Madhav V. Dhodapkar, MBBS, professor, Anise McDaniel Brock Chair, Department of Hematology and Medical Oncology, Georgia Research Alliance Eminent Scholar in Cancer Innovation, Emory University School of Medicine; director, Center for Cancer Immunology, leader, Cancer Immunology Research Program, Winship Cancer Institute of Emory University, discusses the advantages and disadvantages of bispecific antibodies and CAR T-cell therapy in patients with relapsed/refractory multiple myeloma, as well as the potential role for the bispecific antibody linvoseltamab (REGN5458) in this treatment paradigm.

The BCMA- and CD3-directed bispecific antibody linvoseltamab was recently assessed in the first-in-human, phase 1/2 LINKER-MM1 trial (NCT03761108) in patients with relapsed/refractory multiple myeloma. In the dose-expansion portion of this trial, heavily pretreated patients experienced a high and durable overall response rate of 71% with linvoseltamab, comprising a 59% rate of very good partial responses or better and a 30% rate of complete responses or better.

Bispecific antibodies, such as linvoseltamab, can offer several advantages for patients with relapsed/refractory multiple myeloma, Dhodapkar begins. Unlike CAR T-cell therapy, their off-the-shelf availability allows for immediate administration without manufacturing delays. This makes them highly accessible to community physicians and optimal therapies for patients who require prompt treatment because of aggressive disease progression, Dhodapkar explains.

Regarding the safety profiles of these drug classes, CAR T-cell therapy is associated with a higher incidence of cytokine release syndrome than bispecific antibodies, Dhodapkar states. Conversely, bispecific antibodies tend to exhibit a more favorable safety profile.

Both CAR T-cell therapy and bispecific antibodies are active treatment options and have demonstrated an ability to engage and bolster immune responses, Dhodapkar continues. Moreover, these agents often target the same antigens, such as BCMA, he notes. Accordingly, it can be challenging to conclusively state which agent is the optimal choice of therapy based on efficacy alone, Dhodapkar says. The tolerability and accessibility of these agents are therefore 2 key factors guiding treatment decisions in this arena, he emphasizes.

Ultimately, the choice between these drug classes is a complex decision that necessitates close collaboration between community oncologists, specialists at CAR T-cell centers, and patients themselves, Dhodapkar states. Considering factors such as accessibility, safety, and the specific clinical scenario while employing shared decision-making will elucidate the most appropriate therapeutic approaches for patients with relapsed/refractory multiple myeloma, Dhodapkar concludes.

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Madhav V. Dhodapkar, MBBS, discusses the advantages and disadvantages of bispecific antibodies and CAR T-cell therapy in patients with relapsed/refractory multiple myeloma, as well as the potential role for the bispecific antibody linvoseltamab in this treatment paradigm.

Dr Dhodapkar on the Role of Linvoseltamab in Relapsed/Refractory Multiple Myeloma  

Madhav V. Dhodapkar, MBBS, professor, Anise McDaniel Brock Chair, Department of Hematology and Medical Oncology, Georgia Research Alliance Eminent Scholar in Cancer Innovation, Emory University School of Medicine; director, Center for Cancer Immunology, leader, Cancer Immunology Research Program, Winship Cancer Institute of Emory University, discusses efficacy and safety findings from the dose-expansion portion of the phase 2 LINKER-MM1 trial (NCT03761108) of linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma.

The first-in-human LINKER-MM1 trial was a dose-escalation and dose-expansion study that evaluated the BCMA/CD3-directed bispecific antibody linvoseltamab in patients with relapsed/refractory multiple myeloma. Patients evaluated in the phase 2 trial were heavily pretreated with a median of 5 prior lines of therapy (range, 2-14), Dhodapkar says. In the dose-expansion cohort of the trial, patients received step-up dosing of linvoseltamab at 5 mg on day 1 and 25 mg on day 8, followed by 24 hours of hospitalization. In cycles 1 through 3, patients received 200 mg of linvoseltamab once weekly. In cycles 4 and 5, patients received 200 mg of the agent once every 2 weeks. In cycle 6 onward, patients with a very good partial response (VGPR) or better received the agent at 200 mg once every 4 weeks, and patients who did not achieve a VGPR continued to receive the agent at 200 mg once every 2 weeks.

In this cohort, linvoseltamab elicited an overall response rate of 71%. Of these patients, 59% achieved a VGPR or better, and 30% achieved a complete response or better.

Linvoseltamab was well tolerated in this population, and was associated with an acceptable safety profile, including low rates of high-grade cytokine release syndrome (CRS) and neurotoxicity, Dhodapkar explains. Any-grade CRS occurred in 45.3% of patients, and 1 patient experienced grade 3/4 CRS. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 7.7% of patients, and 2.6% of patients had grade 3/4 ICANS. No cases of grade 5 ICANS were reported.

These efficacy and safety data are promising and demonstrate the potential for linvoseltamab to address an unmet need for patients with relapsed/refractory multiple myeloma.

Madhav V. Dhodapkar, MBBS, discusses efficacy and safety findings from the dose-expansion portion of the phase 2 LINKER-MM1 trial of linvoseltamab in patients with relapsed/refractory multiple myeloma.

Dr Dhodapkar on the Use of Linvoseltamab in Relapsed/Refractory Multiple Myeloma

Madhav Dhodapkar, MBBS, clinical research program leader in the Hematology Program at Yale Cancer Center, discusses the changing role of immunomodulatory drugs (IMiDs) in multiple myeloma.

IMiDs have clear immunologic effects, says Dhodapka. IMiD-based combinations offer a lot of potential. There is emerging data on combination checkpoint inhibitors with IMiDs which looks very promising. There is already data showing efficacy between IMiDs and monocolonal antibodies, another immune-targeting agent, says Dhodapka.

The ideal combinations may dependent on the individual patient, as each patient has a unique immune microenvironment. Immune-based combinations may need to be personalized based on molecular profiling, says Dhodapka.

Madhav Dhodapkar, MBBS

Articles

Dr Dhodapkar on the Role of Linvoseltamab in Relapsed/Refractory Multiple Myeloma

Dr Dhodapkar on the Use of Linvoseltamab in Relapsed/Refractory Multiple Myeloma

Dr. Madhav Dhodapkar on IMiD-based Combinations in Multiple Myeloma