves rates of achieving minimal residual disease (MRD) negativity and progression-free survival (PFS) among patients newly diagnosed with multiple myeloma (MM), new research showed.

“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.

“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.

Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.

While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.

For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.

The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.

They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.

The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.

Overall, patients received a median of five induction cycles prior to entering the study.

For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).

A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.

The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).

At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)

The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).

Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.

The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.

Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).

Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.

“Overall, there were no new safety concerns for daratumumab,” he said.

The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”

A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.

In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”

Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”

The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.

Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”

Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”

“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.

“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”

The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.

A version of this article first appeared on Medscape.com.

RIO DE JANEIRO — The addition of daratumumab to lenalidomide maintenance therapy following autologous stem cell transplant (ASCT) significantly improves rates of achieving minimal residual disease (MRD) negativity and progression-free survival (PFS) among patients newly diagnosed with multiple myeloma (MM), new research showed.

“To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard of care lenalidomide maintenance, which is the focus of our trial,” said first author Ashraf Z. Badros, MD, a professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, in presenting the findings at the International Myeloma Society (IMS) 2024.

“These results support the addition of daratumumab not only to induction/consolidation but also to standard of care lenalidomide maintenance for these patients,” he said of the study, which was published concurrently in the journal Blood.

Despite ongoing advancements in regimens for induction, consolidation, and maintenance posttransplant, most patients with MM eventually relapse, driving continuing efforts to optimize treatment strategies and improve long-term outcomes.

While daratumumab, an anti-CD38 monoclonal antibody, is approved in induction and consolidation with ASCT for patients with newly diagnosed MM, the authors sought to investigate the potential benefits of adding it to the standard-of-care therapy lenalidomide in maintenance therapy.

For the phase 3 AURIGA trial, they recruited 200 patients with newly diagnosed MM within 12 months of induction therapy and 6 months of ASCT.

The patients, who were all anti-CD38 naive, received at least four induction cycles, had at least a very good partial response, and were MRD positive following ASCT.

They were randomized 1:1 to receive 28-day lenalidomide maintenance cycles either with (n = 99) or without (n = 101) subcutaneous daratumumab for at least 36 cycles or until disease progression, unacceptable toxicity, or withdrawal.

The patients had similar baseline demographic characteristics; their median age was about 62 years, and 25.3% in the daratumumab and 23.5% in the no-daratumumab group had ISS stage III disease. At the time of diagnosis, 23.9% and 16.9%, respectively, had high cytogenic risk.

Overall, patients received a median of five induction cycles prior to entering the study.

For the primary endpoint, the rate of conversion from MRD positive to MRD negative (at a sensitivity of 10-5 using next-generation sequencing) by 12 months was significantly higher in the daratumumab group than in the lenalidomide-only group, at 50.5% vs 18.8% (odds ratio [OR], 4.51; P < .0001).

A similar benefit with the daratumumab group was observed across all clinically relevant subgroups, including patients with high-risk disease.

The MRD-negative conversion rate was similar at the 10-6 threshold (23.2% vs 5%; OR, 5.97; P = .0002).

At a median follow-up of 32.3 months, the overall rates of MRD negativity were 60.6% and 27.7%, with and without daratumumab, respectively (OR, 4.12; P < .0001)

The achievement of complete response or better also was significantly greater with daratumumab (75.8% vs 61.4%; OR, 2.00; P = .0255).

Likewise, PFS favored daratumumab (hazard ratio, 0.53), and the estimated 30-month PFS rates were 82.7% and 66.4%, respectively.

The daratumumab group received more maintenance cycles than the lenalidomide-only group (median of 33 vs 21.5), and it had higher rates of completion of 12 cycles (88.5% vs 78.6%). Dr. Badros noted that the main reason for discontinuation of therapy in the no-daratumumab arm was disease progression.

Consistent with previous studies, daratumumab was associated with more grade 3/4 treatment-emergent adverse events (TEAEs), occurring in 74.0% patients vs 67.3% patients not receiving daratumumab, including infections (18.8% vs 13.3%), cytopenia (54.2% vs 46.9%), and neutropenia (46.9% vs 41.8%). Dr. Badros noted the significantly longer time of treatment in the daratumumab arm (30 months vs 20 months).

Serious TEAEs occurred in 30.2% daratumumab patients and 22.4% no-daratumumab patients, and fatal TEAEs occurred in 2.1% and 1.0% patients, respectively.

“Overall, there were no new safety concerns for daratumumab,” he said.

The authors noted that the requirement that patients be anti-CD38 naive was partially because of “the D-VRd [daratumumab combined with bortezomib, lenalidomide, and dexamethasone] regimen gaining popularity and increased utilization in the myeloma community for transplant-eligible patients with NDMM, even before the publication of the long-term results of the randomized GRIFFIN and PERSEUS studies.”

A key question, remarked Joseph Mikhael, MD, who is chief medical officer of the International Myeloma Foundation, from the audience, is how applicable the findings are in the modern environment, where most patients now have indeed had prior anti-CD38 treatment.

In response, Dr. Badros explained that “I think this is an important study because it is probably one of the few studies that separates the impact of daratumumab-lenalidomide without prior daratumumab use.”

Dr. Badros noted that results from the PERSEUS trial, of D-VRd, show MRD-positive to MRD-negative conversion rates that are similar to the current trial; “therefore, I really don’t think that using daratumumab up front will prevent using it as maintenance,” he said. “If anything, it actually improves outcomes.”

The findings from continuous treatment “are an important reminder that high-risk patients do not do well if you stop treatment,” he said.

Further commenting on the research at the meeting, María-Victoria Mateos, MD, PhD, an associate professor of medicine at the University of Salamanca in Spain, noted that “the unmet need in maintenance is to upgrade the quality of the response and to increase the conversion of MRD-positivity to MRD negative in order to delay the progression of the disease and prolong the overall survival.”

Regarding the AURIGA trial, “this is very interesting data about the role of daratumumab-lenalidomide maintenance in patients who are MRD positive after autologous stem cell transplantation.”

“What is more important is we are progressing in response-adaptive therapy, and we are generating very useful information to possibly make the majority of patients become MRD negative.

“Developing early endpoints as surrogate markers for long-term outcomes and overall survival is critically important,” she added. “Otherwise, trials may continue for more than 15 years.”

The study was sponsored by Janssen Biotech. Dr. Badros reported relationships with Bristol-Myers Squibb, BeiGene, Roche, Jansen, and GSK. Mateos disclosed ties with AbbVie, Amgen, Bristol-Myers Squibb, GSK, Kite, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, and Sanofi.

A version of this article first appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.