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Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Noopur Raje, MD, has disclosed that she has received funds for research support from Bluebird and consulting fees from Amgen, Bristol-Myers Squibb, Caribou, Celgene, Immuneel, Karyopharm, and Takeda.
Numerous therapies are available for patients with relapsed/refractory (R/R) multiple myeloma (MM) who have received the 3 main classes of agents used to treat MM—anti-CD38 antibodies, proteasome inhibitors, and immunomodulatory agents. However, these patients have historically had limited treatment options and poor outcomes. Recently, selinexor (a selective inhibitor of nuclear export), belantamab mafodotin (a BCMA-directed antibody–drug conjugate) and melphalan flufenamide have been approved for patients with R/R MM who have received at least 4 previous therapies. In March 2021, the FDA approved the BCMA-targeted CAR T-cell therapy idecabtagene vicleucel for the treatment of adult patients with R/R MM after at least 4 previous lines of therapy (including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody). In this commentary, I discuss the data supporting this approval and how I plan to use this product in my practice.
Key Data: KarMMa
Approval of idecabtagene vicleucel (also known as ide-cel) was largely based on the global phase II KarMMa trial, in which 128 patients with R/R MM after at least 3 previous regimens (including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody) received one of 3 dose levels of idecabtagene vicleucel. On average, patients had received 6 antimyeloma regimens (range: 3-16). Most patients were refractory to their last line of treatment and most had been exposed to the proteasome inhibitors bortezomib and carfilzomib and the immunomodulatory drugs lenalidomide and pomalidomide. In total, 84% of patients were triple-class refractory, including all of these drugs plus an anti-CD38 monoclonal antibody, typically daratumumab. In other words, this was a patient population with very difficult-to-treat disease.
The overall response rate for these patients with idecabtagene vicleucel was 73% (82% in the 54 patients who received the highest dose of 450 x 106 cells), including complete responses (CRs) in 33% of patients. Median progression-free survival (PFS) was 8.8 months overall and 12.1 months in the highest-dose group. Those who achieved a CR or a stringent CR had a median PFS of 20.2 months. These are unprecedented results in this patient population and will be practice changing. Although care should always be taken in comparing therapeutics across different clinical trials, for context, selinexor (plus dexamethasone) and single-agent belantamab mafodotin were associated with considerably lower median PFS (<5 months) and response rates (<35%) in similar populations in clinical trials.
As with other CAR T-cell therapies, key adverse events of interest with idecabtagene vicleucel include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome occurred in 84% of patients in KarMMa, but only 5% of these events were of grade 3/4 severity. Neurotoxicity occurred in 18% of patients, with 4% of events being grade 3/4.
Idecabtagene Vicleucel: Real-World Considerations
More so than with standard therapies, autologous CAR T-cell therapies involve advance planning. The patient’s lymphocytes must be collected, genetically modified, and expanded, which can take 4-5 weeks. Moreover, this must be done at centers with FACT (For the Accreditation of Cellular Therapy) to administer idecabtagene vicleucel or other CAR T-cells.
How will I sequence idecabtagene vicleucel with other agents and regimens that are approved for patients in this space, including belantamab mafodotin, another BCMA-targeted agent? Based on clinical data, idecabtagene vicleucel appears to be more active than belantamab mafodotin, and I think that patients who meet the indication and have access and good performance status should preferentially receive idecabtagene vicleucel. Optimal sequencing of these 2 agents, and strategies to combine them, have not yet been formally investigated; clinical trials to answer those questions are being planned. For me, patients who have been treated with and responded to belantamab mafodotin can receive idecabtagene vicleucel, and patients who have received idecabtagene vicleucel may receive belantamab mafodotin, provided they have not relapsed with BCMA-negative or antigen‑negative disease.
Patients with renal failure are exceptions where I would consider using belantamab mafodotin over idecabtagene vicleucel. This is because the use of lymphodepleting chemotherapy (eg, fludarabine) requires a creatinine clearance >30 mL/min. Patients with a creatinine clearance <30 mL/min are not ideal candidates for idecabtagene vicleucel.
The approval of idecabtagene vicleucel for patients with MM is a very exciting advance and should make a big difference in patient care—I expect to use this product broadly going forward. How do you plan to use idecabtagene vicleucel in your practice? Answer the polling question and join the conversation by posting a comment in the discussion section.
Want to know more? Sign up here to attend CCO’s live webinar, “Current and Emerging CAR T-Cell Therapies in Cancer Care” on Wednesday, June 16, during which I will discuss patient case studies and recent advances in CAR T-cell therapy with our esteemed panel, including Caron Jacobson, MD, and Jae H. Park, MD.