“The future of cancer therapy lies in rational combinations that harness the immune system while preserving patient quality of life.” —Vincent T. DeVita, MD
The treatment landscape for relapsed/refractory (R/R) multiple myeloma continues to evolve rapidly as T-cell–redirecting bispecific antibodies, cereblon E3 ligase modulators (CELMoDs), and CAR-T cell therapy move into earlier lines of treatment.
Syed A. Abutalib, MD
Matthew J. Pianko, MD
At the 2026 ASCO Annual Meeting and the 2026 European Hematology Association (EHA) Congress, pivotal phase III studies including MajesTEC-9, SUCCESSOR-2, and MonumenTAL-3 highlighted both B-cell maturation antigen (BCMA)-targeted and BCMA-sparing strategies for patients with early relapse. MajesTEC-9 and SUCCESSOR-2 demonstrated contrasting yet complementary approaches to disease management, whereas MonumenTAL-3 showed that the bispecific antibody talquetamab-cqyv, which binds to GPRC5D on myeloma cells and CD3 on T cells, plus daratumumab, with or without pomalidomide, was superior to standard therapy. Collectively, these studies expand the therapeutic options available for R/R multiple myeloma and underscore the importance of thoughtful treatment selection and sequencing, particularly for patients who may be candidates for BCMA-directed CAR T-cell therapy.
Abstract 7507 (MajesTEC-9): Teclistamab-cqyv Monotherapy vs Investigator’s Choice of PVd or Kd in R/R Multiple Myeloma
Background: MajesTEC-9 was a phase III, open-label, multicenter, randomized trial conducted at 162 sites in 24 countries. The study was presented at the 2026 ASCO Annual Meeting by Roberto Mina, MD, of the Winship Cancer Institute of Emory University.1The trial directly addressed whether monotherapy with the bispecific antibody teclistamab, which binds to BCMA on myeloma cells and CD3 on T cells, could improve outcomes over standard-of-care regimens. Patients included those with early relapsed multiple myeloma after prior exposure to both lenalidomide and an anti-CD38 monoclonal antibody. This represents a population that had been underrepresented in earlier teclistamab studies and in MajesTEC-3 and MajesTEC-1.2-4 At the time that these earlier teclistamab trials were designed and initiated, the widespread incorporation of anti-CD38 monoclonal antibodies (ie, daratumumab) into front-line and early-relapse treatment settings was evolving. As a result, many enrolled patients had variable or absent prior anti-CD38 exposure. This was particularly so in earlier cohorts, reflecting a treatment landscape in which anti-CD38–based regimens had not yet become uniformly established as part of standard induction and maintenance, and, therefore, had not consistently defined the contemporary first-relapse population.
Methods: The study evaluated teclistamab monotherapy (n = 296) vs investigator’s choice of pomalidomide/bortezomib/dexamethasone (PVd) or carfilzomib/dexamethasone (Kd) in patients with R/R multiple myeloma who had received one, two, or three prior lines of therapy, including both lenalidomide and an anti-CD38 monoclonal antibody. A total of 85.2% were anti-CD38–refractory, 79.9% were lenalidomide-refractory, 74.0% were double-refractory to an anti-CD38 antibody and an immunomodulatory drug, and 33.7% were triple-class refractory (ie, resistant to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody). Patients with prior BCMA-directed therapy were excluded.
Results: At a median follow-up of 17.3 months, teclistamab significantly improved progression-free survival (the primary endpoint) compared with PVd or Kd. Median progression-free survival was not reached with teclistamab vs 8.2 months with PVd or Kd; estimated 18-month progression-free survival was 69.8% vs 26.9%, respectively, with a hazard ratio for progression or death of 0.29 (95% CI, 0.23–0.38;P < .001). Teclistamab also improved overall survival. Median overall survival was not reached in either arm, but estimated 18-month overall survival was 79.2% with teclistamab vs 68.6% with PVd or Kd, corresponding to a hazard ratio (HR) for death of 0.60 (95% CI, 0.43–0.83; P = .002). MRD-negative complete response or better at 10-5 by flow cytometry was also more frequent with teclistamab, both in the intention-to-treat population (38.5% vs 6.7%) and among MRD-evaluable patients (86.4% vs 45.5%).
