What’s Changing in Multiple Myeloma? Key Clinical Takeaways from ASCO and EHA 2026

At this year’s American Society of Clinical Oncology (ASCO) Annual Meeting and European Hematology Association (EHA) Congress, new data on multiple myeloma highlighted several important themes, including the ongoing evolution of myeloma care toward earlier intervention, deeper and more durable responses, increasingly individualized treatment sequencing, and broader implementation of novel immune-based therapies.

For myeloma experts and community oncologists, these are the top takeaways:

• Immunotherapy use expanding into high-risk smoldering myeloma: Early data with BCMA-directed bispecific antibodies suggest that highly active immune-based therapies may induce deep responses and potentially delay progression.
• Enhanced outcomes at first relapse: Teclistamab and cereblon E3 ligase modulatory drugs (CELMoDs) are moving into earlier relapse settings, challenging traditional treatment sequencing paradigms and potentially redefining standards at first relapse.
• Fixed-duration therapy: For both newly diagnosed and relapsed/refractory myeloma, emerging data support the feasibility of response-adapted and finite treatment approaches to minimize toxicities and maximize quality of life.
• Post-BCMA treatment strategies: Studies explored treatment sequencing and retreatment approaches following BCMA-directed therapy.
• Beyond BCMA: Emerging therapies targeting GPRC5D and FcRH5 may expand treatment options for patients who relapse after BCMA-directed therapy.
• Expanding bispecific antibody therapy administration: Studies demonstrated new approaches to reducing cytokine release syndrome (CRS), optimizing supportive care, and addressing barriers—potentially facilitating broader bispecific antibody use in practice.

Read more below.

New data on treatment for high-risk smoldering myeloma

High-risk smoldering myeloma has emerged as an important setting for evaluating early treatment. A recent study investigated whether immune-based therapies can induce deep responses and prolong progression-free survival (PFS) before the onset of symptomatic disease.

ERASMM examined a fixed two-year course of single-agent elranatamab (elra), a BCMA×CD3 bispecific antibody, in adult high-risk smoldering myeloma patients. This strategy leveraged a less-exhausted immune system earlier in the disease course to achieve deep remissions (overall response rate [ORR] of 92 percent) and nine-month PFS of 95 percent.

These preliminary findings suggest that elra monotherapy may represent an important step toward time-limited treatment in the precursor phase of myeloma, with deep responses, manageable toxicity, and no early signal of excess mortality. Although follow-up remains limited, the study provides early proof of concept for fixed-duration bispecific antibody therapy in high-risk smoldering myeloma.

Longer follow-up will be necessary to determine whether these deep responses translate into durable delays in progression.

Resources for patients: The MMRF’s Myeloma Matters podcast on smoldering myeloma and information sheet on precursor conditions can help patients better understand high-risk smoldering myeloma and help clinicians navigate conversations about monitoring and potential treatment options.

Novel therapies challenge traditional sequencing in early relapsed patients

The treatment landscape for myeloma patients at first relapse is rapidly evolving. New data suggest that highly active immune-based therapies and next-generation cereblon-targeting agents are moving earlier in the treatment continuum and may reshape traditional sequencing strategies.

Results of the landmark phase 3 MajesTEC-9 trial showed that teclistamab monotherapy significantly outperformed investigator’s choice standard regimens—pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd)—in patients with relapsed/refractory myeloma after one to three prior lines of therapy.

The study included patients refractory to both lenalidomide and anti-CD38 therapies. Teclistamab significantly improved survival outcomes and produced markedly higher complete response (CR) rates than standard therapy (median PFS not reached vs 8.2 months; ≥CR 65.9 percent vs 16.8 percent), albeit with increased infection risk (65.9 percent vs 16.8 percent).

These findings demonstrate that single-agent teclistamab remains highly effective in patients with both lenalidomide- and anti-CD38-refractory disease, a population that is increasing with the widespread adoption of daratumumab-based frontline regimens. These data raise further questions about optimal sequencing of bispecific antibodies, CAR-T therapy, and other BCMA-directed approaches.

The phase 3 SUCCESSOR-2 trial addressed another increasingly common clinical challenge: patients whose disease progresses despite prior exposure to both lenalidomide and anti-CD38 therapy.

