Multiple myeloma is a promising therapeutic target due to the widespread expression of BCMA on myeloma cells. The field of BCMA-targeting drugs in multiple myeloma has undergone significant advancement. Introduction of CAR-T cell therapies ABECMA and CARVYKTI, and most recently TECVAYLI, are examples of the rise of the BCMA space in multiple myeloma. 

Regeneron’s Linvoseltamab is a BCMAxCD3 bispecific antibody in the pipeline for patients with RRMM. In February 2024, the US FDA accepted for Priority Review the BLA for linvoseltamab for RRMM that has progressed after at least three prior therapies, with a target action date for the FDA decision is August 22, 2024. In addition to this, it is also under review for R/R MM by the EMA with EC decision on the regulatory submission of linvoseltamab for the treatment of adult patients with RRMM is planned for the first half of 2025.

14-month median follow-up data from the Pivotal Phase I/II LINKER-MM1 trial of linvoseltamab in patients with relapsed/refractory multiple myeloma were reported during an oral presentation at the EHA Congress 2024. These longer-term results show a deepening of responses following the 11-month median follow-up data presented at the American Association for Cancer Research Annual Meeting in April. Previous results have shown encouraging efficacy and a generally manageable safety profile for linvoseltamab. 

The ongoing, open-label, multicenter Phase I/II dose-escalation and dose-expansion LINKER-MM1 trial is investigating linvoseltamab in 282 enrolled patients with relapsed/refractory MM. The Phase 1 dose-escalation portion of the trial is now complete. The ongoing Phase II dose expansion portion is assessing the safety and anti-tumor activity of linvoseltamab, with the primary endpoint of ORR. Key secondary endpoints include DoR, PFS, rate of minimum residual disease (MRD) negative status and OS.

Key outcomes from the results presented were:

• 71% objective response rate (ORR), with 50% of patients achieving a complete response (CR) or better and 63% achieving a very good partial response (VGPR) or better, as determined by an independent review committee.

• Median DoR of 29 months for all responders, while median DoR was not reached for those who achieved a CR or better. In analyses that were not pre-specified, there was an 81% and 95% estimated probability of maintaining a response at 12 months after achieving a partial response or better among all patients and those who achieved a CR or better, respectively.

• Median PFS was not reached. There was a 70% estimated probability of being progression free at 12 months among all patients; the estimated probability was 96% among those who achieved a CR or better, per an analysis that was not pre-specified.

• Median OS of 31 months for all patients. In analyses that were not pre-specified, the median OS was not reached for patients who achieved a CR or better, and there was a 75% and 100% estimated probability of survival at 12 months among all patients and those who achieved a CR or better, respectively.

• High rates of CRs or better in prespecified subgroups, including 55% among those aged 75 years or older, 48% among those with high cytogenetic risk.

Safety data at the 14-month median follow-up was largely consistent with the 11-month median follow-up. CRS was the most frequent TEAE affecting 46% of patients. Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was observed in 8% of patients, with three cases at Grade 3 and none at Grade 4 or higher. Infections were reported in 74% of patients, with 36% being Grade 3 or 4. The most common Grade 3 or 4 TEAEs (≥20%) were neutropenia and anemia. Six deaths deemed by investigators to be due to TEAEs occurred during treatment or within 30 days of the last dose; five were from infections, and one was from renal failure.

KOL insights

“Despite advances, new treatments are needed that drive meaningful and durable responses to help patients with relapsed and/or refractory multiple myeloma. Treatment with linvoseltamab at the recommended 200 mg dose in the LINKER-MM1 trial demonstrated impressive efficacy, with rapid, deep, and durable responses in patients with multiple myeloma that is highly refractory to standard therapies. This reinforces the potential of linvoseltamab as a promising treatment option.” – MD, United States

Conclusion 

As the second most prevalent blood cancer, there are over 176,000 new cases of multiple myeloma diagnosed globally, with around 35,000 of those cases occurring in the US. In the US, there are approximately 8,000 people who have MM that has progressed after three lines of therapy, and 4,000 whose disease has progressed after four or more therapies.

The multiple myeloma treatment market is rapidly evolving, and current and emerging key players face the biggest risk due to this high degree of innovation. Antibody-drug conjugate (ADC), CAR-T cell treatments, and bispecific antibodies are just a few of the novel modes of action that have recently entered the market for later lines of therapy. The landscape of bispecific antibodies is anticipated to evolve in the coming years, with multiple companies entering the multiple myeloma treatment market with their product. The competition in BCMA-directed bispecific antibodies is rising. TECVAYLI and ELREXFIO, are two BCMA/CD3-targeted bispecific antibodies, have received accelerated FDA approval for the treatment of patients with relapsed or refractory multiple myeloma. Apart from Regeneron Pharmaceuticals, TeneoOne/AbbVie are also evaluating their asset, TNB-383B/ABBV-383, a BCMA × CD3 bispecific antibody for treating R/R multiple myeloma. The outlook for Linvoseltamab and ABBV-383 is encouraging, but not much seems to set them apart from TECVAYLI and ELREXFIO or from one another. Experts speculated that ABBV-383, a medication in Phase I testing for fourth-line MM, may be superior to linvoseltamab because it is delivered subcutaneously and requires fewer dose schedules than the drug from Regeneron. 

Linvoseltamab results presented at the EHA showed 50% of patients achieved a complete response or better and a 71% overall response rate, at 14-months median follow-up in the pivotal Phase I/II LINKER-MM1 trial with safety data at the 14-month median follow-up being consistent with the 11-month median follow-up. The Phase III confirmatory trial (LINKER-MM3) for linvoseltamab in patients with R/R MM is ongoing.

The FDA stated that it is conducting a priority review of Regeneron Pharmaceuticals' linvoseltamab and anticipates making a decision by August 22, 2024 regarding the approval of the BCMA x CD3 bispecific for the treatment of fourth-line patients with relapsed/refractory multiple myeloma. Though preliminary research indicates that the antibody therapy may be useful, questions still surround its capacity to distinguish itself in a field of treatment alternatives that is getting more and more crowded. 

BCMA-targeting therapies are expected to result in noteworthy revenues due to premium pricing and clinical benefit in heavily pretreated patients.