Safety: Grade 3 or 4 adverse events occurred in 84.9% of teclistamab-treated patients and 76.3% of those receiving PVd or Kd; fatal adverse events occurred in 6.5% and 3.5%, respectively. Adverse events led to treatment discontinuation in 10.7% vs 13.1%. Cytokine release syndrome (CRS) occurred in 66.0% of teclistamab-treated patients, primarily grade 1 (48.8%) or grade 2 (16.5%); grade 3 CRS occurred in two patients; no cases of grade 4 or 5 CRS were reported. Immune cell associated neurotoxicity syndrome (ICANS) (ie, confusion, aphasia, headaches) occurred in 4.1% of patients; this was mostly grade 1 or 2 and resolved in all but one patient who experienced grade 3 ICANS that led to teclistamab discontinuation.
Infection risk on teclistamab therapy remains to be an important safety signal. Any-grade infections occurred in 82.8% of teclistamab recipients and 68.2% of PVd or Kd recipients; grade 3 or 4 infections occurred in 41.6% and 29.0%, respectively. Fatal infections occurred in 5.5% vs 2.8%, with most occurring within the first 6 months after treatment initiation. These findings reinforce that early infection prevention, antimicrobial prophylaxis, and proactive immune globulin replacement are not optional adjuncts but central and mandatory components of teclistamab delivery.
Clinical Implications: MajesTEC-9 positions teclistamab monotherapy as a compelling second-line or later option for patients with prior lenalidomide and anti-CD38 exposure, particularly for those in whom a steroid-sparing, non-chemotherapy, monthly maintenance-like immunotherapy platform is attractive. The regimen may be especially valuable in patients for whom BCMA-directed CAR T-cell therapy is not suitable, owing to patient frailty, comorbidities, logistical barriers, manufacturing timelines, or patient preference, thereby expanding access to effective T-cell–redirecting therapy in earlier relapse settings. The magnitude of progression-free survival benefit, overall survival advantage, depth of response, and MRD negativity collectively support the movement of BCMA bispecific therapy earlier in relapse. However, the regimen’s success in real-world practice will depend on infrastructure for step-up dosing, implementation of strategies to reduce the operational impact of CRS and ICANS management on health systems and practices, infection mitigation, hypogammaglobulinemia management, and prompt evaluation of fever or respiratory symptoms.
LBA7506 (SUCCESSOR-2): Mezigdomide/Carfilzomib/Dexamethasone (MeziKd) vs Carfilzomib (Kd)
Background: SUCCESSOR-2 evaluated a different but equally important strategy: adding the potent novel oral cereblon E3 ligase modulator (CELMoD) mezigdomide to a carfilzomib/dexamethasone backbone (MeziKd).5 The trial was presented at the 2026 ASCO Annual Meeting by Paul Richardson, MD, of Dana Farber Cancer Institute.5
Mezigdomide binds cereblon in a manner distinct from traditional immunomodulatory drugs, producing more potent degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos)—two transcription factors essential for myeloma cell growth—enhanced myeloma-cell killing, and immune stimulation. The rationale for combining mezigdomide with a proteasome inhibitor is supported by preclinical synergy and earlier clinical data showing activity in heavily pretreated R/R multiple myeloma, including triple-class-refractory and BCMA-exposed disease.
Methods: The trial enrolled patients with R/R multiple myeloma who had received at least one prior line of therapy and had prior exposure to both lenalidomide and an anti-CD38 monoclonal antibody. The confirmatory analysis population included 479 patients randomized to MeziKd (n = 288) or Kd (n = 191). The population was clinically representative of early relapsed, treatment-exposed R/R multiple myeloma. All patients had prior lenalidomide and anti-CD38 exposure; approximately 92% were triple-class exposed.
