A Winner Emerges in the Battle for Multiple Myeloma CAR-Ts
Multiple myeloma is currently treated with a combination of proteasome inhibitors + steroids + immunomodulators with or without an anti-CD38 antibody. Upon relapse, patients have access to a variety of different therapies, including a combination of the aforementioned drugs as long as they have not been exposed before, as well as anti-BCMA bispecific antibodies, antibody-drug conjugates (ADC), and CAR-T cells. The FDA approved the CAR-T cell products Bristol Myers Squibb’s (BMS)/2SeventyBio’s Abecma (ide-cel) in March 2021 and Johnson & Johnson’s/Legend Biotech’s Carvykti (cilta-cel) in February 2022, both for the fifth line of therapy and beyond (5L+).
Both products have submitted a supplementary biologics license application to expand their label to 2L+ patients (Carvykti) and 3L+ patients (Abecma). Such label expansions can be extremely lucrative given that multiple myeloma is among the most valuable markets in oncology, and it would not be surprising if J&J revised its forecast for Carvykti even higher (currently at $5 billion peak [1]). Based on documents presented at the FDA advisory meeting, and published clinical research, it is clear that Carvykti is gaining the upper hand in its perception among physicians. During the advisory committee meeting on March 15, 2024, 8 members of the panel voted yes to move Abecma up the lines of therapy, whereas all 11 members voted yes for Carvykti.
Data [2] from the Phase III CARTITUDE-4 trial show that even though the median overall survival (mOS) was not reached for either arm, Carvykti resulted in improved mOS versus the standard of care (SoC) arm at a hazard ratio (HR) of 0.57. The 2-year OS was 79% vs 66%. However the SoC was limited only to the PVd or DPd regimens, and crossover to Carvykti was not allowed.
Conversely, data from the Phase III KarMMa-3 trial of Abecma were not as positive. While Abecma led to an improvement in progression-free survival (PFS) over the SoC (13.3 months vs 4.4, HR=0.49), it failed to demonstrate an improvement in OS. However, the SoC arm in KarMMa-3 was more permissive than CARTITUDE-4, with five regimens allowed, and also permitted crossover to Abecma which undoubtedly affected the OS benefit.
It can be argued that what Abecma’s study shows is that CAR-T cells are better administered later on and there is no reason to move them up the lines of therapy. However, with the current clinical trial design firm conclusions cannot be drawn. Physicians’ decisions will be further complicated by the recent FDA investigation into reports of secondary malignancies following CAR-T infusions, particularly of T-cell malignancies. I anticipate that the above trial results and the FDA black box warning will make most physicians prescribe CAR-T cells in the 3L and beyond, even if a 2L label is granted to Carvykti.
By Sakis Paliouras, PhD
References
[1] https://www.reuters.com/business/healthcare-pharmaceuticals/johnson-johnson-still-expects-carvykti-hit-least-5-bln-peak-sales-cfo-2024-01-23/
[2] https://www.fda.gov/media/176988/download
