Myeloma Specialist Answers Community Questions on CAR T-Cell Therapy, MRD, and CELMoDs

Multiple Myeloma Questions From Community Oncologists

Community medical oncologists Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed community-sourced multiple myeloma questions with myeloma specialist, Joseph Mikhael, MD, MEd, of City of Hope, for the Oncology Brothers podcast Rapid Fire Rounds series. 

High-Risk Early Disease: Carfilzomib, Maintenance, and Definition

Drs. Rahul and Rohit Gosain and Dr. Mikhael first responded to questions on early multiple myeloma, starting with whether carfilzomib should be preferred in frontline quadruplet regimens for high-risk patients. While trials have demonstrated carfilzomib is feasible and potentially more effective than bortezomib in frontline therapy, it may not be appropriate for every high-risk patient, such as those with cardiovascular comorbidities, Dr. Mikhael said. For patients with high-risk disease, chasing the deepest possible response is critical, and frontline carfilzomib-based regimens support this goal as long as oncologists carefully monitor for side effects and taper down doses over time, he added.

Dr. Rahul Gosain raised the question of carfilzomib in the maintenance setting, where daratumumab-based or carfilzomib-based regimens are primary options for high-risk patients. When selecting a maintenance regimen, Dr. Mikhael typically favors continuing the agent a patient received in frontline therapy. Otherwise, oncologists should discuss tolerability and treatment logistics with each individual patient. 

The doctors also commented on the evolving definition of high-risk disease. The International Myeloma Working Group and International Myeloma Society published a consensus definition of high-risk multiple myeloma that identifies five features associated with poor prognosis, including TP53 loss or mutation and concurrent abnormalities like immunoglobulin (Ig) heavy chain translocation plus chromosome 1q abnormalities. Fortunately, the disparity between high-risk and standard-risk multiple myeloma is shrinking as novel treatments and new treatment strategies emerge, Dr. Mikhael suggested.

Relapsed or Refractory Disease: CAR T Cells, Supportive Care, Sequencing

Next, the doctors fielded questions related to relapsed or refractory multiple myeloma treatment, including new strategies for CAR T-cell therapy. Patients with relapsed or refractory multiple myeloma referred for CAR T-cell therapy often start preliminary treatment to control their disease before CAR T-cell infusion. This preliminary treatment is separated into two categories: holding therapy and bridging therapy. Holding therapy is given prior to T-cell collection and bridging therapy is given between T-cell collection and CAR T-cell infusion. 

Treatments that affect T-cell activity generally should not be used for holding therapy because they could affect the CAR T-cell manufacturing process. Dr. Mikhael commonly uses quadruplet regimen components or selinexor as holding therapy. After collection is completed, holding therapies may be continued as bridging therapy. However, oncologists could also swap to more intensive agents. Emerging data suggest that a non-BCMA–targeted agent like talquetamab may be an effective bridging therapy prior to BCMA–targeted CAR T-cell therapy in multiple myeloma, Dr. Mikhael said.

Alongside the distinction between holding and bridging therapy, the doctors reviewed important supportive care for CAR T-cell therapy in relapsed or refractory multiple myeloma. Dr. Mikhael emphasized that intravenous IgG (IVIG) should be given to all patients after CAR T-cell infusion to reduce the risk of infection. In his practice, most patients receive IVIG for 6 to 12 months, adjusted based on IgG levels, infection history and risk, and blood counts. In addition to IVIG replacement, Dr. Mikhael recommended following the American Society for Transplantation and Cellular Therapy practice guidelines for antiviral, antifungal, and antibacterial prophylaxis.

Emerging Myeloma Topics: CELMoDs and MRD

Closing the discussion, the doctors considered the development of CELMoDs for multiple myeloma and the role of MRD testing. CELMoDs are a next-generation class of agents that essentially improve upon the mechanism of conventional immunomodulatory drugs like lenalidomide and pomalidomide. Iberdomide and mezigdomide are the primary CELMoDs being studied in multiple myeloma, with iberdomide now being approved by the FDA in combination with daratumumab, hyaluronidase-fihj, and dexamethasone for previously treated patients with relapsed or refractory disease.

Notably, the iberdomide combination was the first ever approval based on data using MRD negativity as a surrogate marker for deep and durable responses. This is an exciting prospect for the myeloma community because it suggests MRD testing can establish long-term treatment benefits, potentially leading to more rapid approvals of novel drugs, Dr. Mikhael said.

Outside clinical trials, MRD is a valuable tool for characterizing responses and guiding treatment decisions. In the frontline setting, data support that MRD status may be effective for selecting patients for transplant. Separately, in the maintenance setting, sustained MRD negativity may serve as a marker to stop indefinite maintenance therapy. Currently, MRD testing in multiple myeloma relies on marrow biopsy, and Dr. Mikhael suggested physicians can incorporate MRD testing into their routine marrow monitoring processes.