5 Key Multiple Myeloma Trial Updates From EHA 2026

Major Multiple Myeloma Presentations at EHA 2026

Rahul Banerjee, MD, FACP, of Fred Hutchinson Cancer Center, joined Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, on the Oncology Brothers podcast to highlight key multiple myeloma trials presented at the 31st European Hematology Association Annual Congress (EHA 2026). 

The doctors covered the CEPHEUS trial’s validation of quadruplet regimens in newly diagnosed patients, the survival benefit of teclistamab in relapsed or refractory myeloma from MajesTEC-3 and MajesTEC-9, the efficacy of talquetamab in MonumenTAL-3, and emerging data on mezigdomide from SUCCESSOR-2.

CEPHEUS

The phase 3 CEPHEUS trial established that daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) improved rates of minimal residual disease (MRD) negativity and progression-free survival (PFS) versus VRd alone in transplant-ineligible or transplant-deferred patients with newly diagnosed multiple myeloma. Authors presented the final 72-month analysis of CEPHEUS at EHA 2026.

Among transplant-ineligible patients with newly diagnosed multiple myeloma, the overall MRD-negativity rates for DVRd versus VRd were 61.1% versus 40% at 10^-5 (odds ratio [OR], 2.35; 95% CI, 1.47-3.77; P = .0004) and 46.5% versus 27.6% at 10^-6 (OR, 2.27; 95% CI, 1.39-3.72; P = .001), respectively. The overall complete response (CR) or better rates were 80.6% for DVRd and 61.4% for VRd (OR, 2.64; 95% CI, 1.54-4.51; P = .0003). Median PFS was not estimable (NE; 95% CI, 74.81-NE) with DVRd versus 50.2 months (95% CI, 41.95-62.95) with VRd (HR, 0.55; 95% CI, 0.39-0.78; P = .0007). The 72-month PFS rates were 59.3% versus 38.3%, respectively. 

The CEPHEUS data further support anti-CD38–based quadruplet regimens as the frontline standard of care for patients with multiple myeloma, regardless of transplant eligibility, Dr. Rahul Gosain said. 

MajesTEC-3

The phase 3 MajesTEC-3 trial previously showed teclistamab plus daratumumab improved PFS, CR or better rates, MRD negativity, and overall survival (OS) compared with daratumumab, dexamethasone, and either pomalidomide or bortezomib (DPd/DVd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. At EHA 2026, Dr. Banerjee presented a follow-up analysis on risk subgroups based on high-risk cytogenetic abnormalities (HRCAs) and functional high-risk (FHR) status. 

For the analysis, the prespecified high-risk subgroup included patients with t(4;14), t(14;16), or deletion 17p. The revised high-risk subgroup included 2 additional HRCAs: gain (1q21) with 3 copies or amplification (1q21) with at least 4 copies. FHR was defined as 1 prior line of therapy with progressive disease within 18 months of transplantation or the start of initial therapy. 

The presentation covered prespecified standard-risk or high-risk, revised standard-risk or high-risk, at least 1 or 2 HRCAs, and FHR or non-FHR subgroups. Overall, the analysis showed teclistamab plus daratumumab significantly improved rates of PFS and MRD negativity plus CR compared with DPd/DVd across cytogenetic risk and FHR subgroups. 

In the current paradigm, bispecific-based combinations like teclistamab plus daratumumab or referral for chimeric antigen receptor (CAR) T-cell therapy are the default considerations for patients with multiple myeloma after first relapse. Dr. Banerjee said that at this point, he uses only DPd in the second line as a bridging therapy before B-cell maturation antigen (BCMA)–directed CAR T-cell therapy. 