Results: At a median follow-up of 10.6 months, MeziKd significantly improved progression-free survival vs Kd, with a median progression-free survival of 18.0 months vs 8.3 months and a hazard ratio (HR) of 0.48. The benefit was consistent and statistically significant across prespecified subgroups, including by number of prior lines, age, anti-CD38 and lenalidomide refractory status, pomalidomide-refractory disease, cytogenetic risk, and presence of extramedullary disease. Progression-free survival 2 (PFS2) also favored MeziKd, with median PFS2 of 23.6 months vs 13.0 months and a HR of 0.53, suggesting that the benefit of MeziKd was not offset by inferior outcomes after subsequent therapy.
Safety: The safety profile was predictable and manageable. Neutropenia was the most common grade 3 and 4 adverse event and was managed with dose modifications and/or growth factor support. Infections were more frequent in patients receiving MeziKd than in those receiving Kd but were generally manageable with standard supportive care.Pneumocystis jiroveci prophylaxis was mandatory. Treatment-emergent hypogammaglobulinemia was relatively uncommon.
Clinical Implications: SUCCESSOR-2 is important because it offers a highly active, non–T-cell-redirection option for patients with lenalidomide- and anti-CD38-exposed or refractory R/R multiple myeloma with utility in settings where immunotherapy access or suitability is limited. MeziKd may be especially attractive when immediate CAR T-cell therapy or bispecific therapy is not feasible, when infection-related risk considerations make bispecific therapy less desirable, or when clinicians aim to preserve T-cell–directed approaches for later lines of treatment. The regimen also has practical appeal: mezigdomide is oral CELMoD administered in a schedule like lenalidomide and pomalidomide, carfilzomib is a well-established proteasome inhibitor widely used in clinical practice, and the weekly carfilzomib dosing schedule facilitates implementation across academic and community oncology settings.
Abstract S100 (MonumenTAL-3):Bispecific Antibody Talquetamab (GPRC5D x CD3) Plus Daratumumab Plus/Minus Pomalidomide vs Daratumumab/Pomalidomide (D/Pd) in Relapsed/Refractory Multiple Myeloma
Background: MonumenTAL-3 was presented by Peter Voorhees, MD, of the Levine Cancer Institute in Charlotte, North Carolina at the 2026 EHA Congress.6 The trial will help define whether the bispecific antibody talquetamab (GPRC5D × CD3) can move effectively into earlier relapse in combination with daratumumab (D), with or without pomalidomide (Pd). Talquetamab targets GPRC5D, an antigen expressed on myeloma cells with limited expression on normal B cells. In the phase I/II MonumenTAL-1 study, talquetamab produced responses in patients with heavily pretreated R/R multiple myeloma, providing the rationale for evaluating GPRC5D-directed therapy in earlier relapse and for investigating whether non–B-cell maturation antigen (BCMA) bispecific combinations can provide a complementary, non-BCMA T-cell–redirecting strategy. The rationale for pairing talquetamab with daratumumab includes daratumumab-mediated immune modulation, including reduction of immunosuppressive regulatory T cells and enhancement of cytotoxic T-cell activity.
Methods: This phase III, open-label, multicenter trial enrolled patients at 182 sites across 18 countries or regions. Eligible patients had R/R multiple myeloma, ECOG performance status 0–2, and at least one prior line of therapy including lenalidomide and a proteasome inhibitor; patients with only one prior line were required to have lenalidomide-refractory disease. Key exclusions included anti-CD38–refractory disease, prior GPRC5D-directed therapy, prior pomalidomide, and T-cell–redirecting therapy within 3 months before randomization. Patients were randomized 1:1:1 to talquetamab plus daratumumab and pomalidomide (Tal-DP; n = 287), talquetamab plus daratumumab (Tal-D; n = 287), or daratumumab/pomalidomide/ dexamethasone (DPd; n = 290). The primary endpoint was independent review committee–assessed progression-free survival.
