Multiple myeloma treatment has evolved significantly in recent years, with new therapeutic approaches offering hope for patients experiencing relapse. Experts are now focusing on optimizing treatment sequences to maximize efficacy while managing potential adverse events.
Strategic Approaches to CAR T-Cell Therapy
For patients with relapsed multiple myeloma, particularly those who are lenalidomide-refractory, chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising option. According to Dr. Jack Khouri, CAR T-cell therapy with ciltacabtagene autoleucel (Carvykti) is now approved for use at first relapse in lenalidomide-refractory patients.
The preparation for CAR T-cell therapy involves three distinct phases: holding therapy, bridging therapy, and lymphodepletion. Each phase serves a specific purpose in optimizing treatment outcomes.
"Holding therapy is important, because that's the treatment that you're giving to the patient when you send them to us, potentially, for CAR T," explains Dr. Khouri. "What we tell people to do a lot of times is to avoid certain treatments that we know could compromise T-cell count and T-cell fitness, and those are mostly alkylators."
Experts recommend avoiding cyclophosphamide before T-cell collection whenever possible, as it can compromise the T-cell repertoire. Conversely, daratumumab or immunomodulatory drugs such as lenvatinib and pomalidomide may enhance T-cell fitness by improving memory T-cell count and T-cell proliferation.
Bridging Therapy Considerations
Bridging therapy—the treatment administered while awaiting CAR T-cell manufacturing—requires careful consideration. Not all patients need bridging therapy, particularly those with minimal disease burden.
"For many people, I don't do anything. I let them be if they have little disease, especially in that we're doing more early CAR T, [so] they don't have as much disease," notes Dr. Khouri.
A critical insight from experts is to avoid B-cell maturation antigen (BCMA)-directed therapies before BCMA-targeted CAR T-cell therapy. Data shows that targeting BCMA before CAR T-cell therapy can result in lower response rates and reduced progression-free survival.
"Do your best to avoid BCMA-directed therapies before CAR T, because we do see less response, if you use teclistimab [Tecvayli], for example, or elranatamab [Elrexfio]," cautions Dr. Khouri.
Instead, bispecific antibodies targeting different antigens, such as GPRC5D-targeted talquetamab (Talvey), may be effective bridging options. Recent data supports this approach for patients awaiting CAR T-cell therapy.
The Role of Selinexor in Relapsed Multiple Myeloma
For patients with multiple relapses, selinexor-based combinations offer promising efficacy. The phase 3 BOSTON trial demonstrated that selinexor, bortezomib, and dexamethasone provided a median progression-free survival of approximately 14 months compared to 9.5 months with bortezomib and dexamethasone alone (HR, 0.70; 95% CI, 0.53-0.93; P = .0075).
Dr. Robert Orlowski highlights the potential of various selinexor combinations: "A number of different results [were reported], including overall response rates [ORRs]. For selinexor/lenalidomide/dexamethasone, the overall response rate was 92%."
Other selinexor-based regimens also show impressive efficacy:
- Selinexor/pomalidomide/dexamethasone: 54% ORR
- Selinexor/carfilzomib/dexamethasone: 78% ORR
These combinations demonstrate median progression-free survival ranging from 9 to 15 months, making them valuable options for patients awaiting additional therapies like CAR T-cells.
Treatment Options After Multiple Relapses
For patients experiencing a fourth relapse, current guidelines recommend several options. After three prior lines of treatment, CAR T-cell therapies like ciltacabtagene autoleucel (Carvykti) and idecabtagene vicleucel (Abecma) are recommended.
After four prior therapies, BCMA bispecifics such as elranatamab (Elrexfio) and teclistamab (Tecvayli) become options, along with the GPRC5D bispecific talquetamab (Talvey).
The International Myeloma Working Group has published consensus guidelines recommending consideration of disease burden and previous kinetics of disease progression when planning treatment. For patients with high disease burden or rapid progression, reducing disease burden before CAR T-cell therapy may decrease the risk of cytokine release syndrome and neurological symptoms.
Managing Treatment-Related Adverse Events
Treatment-related adverse events vary by regimen. With selinexor combinations, common adverse events include peripheral neuropathy, fatigue, nausea, vomiting, decreased appetite, and thrombocytopenia. Interestingly, in the BOSTON trial, the selinexor arm had less neuropathy than the bortezomib/dexamethasone arm because bortezomib was given only once per week in the triplet arm.
"Keep in mind [when using] selinexor that you do have to do vigorous antiemetic prophylaxis as well as in some cases make sure to encourage patients to do some fluids, including oral and sometimes intravenous," advises Dr. Orlowski.
For most selinexor-based regimens, grade 3 or 4 adverse events are primarily hematologic, which many oncologists are experienced in managing through careful monitoring.
As treatment options for relapsed multiple myeloma continue to expand, optimizing treatment sequences and managing transitions between therapies will be crucial to maximizing patient outcomes. The growing arsenal of targeted therapies, including CAR T-cells, bispecific antibodies, and novel drug combinations, offers hope for patients with this challenging disease.