In this patient population, adding the potent CELMoD mezigdomide (mezi) to carfilzomib–dexamethasone (Kd) significantly improved outcomes compared with Kd alone. Clinically meaningful improvements were observed in PFS (18.0 vs 8.3 months) and ORR (80.2 percent vs 53.4 percent). Benefits were consistent across high-risk subgroups, including older patients, those with high-risk cytogenetics, and patients with extramedullary disease. Mezi-Kd nearly doubled PFS compared with a standard proteasome inhibitor–based regimen, supporting its potential role as a second-line option for lenalidomide-refractory disease.

These findings reinforce the potential of next-generation cereblon modulators to overcome resistance to earlier immunomodulatory drug–based therapy while offering the practical advantages of an oral treatment approach.

These studies suggest that BCMA-directed bispecific antibodies and CELMoDs are moving earlier in the treatment continuum, expanding options for patients with early RRMM and prompting new questions about optimal sequencing.

Resource for HCPs: This MMRF Myeloma Matters podcast offers practical perspectives on the evolving use of bispecific antibodies in clinical practice.

Resource for patients: The MMRF’s information sheet on bispecific antibody therapy explains what this treatment is and how it works.

Rethinking myeloma treatment duration

As myeloma treatment outcomes improve, investigators are increasingly exploring whether therapy duration can be individualized based on depth of response instead of continued indefinitely.

Recent studies explored two emerging strategies: fixed-duration approaches intended to reduce the cumulative toxicities of novel therapies and response-adapted approaches that use sustained deep responses, including minimal residual disease (MRD) negativity, to inform treatment discontinuation.

In the frontline setting, the IDEAL trial evaluated fixed-duration CELMoD-based treatment using iberdomide, daratumumab, bortezomib, and dexamethasone (iber-DVd) followed by iberdomide maintenance. The regimen induced deep responses over time (100 percent ORR and 48 percent MRD negativity), with 88 percent of patients achieving 18-month PFS.

Although follow-up remains relatively short, these findings provide early evidence that fixed-duration response-intensive approaches may be feasible in newly diagnosed myeloma while establishing proof of concept for CELMoD-based frontline therapy.

Complementing these frontline findings, the results of a single-institution retrospective cohort study analysis of patients with relapsed/refractory myeloma who discontinued teclistamab or talquetamab after achieving deep responses suggest that some patients may be able to maintain durable disease control without ongoing bispecific antibody therapy.

However, patients who discontinued treatment generally had more favorable baseline disease characteristics, limiting conclusions regarding the impact of treatment cessation itself. Despite these limitations, the study provides an important early signal that fixed- or finite-duration bispecific antibody therapy may be feasible in carefully selected patients and supports prospective evaluation of response-guided treatment-discontinuation strategies.

Rethinking post-BCMA relapse: sequencing, target switching, and emerging immune strategies

As the use of BCMA-directed therapies expands earlier in the treatment course, optimizing outcomes after BCMA exposure has become a key clinical challenge in relapsed/refractory myeloma. Emerging data highlight ongoing activity of novel agents in the post-BCMA setting while also raising important questions regarding sequencing, immune fitness, and target selection.

A phase 1b analysis of etentamig, a next-generation BCMA-targeted bispecific antibody, demonstrated clinically meaningful activity in heavily pretreated BCMA-exposed relapsed/refractory myeloma, including patients previously treated with CAR T or antibody-drug conjugates (ORR 47 percent; median duration of response ~13 months), with a manageable safety profile despite the absence of step-up dosing. Notably, outcomes were strongest in patients with prior CAR T exposure and recent BCMA therapy. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 57 percent and seven percent of patients, respectively, suggesting an improved immune-related adverse event profile.

These data challenge the idea of universal BCMA resistance after prior exposure. The higher ORR and longer PFS in prior CAR T patients suggest that etentamig may be a plausible post–CAR T relapse option, a setting in which treatment choices are often limited and outcomes poor.

Real-world evidence from a retrospective study suggests that treatment sequence—not just agent selection—materially influences outcomes in relapsed/refractory myeloma.

