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Current Strategies for Targeting BCMA in R/R Myeloma

Sagar Lonial, MD

Professor and Chair
Department of Hematology and Medical Oncology
Chief Medical Officer
Winship Cancer Institute of Emory University
Atlanta, Georgia

Sagar Lonial, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celgene, Janssen, and Takeda; consulting fees from AbbVie, Bluebird, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, and Takeda; and other financial or material support from TG Therapeutics.

View ClinicalThoughts from this Author

Released: September 9, 2021

The treatment landscape for relapsed and refractory (R/R) multiple myeloma (MM) has significantly changed since the incorporation of CD38-targeted therapies. In the past few years, we have gone from the CD38 era, where the incorporation of daratumumab and isatuximab transformed treatment options for our patients, and we are now starting to also target B-cell maturation antigen (BCMA). This is for several reasons, including the importance of BCMA signaling to plasma cell survival, the almost universal expression of BCMA on malignant plasma cells, and the more restricted expression of BCMA on plasma cells compared with other cell types.

In this commentary, I discuss the currently approved BCMA-targeted therapies belantamab mafodotin and idecabtagene vicleucel and the factors I consider when choosing between them. Both therapies are approved by the FDA for patients with R/R MM who have received ≥4 previous therapies, which must include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug (our triple class–refractory patient population).

Belantamab Mafodotin
Belantamab mafodotin is an antibody–drug conjugate that received FDA accelerated approval based on data from the phase II DREAMM-2 trial. In this study, the overall response rate was 32% (7% with stringent complete response/complete response and 11% with very good partial response), and the median duration of response was 11 months in patients who received the FDA-recommended dose (2.5 mg/kg IV once every 3 weeks). I often consider belantamab mafodotin in patients who are older or frailer, particularly in patients with R/R MM who require immediate treatment and who cannot afford to wait the 4-6 weeks necessary for CAR T-cell production. Belantamab mafodotin is also an option for patients who do not want to undergo hospitalization or chemotherapy associated with CAR T-cell therapy.

Ocular toxicity, particularly keratopathy, is the most common adverse event (AE) in patients receiving belantamab mafodotin and is caused by a cytotoxic payload agent, monomethyl auristatin phenylalanine F (MMAF). In the DREAMM-2 study, more than 70% of patients developed some form of keratopathy, of whom 18% had significant changes in visual acuity that required dose holds and/or dose modifications. However, 82% of these patients recovered while on treatment and no patients had permanent complete loss of vision. Based on these data, ophthalmologic examinations are required at baseline and before each dose, but if working in partnership with eye care professionals, the potential ocular toxicities with belantamab mafodotin can be easily managed. The second most common AE among patients receiving belantamab mafodotin is hematologic toxicity, which hematologists should be comfortable in treating. Overall, I think these data are intriguing and show that belantamab mafodotin has a place in treating a significant proportion of patients with triple class–refractory R/R MM.

Idecabtagene vicleucel
Idecabtagene vicleucel is a CAR T-cell therapy that received approval on the basis of results from the phase II KarMMa trial, which showed an overall response rate of 73%, median progression-free survival of 8.8 months, and median duration of response (DoR) of 10.7 months. The complete response rate was 28%, and 26% of patients evaluable for measurable residual disease (MRD) were MRD negative (<10-5) and 79% of patients achieving CR or better were MRD negative. For those patients who achieved a CR or better, the median DoR was 19 months (95% CI: 11.3 months to not estimable). These results were unprecedented for refractory MM, and I think the DoR speaks to the power of CAR T-cell therapy in R/R MM.

Before idecabtagene vicleucel infusion, patients undergo chemotherapy with fludarabine and cyclophosphamide for lymphodepletion, and they spend at least 2 weeks in the hospital following infusion, so I generally consider idecabtagene vicleucel therapy for patients who are younger, who are more fit, and who can wait for the manufacture of the CAR T‑cells, with or without bridging therapy. In some instances, patients who would be too sick or frail for autologous stem cell transplant can still be considered for CAR T-cell therapy, as lymphodepletion is less intense and the AEs during hospitalization are less common and less severe than with transplant. Cytokine-release syndrome (CRS) and neurotoxicity are the most significant AEs associated with idecabtagene vicleucel, although they are typically grade 2/3 and only rarely grade 4. Experienced centers can manage and mitigate these AEs through the early use of tocilizumab or corticosteroids.

Choosing the Right Therapy
There are numerous factors I consider when choosing between belantamab mafodotin and idecabtagene vicleucel. A major consideration is how soon patients need to start therapy as well as their fitness and age. Another important factor is patients’ comorbidities. Patients who have preexisting corneal disease are at higher risk of ocular toxicity from belantamab mafodotin, and patients with neurologic disorders or cardiac risk factors may be at higher risk of immune effector cell–associated neurotoxicity syndrome (ICANS) or CRS, respectively, from idecabtagene vicleucel.

As we look to the future, an important question is whether patients who have progressed on a previous BCMA-directed therapy can benefit from another BCMA modality. I will check for BCMA expression in patients who progress after BCMA-directed therapy and have found that 90% retain their BCMA expression, so some patients are likely to benefit from other BCMA-targeting agents.

Your Thoughts
How has your treatment of R/R MM changed since the FDA approval of belantamab mafodotin and idecabtagene vicleucel? 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, “Next-Generation Therapeutic Strategies for Relapsed/Refractory Multiple Myeloma: Targeting BCMA” on Friday, September 10, 2021, during which I will discuss patient case studies and recent advances in BCMA-targeted therapy with Suzanne Lentzsch, MD, PhD, and Thomas G. Martin, MD.

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