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Professor of Medicine
School of Medicine and Public Health
University of Wisconsin
Director, Myeloma Clinical Program
University of Wisconsin Carbone Cancer Center
Natalie S. Callander, MD, has disclosed that she has received funds for research support from Cellectar.
B-cell maturation antigen (BCMA), a transmembrane glycoprotein and a member of the TNF receptor superfamily, is preferentially expressed on mature B-cells and plasma cells in multiple myeloma (MM) and plays an important role in long-term plasma cell survival. The amount of surface BCMA seems to increase as patients progress from MGUS to MM. Because of the localization to plasma cells and the expression on virtually no other cell type, BCMA is an ideal target for MM-specific cellular therapies of all types.
CAR T-cell transplantation technology has evolved greatly during the past 25 years. The current version of BCMA-directed CAR T-cell therapy employs a construct with a single-chain variable fragment that recognizes the BCMA antigen, a spacer, an intracellular costimulatory signaling domain (often 4-1BB), and a CD3ζ intracellular domain to stimulate T-cell activation upon binding.
Current Clinical Evidence
Recently, numerous small trials in heavily pretreated patients with MM have been presented or published. At present, the largest is the KARMMA-2 trial with idecabtagene vicleucel, with 128 patients with a median 6 lines of therapy and 35% of patients with high-risk disease, that was presented at ASCO 2020. Two other smaller studies were also updated at ASCO including the EVOLVE study with orvacabtagene autoleucel (62 patients) and the CARTITUDE-1 study with JNJ-4528/LCAR-B38M (29 patients).
One of the dominant themes in all of these presentations was the extremely high response rates in such heavily pretreated, refractory MM patients, which are really unprecedented, with the EVOLVE and CARTITUDE study posting response rates of 92% and 100%, respectively. It is also clear that with experience, management of adverse events such as cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) has become less burdensome and these procedures are now much safer for patients. Although toxicities (ie, grade 1/2 CRS and cytopenias) occur frequently, these adverse events appear very manageable, and serious nonhematologic toxicity is increasingly rare.
Open Questions and Next Steps
What remains unclear is the durability of responses and where in the sequence of MM therapy CAR T-cell should fall. Although all of the studies showed high initial CR and measurable residual disease–negative status, relapses occur at a relatively high rate. Ongoing phase III studies are planning to address CAR T-cell transplants performed after 1-4 lines of therapy or upfront in patients with high-risk disease. Also uncertain is the mechanism of relapse when patients do progress after CAR T-cell therapy. There appear to be patients who develop BCMA-negative clones post transplant; the strategy to overcome this mechanism of resistance is to employ molecules that inhibit γ-secretase, so that BCMA is not cleaved off the surface of tumor cells and the CAR T-cells can continue to target the MM cells. Another issue is certainly going to be access to this therapy. Currently, only a few academic centers are able to perform these procedures, although the population of patients with relapsed and relapsed/refractory MM continues to grow. Recognizing these challenges, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.
What are your thoughts on BCMA as a target in MM? Please share your thoughts and questions in the discussion box below.