Data Increasingly Favor BCMA-Directed Therapy For Early-Relapse Myeloma

Once a patient with multiple myeloma relapses after frontline quadruplet therapy, autologous stem cell transplant (ASCT), and maintenance, oncologists face an expanding list of second-line options: proteasome inhibitor or CD38-antibody triplets, a daratumumab (Darzalex)-teclistamab (Tecvayli) bispecific combination, or chimeric antigen receptor (CAR) T-cell therapy. Increasingly mature trial data are pushing panels of experts toward T-cell redirecting approaches earlier in that sequence, but that push runs directly into a patient's own priorities when treatment means weeks away from a job or a parent who depends on her care.

In a virtual Case-Based Roundtable event for oncologists across North Carolina, Sikander Ailawadhi, MD, a professor with the Division of Hematology-Oncology at Mayo Clinic in Jacksonville, Florida, walked participants through the evidence supporting early-relapse regimens for relapsed/refractory multiple myeloma (RRMM) and moderated discussion of a case built around a patient reluctant to pursue CAR T. Ailawadhi noted that his own institution's guidelines now favor front-loading the strongest available regimen rather than holding an anti-CD38 antibody in reserve for relapse.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

1. A 56-year-old woman with RRMM presents to the clinic with evidence of disease progression.
2. ECOG PS, 1; ISS class, I; high-risk cytogenetics present.
3. The patient has a full-time job and is the primary caregiver for her parents.​
4. Due to career and family obligations, she prefers to avoid CAR T. ​

• Treatment history: daratumumab, bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (September 2024) resulting in complete response, followed by ASCT and lenalidomide maintenance
• Relapse (June 2026)

EVENT RECAP

Under current NCCN guidelines, early-relapse regimens for patients refractory to an anti-CD38 antibody, bortezomib, or lenalidomide span proteasome inhibitor-immunomodulatory drug (IMiD) doublets, anti-CD38 triplets with carfilzomib (Kyprolis) or pomalidomide (Pomalyst), a daratumumab-teclistamab bispecific combination, and chimeric antigen receptor (CAR) T-cell therapy, with ciltacabtagene autoleucel (cilta-cel; Carvykti) available after 1 prior line and idecabtagene vicleucel (ide-cel; Abecma) after 2 lines.¹

The OPTIMISMM trial (NCT01734928) established pomalidomide plus bortezomib and dexamethasone (PVd) for patients with 1 to 3 prior lines, reporting a median overall survival (OS) of 35.6 months vs 31.6 months for bortezomib-dexamethasone (Vd) at a median follow-up of 64.5 months, with grade 3 or higher neutropenia in 42% of patients.²^,³ The APOLLO trial (NCT03180736) added daratumumab to pomalidomide and dexamethasone (Dara-Pd) in patients with 1 or more prior lines, reporting a median OS of 34.4 months vs 23.7 months for pomalidomide-dexamethasone (Pd) alone at a median follow-up of 39.6 months, with grade 3 or higher neutropenia in 68% of patients.⁴^,⁵ Several other regimens containing an anti-CD38 antibody have also shown efficacy (Table). Taken together, these regimens represent the guideline-supported fallback for a patient who, like the one presented, wants to avoid T-cell redirecting therapy at this stage.

Table: Early Relapse Trials in Multiple Myeloma^2-10

^{AEs, adverse events; Dara-Kd, daratumumab, carfilzomib, and dexamethasone; Dara-Pd, daratumumab, pomalidomide, and dexamethasone; ICANS, immune effector cell–associated neurotoxicity syndrome; Isa-Pd, isatuximab, pomalidomide, and dexamethasone; Isa-Kd, isatuximab, carfilzomib, and dexamethasone; mF/U, median follow-up; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; PVd, pomalidomide, bortezomib, and dexamethasone; Tec-Dara, teclistamab and daratumumab.}

Against that backdrop, Ailawadhi singled out the phase 3 MajesTEC-3 trial (NCT05083169) as the standout: teclistamab (Tecvayli) plus subcutaneous daratumumab (Tec-Dara) yielded a median PFS that had not been reached at a median follow-up of 34.5 months, against 18.1 months for investigator's choice of daratumumab-pomalidomide-dexamethasone or daratumumab-bortezomib-dexamethasone, in patients with 1 to 3 prior lines with most having no prior daratumumab.¹⁰ He described the result as having “blown the rest of the data out of the park,” though he flagged that infections occurred in 54.1% of patients and immune effector cell-associated neurotoxicity syndrome, though rare at 0.4%, remains a monitoring consideration unique to T-cell redirecting therapy.

