Bispecific Therapy in Multiple Myeloma: Strategies for Managing Toxicities

Hamza Hashmi, MD Memorial Sloan Kettering Cancer Center | Cesar Rodriguez, MD Mount Sinai | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Bispecific antibody therapies approved for multiple myeloma share a suite of toxicities, including cytokine release syndrome (CRS), neurotoxicity, and increased infection risk.

• With all agents, prophylaxis with tocilizumab, antivirals, antifungals, and immunoglobulin support is recommended to mitigate side effects.

• Due to its alternate mechanism, talquetamab has distinct skin, nail, and taste toxicities that require specific management strategies and dose adjustments.

• Doses can be paused to allow toxicities to resolve, although step-up dosing may need to be repeated if therapy is held for more than 3 months.

Side Effects of Bispecifics in Multiple Myeloma

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with myeloma specialists Hamza Hashmi, MD, of Memorial Sloan Kettering Cancer Center, and Cesar Rodriguez, MD, of Mount Sinai, to discuss managing side effects of bispecific antibody therapies for patients with multiple myeloma.

The doctors reviewed four agents: talquetamab, teclistamab, elranatamab, and linvoseltamab.s All four agents require a step-up dosing regimen when starting treatment. CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), infections, and neutropenia are notable toxicities shared across bispecific antibodies. CRS and ICANS occur primarily during step-up dosing phases, and the recommended prophylaxis for CRS is tocilizumab 8 mg/kg with or without dexamethasone. 

Talquetamab

Talquetamab is a first-in-class GPRC5D and CD3–directed bispecific antibody approved for relapsed or refractory multiple myeloma after at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Notably, talquetamab is active in patients with prior anti-BCMA therapy, including chimeric antigen receptor T-cell (CAR-T) or bispecific antibodies.

In addition to CRS, ICANS, and infection risk seen across bispecific antibody agents, the side effect profile of talquetamab has distinct GPRC5D–mediated effects including skin and nail changes and dysgeusia. Topical or systemic steroids can be used to manage rashes, and nail hardeners and vitamin E oil can help with brittle nails. Dysgeusia is a more challenging toxicity that requires both dietary modifications and dose modifications, whether by holding or reducing doses or increasing the duration between each dose. 

When starting talquetamab, patients should receive antiviral and antifungal prophylaxis for herpes simplex virus or varicella-zoster virus and Pneumocystis jirovecii pneumonia, respectively. Compared with BCMA–directed bispecific antibodies, talquetamab may have lower rates of infection and hypogammaglobulinemia. However, patients should still receive intravenous immunoglobulin (IVIG) prophylaxis if immunoglobulin G (IgG) levels drop below 400 mg/dL. 

Teclistamab

Teclistamab is an anti-BCMA and CD3 bispecific antibody approved for relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Teclistamab has shown efficacy after prior anti-BCMA CAR-T therapy exposure. 

Compared with talquetamab, infections and hypogammaglobulinemia are more prominent with teclistamab and other BCMA–directed therapies. As with talquetamab, antiviral and antifungal prophylaxis are recommended throughout therapy. However, the doctors recommended that oncologists start IVIG in all patients regardless of IgG levels for infection prophylaxis. Vaccinations can also help reduce the risk or severity of infections. 

Elranatamab

Elranatamab is a BCMA and CD3–directed bispecific antibody approved for relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Elranatamab can be sequenced after BCMA CAR-T therapy or teclistamab. 

The agent is largely comparable to teclistamab, although it uses a fixed dose instead of weight-based dosing. In terms of side effects, Dr. Rodriguez sees slightly more rash with elranatamab compared with teclistamab in his practice. With all bispecifics, a dermatology evaluation is recommended to monitor and manage cutaneous events. 

Linvoseltamab

Linvoseltamab is a more recent anti-BCMA and CD3 bispecific antibody approved for relapsed or refractory multiple myeloma after three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Contrary to the other approved bispecific antibodies, which are administered subcutaneously, linvoseltamab is given intravenously. The step-up dosing schedule for linvoseltamab is only once a week, which may improve logistics for some patients. With linvoseltamab, Dr. Rodriguez has observed infusion-related reactions occurring within a few hours of infusion in a handful of patients, although slowing the infusion rate has mitigated these reactions.

Restarting Bispecific Antibody Therapy After Holds

Closing the discussion, the doctors highlighted the need to hold any bispecific antibody therapy if patients develop active infections or contraindications, as attempting to push treatment through can cause CRS. Data support that bispecific antibody therapy can be paused for several months without compromising efficacy. Step-up dosing does not need to be repeated if treatment was held for less than 3 months, but infusion premedications should be repeated if treatment was delayed at least 2 months.