Results: At the prespecified interim analysis, with median follow-up of 24.6 months, both talquetamab-containing regimens significantly prolonged progression-free survival compared with DPd. The estimated 24-month progression-free survival was 81.3% with Tal-DP, 77.6% with Tal-D, and 51.2% with DPd. The hazard ratio for progression or death was 0.28 for Tal-DP vs DPd (95% CI, 0.20–0.40; P < .001) and 0.33 for Tal-D vs DPd (95% CI, 0.24–0.46; P < .001). Median progression-free survival was not estimable in the talquetamab-containing arms and was 24.4 months with DPd. Talquetamab-based therapy resulted in deeper remissions, reflected by higher rates of complete response and MRD negativity. Complete response or better occurred in 71.1%, 69.0%, and 34.5%, respectively; Very good partial response or better occurred in 85.0%, 82.9%, and 57.6%. MRD-negative complete response at 10−5 by clonoSEQ was achieved in 52.3% with Tal-DP, 46.3% with Tal-D, and 15.9% with DPd. The estimated proportion of responders who remained in response for 24 months was 86.0%, 79.8%, and 59.6%, respectively.
Safety: Serious adverse events occurred in 63.0% with Tal-DP, 52.6% with Tal-D, and 53.7% with DPd. Death was reported in 109 patients who had received at least one dose of the study treatment: 24 patients (8.7%) in the Tal-DP group; 28 (10.2%) in the Tal-D group; and 57 (20.1%) in the DPd group. The deaths were mainly due to adverse events and disease progression. Adverse events during treatment that led to death occurred in 5 patients (1.8%) in the Tal-DP group; 11 (4.0%) in the Tal-D group; and 13 (4.6%) in the DPd group.
The most common grade 3 or 4 adverse event was neutropenia, occurring in 76.4% with Tal-DPd, 29.2% with Tal-D, and 86.2% with DPd, highlighting the contribution of pomalidomide to myelosuppression. CRS occurred in 67.8% with Tal-DPd and 58.4% with Tal-D and was predominantly grade 1 or 2, with median duration of 2 days. ICANS was uncommon, occurring in 2.9% and 1.8%, respectively; all ICANS events resolved. Infections were frequent across all arms: any-grade infections occurred in 87.3%, 84.3%, and 83.0%, and grade 3 or 4 infections in 37.7%, 29.2%, and 42.4%, respectively. Hypogammaglobulinemia occurred in 81.5%, 70.1%, and 62.5%, and IgG replacement was administered in 63.8%, 56.2%, and 36.7%. GPRC5D-associated adverse events were common but generally manageable. Taste changes occurred in 72.8% with Tal-DP and 74.8% with Tal-D; non-rash skin adverse events in 69.2% and 64.6%; nail-related adverse events in 56.2% and 57.3%; and decreased weight in 45.7% and 38.3%. Ataxia or balance disorders occurred in 14.5% and 12.4%, respectively, with grade 3 events in 2.9% and 2.2%; these events led to talquetamab discontinuation in 4.7%(Tal-DP) and 2.2% (Tal-D).
Clinical Implications: MonumenTAL-3 formally establishes GPRC5D-directed bispecific combination therapy as an effective early-relapse strategy and broadens the field beyond BCMA-directed T-cell redirection. Both Tal-DP and Tal-D combinations substantially improved progression-free survival, depth of response, and MRD-negative complete response compared with DPd. The availability of a pomalidomide-free Tal-D arm is clinically important, offering a potent T-cell–redirecting option that may reduce myelosuppression while preserving substantial efficacy. Because Tal-DP appeared numerically to have higher progression-free survival, duration of response, and overall survival but also more hematologic toxicity and severe infections, regimen selection may depend on patient fitness, disease tempo, prior therapies, infection risk, therapy, have prior BCMA exposure, or need for maximal disease control, and tolerance for pomalidomide-related toxicity. For clinical sequencing, MonumenTAL-3 is highly relevant because it provides a non-BCMA antigen-targeted approach that may be used before or after strategy that preserves BCMA-directed therapy.
