Navigating First Relapse in Multiple Myeloma

Treatment decision-making in early relapsed/refractory multiple myeloma has become more multifaceted because of expanded therapeutic options and increasing consideration of prior frontline exposure.

In a recent discussion, the cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, asked Shaji Kumar, MD, of Mayo Clinic, to outline a practical, evidence-based framework to guide clinicians when multiple myeloma progresses after initial therapy.

Most patients receive anti-CD38–based regimens, such as daratumumab- or isatuximab-containing combinations, in the upfront setting. Therefore, the first relapse requires careful consideration of several key factors: patient age and fitness, prior therapies and refractoriness, transplant history, disease biology, and patient preferences regarding treatment intensity and logistics.

CAR T-Cell Therapy: A Preferred Option at First Relapse

For eligible patients, CAR T-cell therapy is preferred at first relapse, according to Dr. Kumar. Data from trials such as CARTITUDE-4 demonstrate high efficacy in earlier lines, with response rates approaching 100% and minimal residual disease negativity achieved in approximately 60% to 70% of patients. CAR T-cell therapy also offers a “one-and-done” approach, Dr. Kumar explained, allowing for treatment-free intervals that may extend several years.

However, both acute and long-term toxicities are a concern. Acute risks include immune effector cell–associated neurotoxicity syndrome and cranial nerve events, which Dr. Kumar said are manageable. Long-term concerns include parkinsonian movement disorders, Guillain-Barré syndrome, prolonged cytopenias, and immune effector cell–associated enterocolitis. Thoughtful patient selection and shared decision-making are critical, Dr. Kumar said.

Bispecifics Offer Accessible Alternatives

For patients who do not have biologically aggressive disease, bispecific antibodies may be highly effective. BCMA-directed therapies like teclistamab have demonstrated meaningful activity in this setting.

Teclistamab plus daratumumab has shown impressive progression-free survival (PFS) in clinical trials, such as MajesTEC-3. In that trial, the 3-year PFS rate was 83%. “That’s a remarkable number that we couldn’t have imagined a few years ago,” Dr. Kumar said.

He explained three concerns with the teclistamab/daratumumab regimen: infection risk, with about a third of patients experiencing grade 3 or 4 infections; continuous therapy until progression; and, importantly, an unclear role in patients already exposed or refractory to daratumumab.

For patients who are daratumumab-refractory, Dr. Kumar said single-agent teclistamab is a reasonable option. Data from MajesTEC-9 suggest sustained efficacy, with approximately 60% of patients progression-free at 18 months.

GPRC5D-targeted therapies, such as talquetamab, also demonstrate strong activity, especially in combination regimens under investigation. However, their toxicity profile often leads clinicians to prioritize BCMA-directed approaches earlier in treatment. Toxicities include dysgeusia, weight loss, gastrointestinal problems, dermatologic effects, and nail changes.

Role of Conventional Regimens

Despite advances in T-cell–redirecting therapies, conventional regimens remain relevant. Combinations such as daratumumab with carfilzomib or pomalidomide-based regimens continue to be appropriate options, especially for patients who may not be ready for cellular therapy, Dr. Kumar said.

ASCT should also be reconsidered at first relapse in patients who deferred transplant up front. Many patients now collect and store stem cells early in their disease course, Dr. Kumar explained, and delaying transplant indefinitely may limit its eventual use. For patients with durable responses to initial therapy, ASCT at first relapse can provide meaningful disease control and potentially bridge to future therapies, he said.

Emerging Agents and Sequencing Considerations

Dr. Kumar discussed how belantamab mafodotin, an antibody-drug conjugate targeting BCMA, remains an option in later lines. However, its use is limited by ocular toxicity, and it is FDA-approved for patients who have received at least 2 prior lines of therapy.

Sequencing remains an area of active investigation. Dr. Kumar discussed how emerging data suggest that administering CAR T-cell therapy before bispecific antibodies may lead to better outcomes compared with the reverse sequence. However, evidence remains limited and largely derived from heavily pretreated populations.

The best treatment algorithm for early relapsed/refractory multiple myeloma is highly individualized, Dr. Kumar explained. While CAR T-cell therapy is often preferred for eligible patients at first relapse, bispecific antibodies provide an effective and accessible alternative.

As therapeutic options continue to expand, community oncologists play a critical role in aligning treatment strategies with patient goals, disease characteristics, and real-world considerations.