Multiple Myeloma and Plasma Cell Disorders in 2026: Bispecifics Move Earlier, MRD Guides Duration, and Amyloidosis Finally Has a Target

Introduction: The Bispecific Era Matures

Multiple myeloma treatment has been transformed by bispecific antibodies directed at BCMA or other plasma cell targets, that are now being studied across the disease spectrum from high-risk smoldering myeloma to relapsed/refractory disease and AL amyloidosis. The data presented at ASCO 2026 provide more clarity on where bispecifics fit in the treatment sequence, how long to use them, and whether they can be used as an earlier intervention. Here are a few key abstracts that help define the landscape.

Elranatamab in High-Risk Smoldering Myeloma: The ERASMM Trial

The ERASMM (EMN34) phase 2 study represents a potentially meaningful departure from the standard watch-and-wait approach for high-risk smoldering myeloma (HR SMM). The trial enrolled fifty patients who met the Mayo 2018 "20-2-20" criteria for high-risk SMM: bone marrow plasma cells greater than 20%, M-spike greater than 2g/dL, or involved free light chain ratio greater than 20:1, requiring two or more of these criteria. The median age was 65; 30% of patients were over age 70.

Elranatamab was given for fixed duration for two years with step-up dosing. The results are striking. After six cycles, the overall response rate (ORR) was 90%, with a complete response (CR) rate of approximately 30% that deepened to 72% over time. Among 29 patients evaluable for MRD by next-generation sequencing (NGS), 90% achieved undetectable MRD at a sensitivity of 10^-6, the most stringent measurement available. At a median follow-up of 14 months, PFS was estimated at 96%.

The safety profile of elranatamab in the HR SMM population was consistent with its use in relapsed/refractory myeloma. Cytokine release syndrome (CRS) occurred in 70% of patients, mostly Grade 1-2 and following step-up doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed, a reassuring signal in an otherwise healthy population who has not yet developed active disease. Neutropenia was the most common hematologic toxicity at 44%, most were Grade 3-4.

Clinical implications: The response rates in high-risk SMM with this bispecific approach are approaching levels seen in treating active myeloma: 92% ORR and 72% CR with fixed-duration of therapy for 2 years. This raises the question of whether waiting for SMM to become active versus starting earlier treatment for high-risk patients is a better strategy. A preferred approach at this point is to enroll HR SMM patients on clinical trials where available, given that elranatamab is not yet FDA-approved in this setting. For patients who are not trial-eligible, shared decision-making with available agents (lenalidomide, daratumumab) remains appropriate, while acknowledging that the bispecific data suggest the possibility of deeper and more durable responses and may be an option in the future.

FORTE Trial: Sustained MRD Negativity Predicts Outcomes

The FORTE trial randomized transplant-eligible (TE) newly diagnosed myeloma (NDMM) patients to various induction and maintenance strategies with or without autologous stem cell transplant (ASCT), with serial MRD assessment every six months for up to five years. The key analysis presented at ASCO 2026 examined how sustained MRD negativity, defined as remaining MRD-negative (10^-5) for one, two, three, four, or five years without intercurrent MRD-positive results, predicted progression-free (PFS) and overall survival (OS).

The findings provide greater clarity on an important clinical question about how long MRD-directed treatment decisions should be followed. Best MRD negativity rates increased from 65% pre-maintenance to 79-80% after three or more years. Among patients who sustained MRD negativity for three, four, or five years, 7-year PFS rates were as high as 85 and 91% confirmed in the 3- and 5-year landmark analyses.

The practical takeaway: MRD negativity over shorter timeframes is meaningful, but better prognostic signals are associated with longer sustained MRD negativity for at least three to five years. This supports longer maintenance even in MRD negative patients rather than therapy cessation after only 1-2 years. And as shown in this analysis, the sweet spot for predicting durable remission appears to be approximately three to five years of sustained MRD negativity.

