Tec/Dara Offers a Path Forward in Relapsed Myeloma When CAR T Is Not an Option

Multiple myeloma treatment has shifted decisively toward quadruplet induction and autologous stem cell transplantation (ASCT) for eligible patients, meaning more patients now enter the relapsed setting having already been exposed to daratumumab (Darzalex). For those who relapse after a quadruplet regimen but are not candidates for chimeric antigen receptor (CAR) T-cell therapy, whether by patient choice, eligibility, or logistics, the question of what comes next has been pressing. The recently approved combination of teclistamab (Tecvayli) plus daratumumab is now becoming a major consideration in the second line of treatment.

In a live Case-Based Roundtable event for oncologists and advanced practice providers in Pittsburgh, Pennsylvania, Prerna Mewawalla, MD, hematologist-oncologist and medical director of apheresis in the Division of Hematology and Cellular Therapy at Allegheny Health Network and associate professor at Drexel University College of Medicine, reviewed MajesTEC-3 trial (NCT05083169) data and moderated discussion of patient selection and real-world administration. Mewawalla noted that the approval places community oncologists at a new decision point, as multiple NCCN category 1 second-line options now exist, and choosing between them requires matching the patient to the therapy.¹

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CASE SUMMARY

• A 50-year-old woman with relapsed/refractory multiple myeloma presents to the clinic with evidence of disease progression after receiving a quadruplet regimen and ASCT.
• Treatment history: July 2024, daratumumab, bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone (Dara-VRd), achieved complete response (CR); November 2024, ASCT followed by lenalidomide maintenance; February 2026, relapse
• ECOG performance status, 1; International Staging System class, I; high-risk cytogenetics present
• The patient has a full-time job and is the primary caregiver for her parents.
• Due to her career and family obligations, the patient does not want CAR T-cell therapy.
• Patient is being considered for teclistamab plus daratumumab or conventional therapy.

EVENT RECAP

In MajesTEC-3, 587 patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior lines including a proteasome inhibitor (PI) and lenalidomide were randomly assigned to receive either teclistamab plus daratumumab or a standard-of-care doublet of daratumumab plus pomalidomide (Pomalyst)/dexamethasone or daratumumab plus bortezomib/dexamethasone. Patients with prior B-cell maturation antigen (BCMA)–directed therapy or anti-CD38 refractoriness were excluded.²

At a median follow-up of 34.5 months, the combination arm showed a median progression-free survival (PFS) that was not reached vs 18.1 months with standard of care; the 36-month PFS rate was 83.4% vs 29.7%. CR rate was 81.8% vs 32.1%, minimal residual disease (MRD) negativity was 58.4% vs 17.1%, and 36-month overall survival (OS) was 83.3% vs 65.0%. Benefit was consistent across subgroups, including in patients with high-risk cytogenetics.

Discussion centered quickly on the real-world boundary: what to do when a patient received daratumumab as part of frontline quadruplet therapy. The conversation distinguished daratumumab-exposed from daratumumab-refractory patients, the latter being those who received daratumumab to disease progression rather than experiencing progression on lenalidomide maintenance. Mewawalla agreed, noting teclistamab’s independent BCMA-directed activity makes the combination viable even in daratumumab-exposed patients who were not refractory to anti-CD38 therapy. One participant suggested that patients who progressed within approximately 6 months of daratumumab-based therapy most plausibly meet the threshold for refractoriness, though the group acknowledged definitions remain unsettled.

On safety, participants took a measured view of the higher infection rate in the combination arm (any grade, 96.5% vs 84.1%; grade 3/4, 54.1% vs 43.4%).² They noted that despite the infection signal, death events were far lower with teclistamab plus daratumumab: 45 vs 96 in the standard-of-care arm, and that systematic prophylaxis would narrow the gap. Cytokine release syndrome (CRS) occurred in 60.1% of patients on the combination but was entirely grade 1 or 2.

The group’s most detailed exchange concerned building the infrastructure to deliver the regimen safely outside of transplant centers. Mewawalla described prophylactic tocilizumab (Actemra) combined with take-home dexamethasone, rapid-response team availability, and emergency department access as the conditions enabling outpatient step-up dosing at satellite sites, an approach she reported reduced CRS rates to below 15% from the trial’s 60%.³ Participants from the University of Pittsburgh Medical Center described completing step-up dosing inpatient before transferring patients to community infusion sites for ongoing cycles. On intravenous immunoglobulin (IVIG), Mewawalla’s center initiates it for all patients after the first full cycle regardless of IgG level, citing data from the American Society of Hematology (ASH) linking IVIG to reduced mortality in patients on BCMA bispecific therapy.⁴

For patients who decline CAR T or cannot access it like the case patient, the MajesTEC-3 data and this discussion support teclistamab plus daratumumab as a well-evidenced second-line option, provided the practice can build the prophylaxis and administration infrastructure the regimen requires. How the picture changes for patients who are candidates for CAR T will be explored in part 2 of this series.

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_{DISCLOSURES: Mewawalla previously reported advisory board roles with Pfizer and Johnson & Johnson.}

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple Myeloma, version 5.2026. Accessed February 12, 2026. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

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

3. Scott SA, Marin EM, Maples KT, et al. Prophylactic tocilizumab to prevent cytokine release syndrome (CRS) with teclistamab: A single-center experience. Blood Cancer J. 2023;13(1):191. Published 2023 Dec 20. doi:10.1038/s41408-023-00963-y

4. Tan CJ, Zhang M, Cho J, et al. Real-world analysis of infections after bispecific antibodies targeting anti-B-cell maturation antigen (BCMA) and protective impact of intravenous immunoglobulin (IVIG) in patients with multiple myeloma. Blood. 2025;146(suppl 1):4595. doi: 10.1182/blood-2025-4595