From the Journals

Maintenance therapies boost MM survival rates


Following stem cell transplant, intensive maintenance therapy with the triplet of carlfilzimb, lenalidomide, and dexamathase (KRd) achieved superior progression-free survival (PFS) in patients with multiple myeloma (MM) versus lenalidomide alone (K), according to interim results of the phase 3 ATLAS trial.

These results, published in The Lancet Oncology, are not yet practice-changing, but they add to a growing body of evidence supporting this approach.

Andrzej Jakubowiak, MD, professor of medicine, University of Chicago

Dr. Andrzej Jakubowiak

“Bearing in mind that ATLAS trial data come from unplanned interim analysis, we found that the benefit of combination therapy (KRd) is clearly seen, especially for standard risk patients. We think that, since there are no vast differences in toxicities, there is quite convincing data for considering KRd maintenance for the post autologous stem cell transplantation treatment of MM patients,” ATLAS study coauthor Andrzej Jakubowiak, MD, professor of medicine at the University of Chicago, said in an interview.

Among patients receiving KRd (n = 93), median PFS was 59 months (95% confidence interval) compared with 41 months in the R group (hazard ratio, 0.51, P = .012). These results come from data collected between 2016 and 2020, from 12 academic and clinical centers in the United States and Poland. The cohort included 180 adults randomly assigned to each study arm, (47% were female, median age 59 years) The most common adverse events were neutropenia 48% vs. 60%, thrombocytopenia 13% vs. 7%, and lower respiratory tract infections 8% vs. 1% in the KRd and R groups, respectively. Serious adverse events were reported in 30% of patients in the KRd arm (including one death due to severe pneumonia) and 22% in the R group.

“As expected, there is a slightly higher toxicity in the KRd arm but mostly low-grade events occurred. We believe in KRd maintenance because it provides a longer remission for a relatively small price. The longer a patient is in remission, the better chance that, if relapse does occur, there will be more therapeutic options available to return to remission,” said Dr. Jakubowiak.

Although all patients in the trial received stem cell therapy, the induction therapies were varied.

“We designed the study similarly to the CALGB maintenance trial, one of the key phase 3 trials leading to the approval of lenalidomide as post transplantation maintenance. With so many changes currently occurring MM therapies, having a fixed induction can be its own limitation. Importantly, with our study design we found that all comers may benefit from KRd maintenance,” he said.

It is important to note that KRd treatment occurred for 36 cycles unless a patient withdrew, died, or achieved minimal residual disease (MRD) status.

“Per study design, the duration of KRd treatment was shortened to eight cycles for patients without high-risk cytogenetics who achieved MRD-negativity after cycle six. For these patients, treatment was converted from KRd to R maintenance as of cycle nine. Despite treatment deescalation, this subset of patients (44% of all KRd patients) contributed strongly to KRd PFS. While this approach will need to be validated in a randomized setting, the results provide a proof of concept that if you achieve MRD-negative status and have standard risk cytogenetics, you don’t have to go on a long KRd treatment,” said Dr. Jakubowiak.

Urvi Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, noted the importance of the study as “the first randomized phase-3 trial suggesting progression free survival superiority of an alternative maintenance therapy to lenalidomide alone.”

Urvi Shah, MD, Memorial Sloan Kettering Cancer Center, New York

Dr. Urvi Shah

Dr. Shah did have concerns about the applicability of the study, especially regarding the use of varied induction regimens, saying, “Only 11%-13% of patients in this study got lenalidomide during induction and 4%-6% got carfilzomib induction. Therefore, most patients were getting new drugs during maintenance different from their induction agents, which has the downside of leaving fewer options for patients when they relapse.”

Asked about these concerns, Dr. Jakubowiak responded, “Our team’s perspective is to ‘buy’ the longest remission possible using the most effective available treatment strategy. If we do this, there is a good chance that when the patient relapses, we will have availability of new drugs.”

He added the caveat: “There’s a small proportion of patients who will be progressing while on treatment and will be potentially more challenging to treat if already given KRd. It has been proposed that KRd maintenance might be primarily considered for patients with high-risk cytogenetics. However, at this interim analysis, there were not enough events in high-risk patients to comment on KRd’s usefulness as a maintenance therapy in this population.”

The KRd arm of the ATLAS trial had a high dropout-rate for reasons other than toxicity and death, but “because consent for collecting data was discontinued, we can’t really dig deeper into explaining why they dropped out, but half of the patients who discontinued in the KRd arm did so after already completing KRd treatment and were already on R maintenance. Once taking this into consideration, the dropout rates in both arms are similar, and the data does not appear skewed,” said Dr. Jakubowiak.

In conclusion, Dr. Jakubowiak noted that the phase-2 FORTE trial, also published recently in The Lancet Oncology, provides supportive data for maintenance therapy with KR versus K.

“It is quite important that the results of both trials be presented to public so that people know that KR or KRd could be reasonably considered for posttransplant maintenance,” he said.

Dr. Shah opined that as yet, the results of neither study were practice changing for maintenance therapy in the United States. She said she would consider using KR maintenance for select patients with high-risk myeloma who received these drugs as induction therapy and where there was concern about early progression, given that this aggressive treatment allows for a longer time in remission.

Dr. Shah noted that in these trials, overall survival data on dual maintenance is still being awaited, and that those results would be important when considering whether to switch patients to a more expensive, toxic, and involved therapy that required regular infusion visits for maintenance.

What Dr. Shah found the most groundbreaking and applicable aspect of the study was that “in the ATLAS trial, they’re adapting treatments to disease response, and if patients achieve MRD negativity, which we know is the best kind of response, therapy was deescalated to lenalidomide single agent. I think this is something that we will see more of in newer study designs and this will help individualize patient treatments to their response.”

Dr. Jakubowiak disclosed consulting fees and honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gracell, GlaxoSmithKline, Janssen, and Sanofi-Aventis. Dr. Shah disclosed ties with Sanofi, Bristol Myers Squibb and Janssen.

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