Discussing Proper Utilization of BCMA Bispecifics in Early Relapse Multiple Myeloma

Over the past few years, BCMA-directed bispecific antibodies have evolved into a very significant modality of treatment for patients with early relapse multiple myeloma, and still the treatment paradigm continues to evolve as new phase 3 data, combination approaches, and treatment sequences reveal themselves.

As such, CancerNetwork® hosted a Training Academy where a panel of experts gathered to discuss the role of BCMA-directed bispecific antibodies in early relapse multiple myeloma.The panel was moderated by Luciano Costa, MD, a professor of medicine in the Division of Hematology and Oncology at the University of Alabama at Birmingham Marnix E. Heersink School of Medicine. He was joined by Muhamed Baljevic, MD, an associate professor of medicine in the Division of Hematology/Oncology, director of the Multiple Myeloma Program, director of the Vanderbilt Amyloidosis Multidisciplinary Program at Vanderbilt-Ingram Cancer Center (VICC), and co-chair of the VICC Protocol Review and Monitoring System, and Carol Ann Huff, MD, a physician and professor of clinical oncology at Johns Hopkins Medicine.

Here are their key takeaways:

The Early Relapse Landscape

• Defining Early Relapse
  • Early relapse is when a patient relapses within 3 to 4 years of transplant after receiving quadruplet therapy.
  • A patient who received a therapy but has been off it for 6 to 9 months is not refractory to that specific therapy.
  • If a patient progresses through a drug in a maintenance setting, they are potentially refractory and the agent progressed upon should not be utilized in the next line of therapy.
• Unmet Needs in Second Line Therapy
  • Includes patients with early progression, who have multiple genetic aberrations, and who are elderly, frail, and comorbid.
• The Role of BCMA-Directed Bispecific Antibodies
  • There is a key role for BCMA-targeted bispecific antibodies in second-line therapy for patients with high-risk disease.
    • Managing toxicities remains a challenge, and sequencing is also important.

Safety and Mitigation of BCMA-Directed Bispecific Toxicity

• While the efficacy is unprecedented, managing the “signature risks”, specifically cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is paramount for community adoption.
  • Prophylactic tocilizumab (Actemra) helps mitigate the incidence of CRS across the board and reduces the severity to grade 1.
• For patients with grade 3 neutropenia, use G-CSF earlier, and be aggressive with gamma globulin supplementation.

Treatment Considerations

• In the second line, a patient considered lenalidomide (Revlimid)-refractory could receive an anti-CD38 backbone or a proteasome inhibitor backbone.
  • At least 3 agents would need to be combined in those backbones.
• Responses with teclistamab (Tecvayli) and daratumumab (Darzalex) are “magnitudes of order” better than other second-line and later therapies and offer an “unprecedented” potential for remission.
• Teclistamab and daratumumab may provide a long duration of therapy for patients who received a triplet, transplant, and single-agent maintenance.
  • Some patients may never need a different therapy, depending on their age.

Patient Case 1

• A 58-year-old patient with transplant-eligible, early relapse multiple myeloma with standard-risk cytogenetics, and prior receipt of a daratumumab-based quadruplet induction regimen, autologous transplant, and lenalidomide maintenance.
  • Patient experienced biochemical and clinical relapse 3.5 years post-transplant.
• Second-line CAR T-cell therapy is a consideration, with ciltacabtagene autoleucel (cilta-cel; Carvykti) having impressive data.
• The regimen from the phase 3 MajesTEC-3 trial (NCT05083169)—teclistamab plus daratumumab—is also an option.
  • This patient would be expected to have a rapid and deep response.
  • For patients achieving deep responses, de-escalating teclistamab to monthly or less frequent dosing can optimize safety and quality of life.
• Decisions between CAR T-cell therapy and other options are not “cut and dry”, and CAR T-cell therapy is not the only appropriate second-line option.

Patient Case 2

• A 72-year-old patient with early relapse multiple myeloma with comorbid cardiovascular disease who is anti-CD38 exposed, lenalidomide-refractory, and not an ideal candidate for CAR T-cell therapy.
  • Prior treatment was a daratumumab-based frontline therapy, and they relapsed 24 months after transplant.
• Teclistamab plus daratumumab may be viable since CAR T-cell therapy is not.
• This may require inpatient step-up dosing because of cardiovascular comorbidities.
  • It would be necessary to monitor those with a particularly high disease burden.
• Regimens like daratumumab plus carfilzomib (Kyprolis) and dexamethasone (D-Kd), isatuximab (Sarclisa) plus Kd, or carfilzomib-based treatments are non-ideal.
• More favorable regimens are daratumumab plus pomalidomide and dexamethasone or isatuximab plus pomalidomide and dexamethasone.
• Patients should be guided based on overall fitness.