“A Home Run” For Myeloma: What’s Next After The MajesTEC-3 Practice-Changing Results For Relapsed/Refractory Multiple Myeloma

The MajesTEC-3 phase III study landed with uncommon force in the multiple myeloma community. Multiple leaders told SurvivorNet they were “incredibly impressed” by the results—data strong enough to prompt regulators to pursue an accelerated review pathway.

Dr. María-Victoria Mateos, a Consultant Physician in the Hematology Department at the University Hospital of Salamanca, and an Associate Professor of Medicine, presented the first detailed results from MajesTEC-3, a Phase 3 randomized study evaluating Tecvayli (teclistamab-cqyv) in combination with Darzalex Faspro (daratumumab hyaluronidase-fihj) compared with standard-of-care triplets in relapsed/refractory multiple myeloma (RRMM). Early reactions across the meeting floor describe this as one of the most striking immunotherapy combinations to reach Phase 3 in myeloma. 

Myeloma expert Dr. Sagar Lonial, Professor of Hematology at Emory University, echoed that sentiment, describing MajesTEC-3 as “as close to a home run as you get, if it’s not a home run.”

Study Overview

MajesTEC-3 (NCT05083169) enrolled 587 patients with RRMM who had received 1-3 prior lines of therapy, including exposure to both a proteasome inhibitor and an Immune-Mediated Inflammatory Diseases (IMiD). Those with only one prior line were required to be lenalidomide-refractory, reflecting real-world patterns where first-relapse patients often progress on maintenance.

• Experimental arm: Step-up dosing of Tecvayli followed by full-dose treatment in combination with Darzalex Faspro
• Control arms: Darzalex / pomalidomide / dexamethasone (DPd) or Darzalex / bortezomib / dexamethasone (DVd)

The primary endpoint was progression-free survival (PFS) per International Myeloma Working Group (IMWG) criteria. Secondary end-points included overall survival (OS), response rates, Minimal Residual Disease (MRD) negativity, duration of response, time to next treatment, and safety.

Efficacy: PFS & OS Strongly Favor Tecvayli + Darzalex Faspro

After nearly three years of follow-up, the Tecvayli/Darzalex combination showed a statistically significant and clinically dramatic improvement in PFS, generating considerable excitement at ASH. Topline efficacy results:

• 36-month PFS: 83.4% with Tecvayli + Darzalex vs. 29.7% with standard-of-care
• Median PFS: Not reached in the experimental arm vs. 18.1 months in the SOC arms

Dr. Lonial emphasized the magnitude of effect.

“The remission was roughly five times longer in the Tec-Dara arm compared to the DPD arm. About 83% of patients were still in remission at three years versus only 20–30% with DPD. This is probably one of the longest PFS outcomes ever seen in a relapsed myeloma population.”

The first interim OS analysis demonstrated a statistically significant overall survival advantage, prompting the independent data monitoring committee (IDMC) to recommend unblinding the study early. This level of dual PFS and OS benefit is unprecedented for a BCMA-targeted bispecific antibody in a Phase 3 setting.

Depth of Response, MRD, and Safety

Available data indicate higher overall response rates (ORR) and complete response (CR) rates with Tecvayli + Darzalex. Markedly improved MRD-negativity rates, consistent with deeper immunologic control. The safety profile showed no new safety signals. 

Dr. Lonial discussed the biological synergy behind the regimen, “It is thought that the combination of Tec and dara has synergy, Dara eliminates cells that may limit bispecific activity, releasing more effective T-cell engagement. It’s immune therapy on steroids, if you will.” These findings reinforce the biological synergy of combining a BCMA-directed bispecific with a CD38 antibody early in the treatment course, when T-cell function remains stronger and more responsive.

Why This Matters: A Potential Paradigm Shift

MajesTEC-3 is the first Phase 3 study in RRMM to demonstrate both PFS and OS superiority for a bispecific-based combination over standard-of-care antibody/IMiD or antibody/PI triplets.

Experts are already calling the magnitude of benefit “paradigm-shifting,” with an 83% 3-year PFS more reminiscent of frontline regimens than relapsed-disease trials. Dr. Lonial expanded on the clinical implications.

“This certainly is potentially practice-changing. One of our standard early-relapse triplets involved Dara, but the Tec-Dara data is clearly better. Some practices may choose CAR-T or bispecifics depending on expertise, but this trial will push community colleagues to adopt bispecifics earlier. It’s a great opportunity for patients.”

As for the broader impact, Dr. Lonial reflected on how far myeloma therapy has progressed.

“Twenty-five years ago, chemotherapy was the mainstay, and survival was two to three years. Now median survival is 10-15 years, and that’s before incorporating results like MajesTEC-3. It’s an incredibly exciting time to see this impact in real time for patients.”

If the full ASH dataset confirms these results, Tecvayli + Darzalex Faspro could rapidly become a new standard of care for early relapse.

The findings may accelerate a broader move toward introducing bispecifics earlier in the treatment course. It may open the door to second-line or even frontline combinations exploring dual-antibody immunotherapy.

References

• Mateos MV, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of DPd or DVd in patients with RRMM: Results of MajesTEC-3. Presented at: 2025 ASH Annual Meeting; December 6–9, 2025; Orlando, FL. Abstract LBA-6.
• Johnson & Johnson. TECVAYLI plus DARZALEX FASPRO combination regimen significantly improves progression-free survival and overall survival versus standard of care. October 16, 2025.
• ClinicalTrials.gov. MajesTEC-3: A study of teclistamab plus daratumumab SC versus DPd or DVd in RRMM. Updated October 10, 2025.