Optimizing Treatment Strategies for Relapsed Multiple Myeloma: From CAR T-Cell Therapy to Novel Combinations

Multiple myeloma (搜索)搜索该疾病 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 (搜索)搜索该疾病, particularly those who are lenalidomide查看药品详情-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查看药品详情 (Carvykti查看药品详情) 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查看药品详情 or immunomodulatory drugs such as lenvatinib and pomalidomide查看药品详情 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 (搜索)搜索该靶点)-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 (搜索)搜索该靶点-directed therapies before CAR T, because we do see less response, if you use teclistimab [Tecvayli查看药品详情], for example, or elranatamab查看药品详情 [Elrexfio查看药品详情]," cautions Dr. Khouri.

Instead, bispecific antibodies targeting different antigens, such as GPRC5D (搜索)搜索该靶点-targeted talquetamab查看药品详情 (Talvey查看药品详情), 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查看药品详情-based combinations offer promising efficacy. The phase 3 BOSTON trial demonstrated that selinexor, bortezomib查看药品详情, 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查看药品详情 combinations: "A number of different results [were reported], including overall response rates [ORRs]. For selinexor/lenalidomide查看药品详情/dexamethasone, the overall response rate was 92%."

Other selinexor查看药品详情-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查看药品详情 (Carvykti查看药品详情) and idecabtagene vicleucel查看药品详情 (Abecma查看药品详情) are recommended.

After four prior therapies, BCMA (搜索)搜索该靶点 bispecifics such as elranatamab查看药品详情 (Elrexfio查看药品详情) and teclistamab查看药品详情 (Tecvayli查看药品详情) become options, along with the GPRC5D (搜索)搜索该靶点 bispecific talquetamab查看药品详情 (Talvey查看药品详情).

The International Myeloma Working Group (搜索)搜索该词条 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查看药品详情 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查看药品详情/dexamethasone arm because bortezomib was given only once per week in the triplet arm.

"Keep in mind [when using] selinexor查看药品详情 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查看药品详情-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 (搜索)搜索该疾病 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.