Case Reports

Simultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma

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After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Thrombotic Microangiopathy Before and After Plasma Exchange Show Persistent Renal Insufficiency

Workup for alternative causes of thrombocytopenia included a negative heparin-induced thrombocytopenia panel and a disseminated intravascular coagulation (DIC) panel showing elevated fibrinogen (515 mg/dL; reference range, 200-400 mg/dL) and mildly elevated international normalized ratio (INR) (1.3). Blood cultures were negative, and a 22-pathogen gastrointestinal polymerase chain reaction (PCR) panel failed to identify viral or bacterial pathogens, including Escherichia coli O157:H7. C3 (81 mg/dL; reference range, 90-180 mg/dL) and C4 (16 mg/dL; reference range, 16-47 mg/dL) complement levels were borderline to mildly reduced.

Based on this constellation of findings, a diagnosis of TMA was made, and the patient was started empirically on plasma exchange and pulse-dosed steroids. After 4 cycles of plasma exchange, the platelet count had normalized from its nadir of 29 K/µL. ADAMTS13 activity (98% enzyme activity) ruled out thrombotic thrombocytopenic purpura (TTP), and the patient continued to have anuric renal failure (creatinine, 8.62 mg/dL) necessitating the initiation of hemodialysis. Given persistent renal insufficiency, a diagnosis of atypical hemolytic uremic syndrome (HUS) was considered, and eculizumab 900 mg was administered on days 8 and 15 with stabilization of renal function. By the time of discharge on day 18, the patient’s creatinine level had decreased to 3.89 mg/dL, and platelet count was 403 K/µL. Creatinine normalized to 1.07 mg/dL by day 46.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for mutations in the following genes associated with atypical HUS: CFH, CFI, MCP (CD46), THBD, CFB, C3, DGKE, ADAMTS13, C4BPA, C4BPB, LMNA, CFHR1, CFHR3, CFHR4, and CFHR5. The patient subsequently remained off all antimyeloma therapy for > 1 year until eventually starting third-line pomalidomide plus dexamethasone without reinitiation of proteasome inhibitor therapy.

Demographics and Myeloma-Specific Characteristics

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m2 on days 1 and 2 and 27 mg/m2 on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m2 on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m2 on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.


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