Discussion: Positioning in the Modern Relapsed/Refractory Multiple Myeloma Landscape
If depth of response, MRD negativity, and durability of remission are considered the primary efficacy endpoints, the available evidence support a therapeutic hierarchy led by the CAR T-cell therapy ciltacabtagene autoleucel (CARTITUDE-4),7 which has demonstrated the deepest and most durable responses, while providing a treatment-free interval. This is followed by teclistamab (MajesTEC-9)1 and talquetamab-based regimens (MonumenTAL-3),6 both of which achieved high rates of complete response and MRD negativity accompanied by substantial improvement in progression-free survival. Notably, MajesTEC-9 also demonstrated a statistically significant overall survival benefit at interim analysis, whereas MonumenTAL-3 reported numerically favorable, although not yet statistically significant, overall survival findings at the interim analysis. MeziKd (SUCCESSOR-2)5 also confer clinical benefit and a robust improvement in progression free survival through a mechanistically distinct CELMoD-based strategy with encouraging efficacy signals in patients with extramedullary disease. Nevertheless, such a ranking should be interpreted with considerable caution, as cross-trial comparisons are inherently limited by variations in study design, eligibility criteria, patient populations, endpoints, and duration of follow-up. Ultimately, treatment selection in clinical practice is determined not only by efficacy but also by patient fitness, disease biology, access to cellular therapy, the urgency of treatment initiation, toxicity profile, and individual preferences regarding continuous or finite-duration treatment strategies.
For full details of the study abstracts, visit asco.org and ehaweb.org.
DISCLOSURE: Dr. Abutalib reported a relationship with AstraZeneca and Geron. Dr. Pianko has received research funding and/or consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb/Celgene, CellCentric, C4 Therapeutics, Johnson & Johnson, Kite/Gilead, GlaxoSmithKline, Nektar, Pfizer, Regeneron, and Sanofi. Dr. Pianko is an investigator on MonumenTAL-3.
REFERENCES
1. Mina R, Touzeau C, Hungria V, et al: MajesTEC-9: A phase III randomized study of teclistamab monotherapy vs investigator’s choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in patients with relapsed refractory multiple myeloma. 2026 ASCO Annual Meeting. Abstract 7507. Presented May 29, 2026.
2. Costa LJ, Bahlis NJ, Perrot A, et al: Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med 394:739-752 2026.
3. Garfall AL, Nooka AK, van de Donk NWCJ, et al: Long-term follow-up from the phase I/II MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol 42:7540, 2024.
4. Moreau P, Garfall AL, van de Donk NWCJ, et al: Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 387:495-505, 2022.
5. Richardson PG, Schjesvold F, Fu C, et al: Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma: Results from the phase III SUCCESSOR-2 trial. 2026 ASCO Annual Meeting. Abstract LBA7506. Presented May 29, 2026.
6. Voorhees P, Mina R, Rodriguez-Otero P, et al: Phase III, randomized study of talquetamab plus daratumumab ± pomalidomide vs daratumumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: MonumenTAL-3. 2026 European Hematology Association Congress. Abstract 2503. Presented June 13, 2026.
7. San-Miguel J, Dhakal B, Yong K, et al: Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med 389:335-347, 2023.
Dr. Abutalib is Director of the Cancer Hematology, Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Pianko is Clinical Associate Professor of Internal Medicine at the University of Michigan, Ann Arbor, and a member of the Multiple Myeloma & Amyloidosis Program at the Rogel Cancer Center of the University of Michigan.