MajesTEC-9

The phase 3 MajesTEC-9 study evaluated teclistamab monotherapy against pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients with relapsed or refractory multiple myeloma after 1 to 3 prior lines of therapy. After a median follow-up of 17.3 months, the median PFS was not reached with teclistamab versus 8.2 months with PVd/Kd (HR, 0.29; 95% CI, 0.23-0.38; P < .0001), with 18-month PFS rates of 69.8% and 26.9%, respectively. Teclistamab also significantly improved OS compared with PVd/Kd (HR, 0.60; 95% CI, 0.43-0.83; P = .002), according to the interim analysis presented at EHA 2026.

MajesTEC-9 offers important guidance for second-line treatment of multiple myeloma now that anti-CD38 antibody–based quadruplet regimens have been widely adopted in the first-line setting, Dr. Banerjee said. Although the data support teclistamab monotherapy’s benefit for CD38-exposed patients, Dr. Banerjee noted that he typically starts with teclistamab plus daratumumab if there is any possibility a relapsed patient is still sensitive to anti-CD38 antibodies.

The doctors emphasized the importance of prophylactic tocilizumab and immunoglobulin replacement for patients with relapsed or refractory multiple myeloma receiving bispecific antibodies to reduce the risk of cytokine release syndrome and infectious complications.

MonumenTAL-3

The phase 3 MonumenTAL-3 trial evaluated talquetamab with either daratumumab and pomalidomide (Tal-DP) or daratumumab alone (Tal-D) versus DPd in patients with relapsed or refractory multiple myeloma after 1 or more prior lines of therapy. After 24.6 months of median follow-up, Tal-DP (HR, 0.28; 95% CI, 0.20-0.40; P < .0001) and Tal-D (HR, 0.33; 95% CI, 0.24-0.46; P < .0001) significantly improved PFS compared with DPd, with 24-month PFS rates of 81.30% (95% CI, 75.8-85.7), 77.6% (95% CI, 71.7-82.5), and 51.2% (95% CI, 44.8-57.1), respectively. Tal-DP also significantly improved OS compared with DPd (HR, 0.47; 95% CI, 0.30-0.73; P = .0006). 

Compared with DPd, both Tal-DP and Tal-D significantly improved objective response rate (ORR), CR or better rates, and MRD negativity plus CR or better rates, according to the presentation.

Talquetamab, a GPRC5D-directed CD3 bispecific antibody, targets GPRC5D rather than BCMA, distinguishing it from the other bispecific antibodies and CAR T-cell therapies approved for relapsed or refractory multiple myeloma. Although its distinct targeting mechanism may avoid some BCMA-related adverse effects, talquetamab is associated with distinct skin, nail, and taste toxicities. Management recommendations for these adverse effects are still evolving, although spacing out doses was an effective strategy in the trial, Dr. Banerjee said.

SUCCESSOR-2

The phase 3 SUCCESSOR-2 trial evaluated mezigdomide, an oral CELMoD, plus carfilzomib and dexamethasone (MeziKd) against Kd in patients with relapsed or refractory multiple myeloma previously treated with an anti-CD38 monoclonal antibody and lenalidomide. In the safety and efficacy analysis, the median PFS was 18 months (95% CI, 14.5-22.1) with MeziKd versus 8.3 months (95% CI, 5.6-10.7) with Kd (HR, 0.48; 95% CI, 0.36-0.63; P < .0001). 

Overall, the MeziKd arm had an ORR of 80.2% and a CR or better rate of 26.7%, while the Kd arm had an ORR of 53.4% and a CR or better rate of 8.9%. Grade 3 to 4 treatment-emergent adverse events occurred in 83.7% versus 56.5%, neutropenia in 61.1% versus 9.1%, and infections in 34.0% versus 15.6% of the MeziKd and Kd arms, respectively.

CELMoDs offer more potent activity than conventional immunomodulatory drugs, and SUCCESSOR-2 showed mezigdomide was effective even in patients refractory to lenalidomide or pomalidomide. While CELMoDs offer direct anti-myeloma activity, they also promote T-cell function, which may support combining them with or sequencing them before CAR T-cell or bispecific T-cell engager therapies, Dr. Banerjee said.