Teclistamab in Second-Line Myeloma: MajesTEC-9

Teclistamab, a BCMA-directed bispecific antibody, was initially approved in the fifth-line setting for relapsed/refractory myeloma (RRMM). MajesTEC-9 is a phase 3 randomized trial that investigated use of teclistamab in as early as second-line therapy, enrolling patients with one to three prior lines who had received an anti-CD38 monoclonal antibody (mAb), with no prior BCMA-directed therapy exposure. Patients were randomized to receive either teclistamab monotherapy versus investigator's choice of standard of care (SOC).

The results favor teclistamab substantially. Overall response rate (ORR) was over 84% with teclistamab versus 54% with SOC. Complete response (CR) rates were 66% versus approximately 17%. Similarly, MRD negativity (10^-5) rates were dramatically higher with teclistamab compared to SOC. The higher and deeper responses with teclistamab were also associated with improved PFS and OS curves favoring the bispecific.

The safety profile was consistent with the known experience in later-line disease: CRS was manageable and all events resolved; ICANS occurred in approximately 4%; hypogammaglobulinemia was common at 69%, reinforcing the importance of IVIG supplementation for patients receiving BCMA-directed bispecifics.

The median age was 70, with about 30% of patients age 75 or older. Approximately 35% had high-risk cytogenetics and nearly 80% of patient enrolled patients had receive 2 or 3 prior lines of therapy, underscoring the potential benefit and safety of moving teclistamab to earlier lines of therapy.

Clinical implications: For patients with myeloma relapsing after one to three prior lines who are not CAR-T candidates or who need a response quickly, teclistamab as monotherapy is a compelling second-line option. The CAR-T versus bispecific sequencing question remains critical: if CAR-T is a future consideration, preserving T-cell fitness by avoiding prior BCMA-directed bispecific therapy is a meaningful consideration.

Etentamig in BCMA-Exposed Patients: The Sequencing Question

The MONVISO phase 1b study examined etentamig, another BCMA-directed bispecific with a distinct structural design, in patients with relapsed/refractory myeloma (RRMM) who had prior BCMA-directed therapy exposure. This is the critical question for the field: once a patient has received one BCMA bispecific or BCMA-directed CAR-T, can they still benefit from another BCMA-targeted agent?

Arm B enrolled patients who had received at least 2 prior LOT that included treatment with BCMA-directed therapy (CAR-T or bispecific). ORR was 48% overall and was 64% in patients whose last prior therapy was BCMA CAR-T, a meaningful result that suggests etentamig is a viable option even for patients who have progressed after BCMA CAR-T. 

Arm C results enrolled 60 patients with or without prior BCMA therapy and suggests that etentamig may be safely administered in the outpatient setting.  For Arm C, median age was 76. Median prior LOT was three. CRS was lower than what has been observed with other bispecifics and estimated at 27% (without prophylactic tocilizumab). When prophylactic tocilizumab was used, no CRS events were observed, a strategy worth considering for frail or older patients receiving BCMA bispecifics in the outpatient setting.

The sequencing insight: CAR-T first, bispecific second is the preferred sequence when both options are available. Prior BCMA bispecific therapy before CAR-T tends to reduce CAR-T efficacy by approximately twenty to thirty percent, while bispecific antibodies given after CAR-T appear to retain meaningful activity. For patients who relapse quickly after CAR-T (under six to nine months), the likelihood of response to a subsequent BCMA-directed agent is lower, and spacing these therapies out is preferred when clinically feasible.

Linvoseltamab in AL Amyloidosis: The LINKER-AL2 Trial

Light-chain (AL) amyloidosis has historically been an underserved disease with limited systemic options beyond daratumumab-based regimens. The LINKER-AL2 phase 1/2 trial examines linvoseltamab, another BCMA-directed bispecific, in 20 patients with relapsed/refractory systemic AL amyloidosis, including cardiac involvement in 45% and renal involvement in 40%. 60% of enrolled patients had received prior daratumumab.

