New Considerations Arise in Sequencing After Second Relapse in Multiple Myeloma

With the FDA indications for chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers moving earlier in the treatment course of multiple myeloma, clinical decisions on sequencing and prioritizing these therapies become increasingly important. During a live event, Syed Abbas Ali, MBBS, associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, and participants examined how the accumulated data from the phase 3 KarMMa-3 trial (NCT03651128), the updated phase 3 CARTITUDE-4 (NCT04181827) analysis, and recent FDA label changes reshape treatment sequencing decisions. They also discussed how community oncologists are integrating chimeric antigen receptor (CAR) T-cell bispecific antibodies and the use of antibody-drug conjugates for patients at second relapse and beyond.

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This is part 2 of a 2-part series. Read part 1.

CASE SUMMARY 2

• A 70-year-old man who was diagnosed 6 years ago with Revised International Staging System (R-ISS) stage II/R2-ISS stage III IgG-λ multiple myeloma presents to his oncologist at second relapse.
• Medical history: hypertension (well-controlled); peripheral neuropathy.
• Patient received previous treatments with: bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd), followed by lenalidomide maintenance; achieved very good partial response (VGPR) post induction therapy; underwent autologous stem cell transplant (ASCT); achieved VGPR post ASCT; later progressed on lenalidomide maintenance.
• CAR T-cell therapy was discussed; however, the patient ultimately was initiated on daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone (DKd).
• The patient now has disease progression.
• ECOG performance status: 1
• At second relapse, the patient and his clinical team revisited discussions, and he was referred for CAR T-cell therapy evaluation.

This second case presented by Ali anchored a wide-ranging discussion about how clinicians should think about the order of immunotherapy in relapsed myeloma and what happens when a patient who declined CAR T at first relapse is now facing a second progression.

Ali began by reviewing the current bispecific landscape: teclistamab (Tecvayli), elranatamab (Elrexfio), and linvoseltamab (Lynozyfic) are all B-cell maturation antigen (BCMA)–directed, whereas talquetamab (Talvey) targets GPRC5D. This distinction carries direct consequences for sequencing. International Myeloma Working Group guidance, published in Leukemia in 2025, recommends pursuing T-cell redirecting therapy before BCMA-directed antibody-drug conjugates when a patient is eligible for both, and using a different mechanism or antigen target for patients progressing on or shortly after BCMA-directed therapy.¹ It also recommends CAR T before any BCMA-directed bispecific; giving a bispecific first does not meaningfully compromise subsequent CAR T outcomes if at least 6 months have elapsed, but the reverse is not true.

For patients who have already received a BCMA bispecific and then relapse, options narrow. Ali described talquetamab as his preferred bridge to CAR T as well as subsequent therapy: its GPRC5D target preserves future BCMA-directed CAR T options, and it can serve both as tumor cytoreduction and a standalone line. He also mentioned that the combination of teclistamab-talquetamab is active but is associated with high rates of infection.

For the antibody-drug conjugate belantamab mafodotin (Blenrep), ocular toxicity concerns were the defining experience for most participants. One recalled coordination with ophthalmology as the main challenge. Grigori Okoev, MD, of Cancer Care Associates of York in Pennsylvania, suggested that newer combination regimens have changed the calculus: Given less frequently in combination than as a monotherapy, the drug produces fewer ocular events and carries no cytokine release or neurotoxicity burden like the T-cell redirecting therapies. “It is going to provide another option for patients in the community,” he said, highlighting older or frail patients not suited for CAR T or bispecific step-up dosing. Ali added that there is a signal suggesting anti-BCMA activity from antibody-drug conjugates may persist even after BCMA-directed T-cell therapy has failed,² which could give belantamab a role in post–CAR T sequencing.

For the Case 2 patient at second relapse, participants voted to refer for CAR T (70%) or a bispecific on a clinical trial (30%); no one selected a conventional doublet or triplet. Although idecabtagene vicleucel (Abecma; ide-cel) is indicated after the second relapse, the group did not favor its use as opposed to ciltacabtagene autoleucel (Carvykti; cilta-cel). Ali described treating only 1 patient at Hopkins; 3 others had rescinded consent. He placed ide-cel as increasingly difficult to justify against current bispecifics and cilta-cel.

Ali reviewed the KarMMa-3 trial of ide-cel with the participants. Enrolling patients with 2 to 4 prior lines, including a proteasome inhibitor, an immunomodulatory drug, and daratumumab, the trial showed an overall response rate of 71% with ide-cel vs 42% with standard of care (OR, 3.36; 95% CI, 2.17-5.22), with stringent complete responses in 26% vs 5%.³ Ali acknowledged the overall survival benefit but noted the standard-of-care comparator may not represent the most effective current alternatives.

The July 2025 FDA removal of the Risk Evaluation and Mitigation Strategy program for CAR T products⁴ changed the conversation most visibly for patients. The previous requirement to remain near the treating center for 30 days had been a concrete barrier, and the updated label's shorter monitoring window especially matters for Okoev's patients in Pennsylvania, who view a trip to a CAR T center in Baltimore, which can take more than an hour, as challenging. Gao noted that manufacturer programs exploring fully outpatient CAR T delivery could be the longer-term answer: If the product no longer requires inpatient infrastructure, the entire referral calculus changes for patients who want to stay local.

Infrastructure for the inpatient-to-outpatient transition and infectious prophylaxis post CAR T also drew attention. Ali outlined his standard approach: One year each of acyclovir and Pneumocystis jirovecii pneumonia prophylaxis, routine intravenous immunoglobulin (IVIG), transitioning to a subcutaneous option where insurance allows, and granulocyte colony-stimulating factor (G-CSF) initiated earlier than previously practiced, without the historical concern that early G-CSF would worsen cytokine release syndrome. He also proactively checks disease-specific antibody titers before any BCMA-directed therapy, ensuring meaningful immunoglobulin levels are established before IVIG renders them uninterpretable.

After the full second-case discussion, all 10 participants indicated they were very likely to refer patients for CAR T at second relapse. The more difficult conversation, Ali acknowledged, is the first-relapse decision, balancing a real overall survival benefit against treatment-related mortality, and building the early community partnerships that allow seamless referral before urgency forces a suboptimal treatment selection.

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_{DISCLOSURES: There were no known relevant disclosures.}

REFERENCES

1. Costa LJ, Banerjee R, Mian H, et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. 2025;39(3):543-554. doi:10.1038/s41375-024-02482-6

2. Bertuglia G, Di Nicola A, Gay F, Larocca A, Bruno B, D'Agostino M. Current positioning and future development of belantamab mafodotin and other antibody-drug conjugates to treat multiple myeloma. Front Oncol. 2026;16:1822419. doi:10.3389/fonc.2026.1822419

3. Ailawadhi S, Arnulf B, Patel K, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024;144(23):2389-2401. doi:10.1182/blood.2024024582