Continued Progress in the Relapse Refractory Multiple Myeloma Landscape
What a promising time for patients with heavily treated relapsed or multiple myeloma. The US FDA has granted 2 recent approvals which aim to further impact the lives of patients with this devastating disease. However, if you are trying to bring a therapeutic asset through clinical development in this space, you may have to get behind two more available treatment options.
Until recently, relapsed or refractory multiple myeloma patients’ therapeutic options have been CAR-T, a second-generation proteasome inhibitor such as Carfilzomib (CAR) or Ixazomib (IXA), class-switching to a different class of drug with a novel mechanism, or the introduction of monoclonal antibody therapy.
Last spring (2022) Johnson & Johnson and Legend Biotech launched Carvykti, the 2nd approved CAR-T therapy for relapsed or refractory multiple myeloma post 4L+ standard of care, which continues to grow in multiple myeloma despite the introduction of what may be considered more convenient options, as it angles for earlier lines of treatment. The FDA has set April 5, 2024, as the target decision date for Carvykti’s application as a second- to fourth-line myeloma treatment.
Adding to the arsenal, on October 25, 2022, the US FDA granted accelerated approval to teclistamab-cqyv (Tecvayli, Janssen Biotech, Inc.), as the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, those also required by Carvykti CAR-T therapy.
However, recently two more therapeutic options were added to the growing list of therapeutic options for patients with relapsed refractory multiple myeloma.
US-FDA granted accellerated approval
On August 10th 2023, the US FDA granted accelerated approval of TALVEY™ (talquetamab-tgvs) a first-in-class bispecific GPRC5D-directed CD3 T-cell engager for adult patients with multiple myeloma who have also failed at least the same four prior lines of therapy as the others.
Just days later, on Monday, August 14th 2023, the FDA approved another off-the-shelf, BCMA-directed drug, Pfizer’s Elrexfio, or elranatamab-bcmm, for the same indication. All four recent approved therapies -eligible patients will have to have had the gold standard of care multiple myeloma regimens of; a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.
Elrexfio will be in direct competition with Johnson & Johnson’s Tecvayli, as both drugs are bispecific antibodies which assist T cells in targeting BCMA-expressing cancer cells. Both therapies’ efficacy data are quite similar, both are sub-Q injections, but Elrexfio may have a convenience angle—yet the pitch has yet to be fully established.
Elrexfio, Tecvayli and Talvey are off-the-shelf drugs called “bispecific” antibodies, binding to proteins on both diseased cells and T cells to trigger an immune response. While Elrexfio and Tecvayli both target a protein called BCMA that’s found on malignant plasma cells, Talvey is aimed at another one known as GPRC5D. All of these newer multiple myeloma drugs have immune-related side effects that can require hospitalization or stays nearby for monitoring.
These new multiple myeloma drugs are immune-therapies, and therefore have immune-related side effects that can require hospitalization or ‘close vicinity’ stays for monitoring. For Elrexfio, the FDA is mandating a 48-hour hospital stay after the first dose and 24 hours after the second dose in a “step-up” schedule. Patients taking Tecvayli and Talvey must stay 48 hours in the hospital after each of their step-up doses. Elrexfio has a single fixed dose, while Tecvayli and Talvey’s dose is weight-dependent. Once the step-up period is completed, patients receive an Elrexfio shot every other week, compared with the weekly shots of the J&J drugs.
Talvey – a bispecific antibody
Talvey is a bispecific antibody targeting T-cell CD-3 receptors and G protein-coupled receptor class C group 5 member D (GPRC5D) developed by Janssen. The regulatory decision was based on the talquetamab Phase 2 MonumenTAL-1 study, which included patients who had received at least four prior lines of therapy and who were not exposed to prior T-cell redirection therapy. This trial showed meaningful overall response rates (ORR).of 73.6% (95 percent Confidence Interval [CI], range, 63.0 to 82.4) with a median follow-up of nearly 6 (range, 0 to 9.5) months from first response among responders, 58 percent of patients achieved a very good partial response (VGPR) or better, including 33% of patients achieving a complete response (CR) or better. Responses were durable with a median duration of response not reached in the 0.8 mg/kg SC biweekly dose group and 9.5 months in the 0.4 mg/kg SC weekly dose group. Among patients receiving the 0.8 mg/kg SC biweekly dose, an estimated 85 percent of responders maintained response for at least 9 months
The regulatory decision for Elrexfio is supported by data from the phase 2 MagnetisMM-3 trial (NCT04649359), which showed that elranatamab elicited an overall response rate (ORR) of 57.7% (95% CI, 47.3%-67.7%) in roughly 100, BCMA-directed therapy naive patients. The data boasted a complete response (CR) rate of 25.8%, a very good partial response (VGPR) rate of 25.8, and a partial response (PR) rate of 6.2%. Notably, 82% of responders were estimated to continue to respond to treatment for 9 months or longer. The median time to response was 1.22 months (range, 0.9-6.5), and the median duration of response (DOR) was not yet reached (NR; 95% CI, 12.0-not evaluable [NE]). At a median follow-up of 11.1 months (95% CI, 10.6-12.0), the 6-month and 9-month DOR rates were 90.4% (95% CI, 78.4%-95.9%) and 82.3% (95% CI, 67.1%-90.9%), respectively (see FDA release for details).
What’s to come?
Of special note, Pfizer advanced this first-in-patient trial to approval in less than five years, which is impressive to say the least. Yet, continued approval is contingent upon further verification and validation of clinical benefit in the confirmatory, PIII MagnetisMM-5 trial (NCT05020236). in patients with double class–exposed, relapsed/refractory disease.
Overall message, great news for patients needing treatment options for multiple myeloma, bad news for those with potential assets in clinical development, as this continues to be a highly competitive space as both investigator sites and patients have many options to turn to over clinical trial participation.
OncoBay Clinical specializes in immune-oncology with deep experience in relapsed refractory multiple myeloma. Our deep academic acumen can be instrumental in maneuvering through this competitive space and bringing your study to the forefront of focus.