Phase 1 results: CRS occurred in 50% of patients but was all Grade 1-2 (no Grade 3-4 events). Infections were common at 85%, with neutropenia the most frequent hematologic toxicity. The efficacy data are promising: the complete hematologic response (CR) rate was 100% at the higher dose of Linvo 240 mg and 71% at Linvo 80 mg. The median time to response was approximately 1.5 months. Organ responses followed: 73% renal response and 50% cardiac response. Normalization of involved free light chain levels occurred by day 15 at both dose levels.

Why this matters for amyloidosis: In AL amyloidosis, even mildly elevated free light chains cause ongoing organ damage; cardiac and renal toxicity accumulate with each increment of light chain burden. The ability to achieve complete hematologic responses rapidly, including in prior daratumumab-exposed patients, is clinically important. This early data demonstrates the significant potential value of bispecifics for RR AL amyloidosis and supports investigations of using bispecifics in the newly diagnosed context as well.

For Patients

If you have been diagnosed with multiple myeloma or a related plasma cell disorder, the treatment landscape in 2026 is rapidly evolving. A new class of drugs called bispecific antibodies, which recruit your own immune system to attack myeloma cells, are now being studied from the earliest high-risk stages of smoldering disease through relapsed and refractory myeloma. If you have high-risk smoldering myeloma, ask about clinical trial opportunities to understand the different options. If you have active myeloma that has relapsed after prior treatment, ask whether a bispecific antibody is appropriate and where CAR-T cell therapy fits in your treatment plan. For patients with AL amyloidosis, new options are emerging that can produce deep responses even after prior treatments.

Key Takeaways

• ERASMM (EMN34): Elranatamab in high-risk smoldering myeloma produces 90% ORR, 72% CR, 90% undetectable MRD at 10⁻⁶, 96% PFS at 14 months median follow-up; fixed 2-year duration; ICANS 0%; CAR-T preserved for future use.

• FORTE: Sustained MRD negativity for 3 to 5 years (not shorter) is the key prognostic threshold; 5-year sustained MRD negativity predicts 91% 7-year PFS; supports longer maintenance in MRD-negative patients.

• MajesTEC-9: Teclistamab monotherapy in 1–3 prior line myeloma (no prior BCMA): 85% ORR vs 54% SOC; 66% CR vs 17%; safety profile consistent with known teclistamab experience; IVIG supplementation essential.

• MONVISO: Etentamig achieves 64% ORR in patients whose last prior therapy was BCMA CAR-T; outpatient administration feasible; prophylactic tocilizumab eliminates CRS.

• LINKER-AL2: Linvoseltamab in R/R AL amyloidosis: 100% hematologic response at high dose (all CRs); 73% renal response, 50% cardiac response; light chain normalization by day 15; active in prior daratumumab-exposed patients.

• CAR-T first, bispecific second is the preferred sequence; prior BCMA bispecific reduces CAR-T efficacy by ~20–30%; bispecific after CAR-T retains meaningful activity.

References

1. Touzeau C, et al. Safety and efficacy of elranatamab in high-risk smoldering myeloma: ERASMM (EMN34). ASCO 2026. Abstract C4-24.

2. Gay F, et al. FORTE trial: impact of sustained MRD negativity on PFS and OS. ASCO 2026. Abstract C2-3.

3. Moreau P, et al. MajesTEC-9: teclistamab vs standard of care in 1–3 prior line myeloma. ASCO 2026. Abstract LBA7001.

4. Chhabra S, et al. Etentamab in RRMM with prior BCMA-targeted therapy. MONVISO. ASCO 2026.

5. Wechalekar A, et al. LINKER-AL2: linvoseltamab in relapsed/refractory systemic AL amyloidosis. ASCO 2026.

6. Foster L. "Best of 2026 ASCO Annual Meeting: Multiple Myeloma / Plasma Cell Disorders." Presented at the 2026 Best of Oncology, Seattle, WA, June 2026.