Pfizer has paused enrolment of its pivotal Phase II MagnetisMM-3 study of bispecific antibody therapy elranatamab, which is being investigated in relapsed/refractory multiple myeloma patients, due to three cases of peripheral neuropathy observed in the ongoing Phase I MagnetisMM-1 study of the drug. The MagnetisMM-3 trial was initiated by Pfizer in February following encouraging results from its Phase I study, in which an 83% response rate was seen in heavily pre-treated patients. Pfizer will now provide additional information to the US Food and Drug Administration (FDA).
From the 1990s onwards, the treatment of multiple myeloma patients was revolutionised by the introduction of immunomodulatory agents and proteasome inhibitors such as Celgene’s Thalomid (thalidomide), Bristol Myers Squibb’s Revlimid (lenalidomide) and Takeda’s Velcade (bortezomib). More recent approvals for several novel agents have also increased the therapeutic options for multiple myeloma patients.
Multiple myeloma is not, however, considered curable, and many patients will eventually progress. With each additional line of therapy, the chances of a long-lasting response are reduced. There is thus a need for novel treatments with efficacy in relapsed/refractory patients.
The B-cell maturation antigen (BCMA) is preferentially expressed on B-lymphocytes and its overexpression is associated with multiple myeloma. As such, targeting BMCA has emerged as a highly efficacious approach in tackling multiple myeloma. Two BCMA-targeting therapies are currently available, namely GlaxoSmithKline’s monoclonal antibody conjugate, Blenrep (belantamab mafodotin), and Bristol Myers Squibb and bluebird bio’s recently approved chimeric antigen receptor (CAR)-T cell therapy, Abecma (idecabtagene vicleucel).
Another BCMA-targeting cell therapy from Johnson and Johnson, ciltacabtagebel autoleucel, is also expected to be approved soon, with applications currently being considered by both the FDA and European Medicines Agency (EMA). This is an area that looks set to become much more competitive in the future, with more than 65 BCMA-targeting therapies currently in clinical development for the treatment of multiple myeloma. The pause in enrollment for the MagnetisMM-3 trial could therefore be a big blow for Pfizer.
Elranatamab is one of the more advanced bispecific BCMA-targeting antibody therapies in the pipeline. Five other BCMA-targeting bispecifics are currently in Phase I/II development, but only Johnson and Johnson and Regeneron have so far also initiated potentially registrational Phase II trials. The bispecific antibodies are aiming to compete favourably with marketed BCMA-targeting therapies Blenrep and CAR-T therapies Abecma and ciltacabtagebel autoleucel. Blenrep appears to be much less effective than CAR-T therapies, and is also associated with some unusual eye-related side effects that may discourage uptake.
Although Abecma and ciltacabtagebel autoleucel have shown excellent responses, the complexity associated with cell therapies inevitably limits their uptake, as specialist centres are required and the production time of around four weeks may be too long for some patients to wait. It remains to be seen which BCMA-targeting therapy will come out on top, but with an array of potentially highly effective therapies likely to emerge in the next five years, the outlook for relapsed/refractory multiple myeloma patients is looking more promising.
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