As the MajesTEC-3 trial population was generally treated with a triplet in the first line, it raised questions about the current sequencing approach in certain patients. Barry Paul, MD, of Atrium Health Levine Cancer Institute, noted that in a very frail patient, “I may not use a CD38 in [the] front line because if and when they progress, I can give them [daratumumab and teclistamab], which has unprecedented efficacy,” as opposed to teclistamab alone or another regimen.

Ailawadhi did not support the possibility of saving an anti-CD38 antibody for later use paired with teclistamab based on these results. “If you can start [with a quadruplet], you always start with the [quadruplet],” he said, arguing that Mayo Clinic's evolving guidelines prioritize giving patients the strongest regimen up front rather than banking a mechanism for relapse, on the reasoning that disease control achieved early outweighs theoretical benefit from a later-line pivot. However, teclistamab as monotherapy or with another combination has not yet been approved in the second line, making cilta-cel the only other approved T-cell redirecting therapy option.

When a patient like the one presented declines CAR T outright, Haley Simpson, MD, of UNC, stated, “The data [have] convinced me that patients should get BCMA [B-cell maturation antigen] T-cell redirecting therapy in the second line.” For a practice that cannot deliver a bispecific or CAR T therapy, she argued the answer is referral, or else the patient “should be counseled that they are not receiving necessarily the most up-to-date myeloma therapy." She added that a triplet-based regimen still “can [be] and is appropriate,” but that patients deserve to understand it as a second-best choice given current data. Ailawadhi supported Simpson's position, telling the group that early referral for BCMA-targeted therapy, even from practices that cannot administer it themselves, should be considered standard of care, and that pharmaceutical or foundation resources often exist to help patients bridge the logistics of traveling for that treatment.

For this patient, a triplet regimen chosen to respect her preference, although reasonable and guideline-supported, should come with an explicit conversation about what she may be trading away, and whether a referral for a second opinion at a center offering bispecific or CAR T therapy belongs in that conversation regardless of her initial answer.

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_{DISCLOSURES: Ailawadhi previously reported consultancy for Sanofi, Bristol Myers Squibb, BeOne, Janssen, Regeneron, Cellectar, Pfizer, GSK, Ascentage, Kite/Arcellex, and institutional research funding from Sanofi, GSK, BMS, Genentech, Janssen, Cellectar, Abbvie, Ascentage, and Astra Zeneca.}

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple Myeloma, version 1.2027. Accessed September 15, 2026. https://tinyurl.com/37vy9pm2

2. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi:10.1016/S1470-2045(19)30152-4

3. Richardson P, Beksaç M, Oriol A, et al. Pomalidomide, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: final survival and subgroup analyses from the OPTIMISMM trial. Eur J Haematol. 2025;114(5):822-831. doi:10.1111/ejh.14365

4. Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812. doi:10.1016/S1470-2045(21)00128-5

5. Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow-up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023;10(10):e813-e824. doi:10.1016/S2352-3026(23)00218-1

6. Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76. doi:10.1016/S1470-2045(21)00579-9

7. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5

8. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis. Haematologica. 2024;109(7):2239-2249. doi:10.3324/haematol.2023.284325

9. Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized phase 3 study. Blood Cancer J. 2023;13(1):72. doi:10.1038/s41408-023-00797-8

10. Costa LJ, Bahlis NJ, Perrot A, et al; MajesTEC-3 Trial Investigators. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2026;394(8):739-752. doi:10.1056/NEJMoa2514663