Patients who received CAR T-cell therapy before a bispecific antibody (teclistamab, talquetamab, or elranatamab) had longer overall survival than did those who received a bispecific antibody first (5-year survival 57.1 percent vs 25.5 percent; median overall survival not reached vs 3.6 years). These findings were consistent regardless of whether the bispecific antibody targeted BCMA or GPRC5D.

The safety profile differed by sequence: CAR T first was associated with higher ICANS after first therapy (22 percent vs 10.7 percent); bispecific antibody first was associated with higher ICU admissions and more CRS after second therapy, but infection, sepsis, and one-year mortality were similar.

These findings imply that earlier CAR T use may confer a survival advantage, supporting a shift toward using CAR T before bispecific antibodies when feasible. However, differences in baseline patient characteristics and treatment selection between the cohorts may have contributed to the observed outcomes. These findings highlight the potential importance of treatment sequencing and suggest that the order in which CAR T-cell therapies and bispecific antibodies are used may influence both efficacy and safety outcomes. Randomized studies will be needed to confirm these observations and define optimal sequencing strategies.

Resources for patients: The MMRF’s information sheets on bispecific antibody and CAR T therapies can help patients understand how these treatments work and how they are used.

Expanding options beyond BCMA

As BCMA-directed therapies become more widely used, alternative targets are emerging for patients who relapse after treatment with a BCMA-targeting agent. In patients with relapsed/refractory myeloma treated after one to three prior lines of therapy, the GPRC5D-directed CAR T-cell therapy arlocabtagene autoleucel (arlo-cel) demonstrated high efficacy, with an ORR of 96 percent, CR rate of 67 percent, and 12-month PFS of 74 percent. Responses were durable, and severe CRS or ICANS were not observed, though GPRC5D-related nail, skin, and oral toxicities were common.

In a separate pooled analysis, the FcRH5-targeting bispecific antibody cevostamab demonstrated meaningful activity in heavily pretreated patients previously exposed to BCMA-directed CAR T, achieving an ORR of 43.9 percent and a median duration of response of 17.4 months despite high-risk disease characteristics. These findings demonstrate that effective immune redirection remains possible beyond BCMA and support the growing role of alternative targets such as GPRC5D and FcRH5 in the management of post-BCMA relapse.

Expanding bispecific antibody therapy

As bispecific antibodies become increasingly integrated into the treatment of relapsed/refractory myeloma, attention is shifting toward strategies that can improve safety, reduce treatment complexity, and enable broader use beyond specialized centers. New data highlight emerging approaches to mitigating toxicity and addressing implementation challenges in community oncology settings.

Key findings included:

• Reducing CRS: In the phase 2 Optec/Optal study, prophylactic tocilizumab administered before step-up dosing of teclistamab or talquetamab substantially reduced CRS rates compared with historical experience, with all observed CRS events limited to grade 1. These findings suggest that proactive CRS prevention may help simplify bispecific antibody initiation and improve treatment feasibility.
• Preventing infections: A large retrospective analysis found that early intravenous immunoglobulin (IVIG) use within four weeks of talquetamab initiation was associated with lower infection rates and reduced one-year mortality compared with no early IVIG use. Although prospective validation is needed, the results highlight the potential importance of early supportive care strategies in patients receiving T-cell–redirecting therapies.
• Expanding access in community settings: An interrupted time series analysis from Florida demonstrated that peer-led operational discussions focused on bispecific antibody implementation were associated with increased utilization and expansion of treatment sites, particularly in community oncology practices. These findings suggest that targeted educational and workflow-focused initiatives may help reduce barriers to adoption outside academic centers.

These findings emphasize that expanding bispecific antibody use will require corresponding toxicity management and supportive care. Improvements in toxicity management, supportive care, and operational readiness may help make these highly active therapies more accessible across diverse treatment settings. As bispecific antibody use continues to grow, practical implementation strategies will be increasingly important.

Resource for HCPs: This MMRF Myeloma Matters podcast highlights practical considerations using bispecific antibodies in clinical practice.

Resource for patients: The MMRF offers an information sheet on bispecific antibody therapy that explains how these treatments work and what patients can expect during treatment, including common side effects and safety monitoring.

Jointly provided by the MMRF and RedMedEd.

This content is supported by sponsorships from Legend Biotech USA Inc. and Pfizer Inc., as well as an educational grant from Johnson & Johnson.