Introduction

Multiple myeloma had another eventful year at the 2026 ASCO Annual Meeting, with notable data across nearly every stage of disease: earlier use of bispecific antibodies in relapsed disease, a new class of oral drugs for heavily pretreated patients, an early but striking in vivo CAR-T approach, and a genuine step toward treating smoldering myeloma before it becomes symptomatic. Four studies in particular are worth a closer look.

MajesTEC-9: Teclistamab Moves Earlier in Relapsed Myeloma

MajesTEC-9 tested teclistamab monotherapy against investigator's choice (pomalidomide-bortezomib-dexamethasone or carfilzomib-dexamethasone) in patients with relapsed/refractory myeloma with 1 to 3 prior lines of therapy. Teclistamab significantly improved progression-free survival, reducing risk of progression or death by 71% overall (HR, 0.29; 18-month PFS 69.8% versus 26.9% with investigator's choice). Overall survival was also improved (HR, 0.60, 95% CI, 0.43–0.83; P=.002; 18-month OS 79.2% versus 68.6%). Safety was consistent with the known profile of teclistamab monotherapy, with CRS mostly low-grade and resolving without need for discontinuation in the large majority of cases, and ICANS infrequent.

Combined with prior data from MajesTEC-3 and CARTITUDE-4, this reinforces that anti-BCMA T-cell redirecting therapy, whether bispecific antibody or CAR-T, is well-supported as early as second-line treatment in relapsed myeloma. This is a meaningful shift from historical sequencing where these therapies were reserved for later lines.

SUCCESSOR-2: Mezigdomide, a forthcoming CELMoD

CELMoDs (cereblon E3 ligase modulators) are a newer class of targeted agents, which can be described as a "next generation" of the immunomodulatory drugs (IMiDs) that came before them. Compared to IMiDs like thalidomide, lenalidomide, and pomalidomide, CELMoDs like mezigdomide and iberdomide offer greater cereblon binding, deeper substrate degradation, and an improved toxicity profile. SUCCESSOR-2 tested mezigdomide plus carfilzomib-dexamethasone (MeziKD) against carfilzomib-dexamethasone (KD) alone in 479 patients with relapsed/refractory myeloma (288 MeziKD, 191 KD), a heavily pretreated population: 92.1% triple-class exposed, 85.8% anti-CD38 refractory, 75.8% lenalidomide-refractory, and median 2 (range 1–9) prior lines of therapy.

MeziKD significantly reduced the hazard of progression or death by 52% (HR, 0.48; 95% CI, 0.36–0.63; P<.0001), with median PFS of 18.0 months versus 8.3 months with KD alone, at a median follow-up of 10.6 months.

Mezigdomide (via the SUCCESSOR-1 and SUCCESSOR-2 trials) and its sibling CELMoD iberdomide (via the EXCALIBUR trial) together offer a convenient, highly effective, and well-tolerated oral drug option for relapsed/refractory myeloma that is particularly attractive for community practitioners without easy access to cellular therapy or complex bispecific step-up dosing schedules.

InMMyCAR: Another Look at In Vivo CAR-T therapy

Every CAR-T product currently available requires ex vivo manufacturing: cells are collected from the patient, engineered outside the body, and reinfused, a process that takes weeks and requires lymphodepleting chemotherapy beforehand. The InMMyCAR trial tested a fundamentally different approach: KLN-1010 is a lentiviral composite infused directly into the patient, causing their own T cells to express an anti-BCMA construct in vivo, without ex vivo bioengineering and notably without a lymphodepletion requirement.

In this update of the phase 1 study, the objective response rate was 100% across 18 evaluable patients, with 67% achieving a complete response or better among patients with at least 4 months of follow-up. MRD-negative bone marrow responses were seen in 100% of evaluable patients. Adverse events were manageable, consistent with what's expected from T-cell engaging therapy and seemingly improved rates of CRS and ICANS/neurotoxicity, without the additional toxicity of lymphodepleting chemotherapy on top.

This is exceptionally early, small-numbers data, but if in vivo CAR-T generation can be validated at scale, it could be genuinely transformative not just for myeloma but across oncology by removing the manufacturing bottleneck and lymphodepletion toxicity that currently limit CAR-T access.

ERASMM: Treating High-Risk Smoldering Myeloma

Smoldering multiple myeloma sits in a gray zone: it is by definition not yet symptomatic myeloma requiring treatment, but high-risk smoldering disease carries a substantial risk of reaching that symptomatic milestone. And hence, there’s been tremendous interest in early intervention with numerous trials exploring early plasma-cell directed therapy, perhaps most notably the AQUILA trial using daratumumab. The ERASMM (EMN34) is a phase 2 study of elranatamab, a BCMA-directed bispecific antibody, given as monotherapy in high-risk smoldering myeloma, defined by having at least two 20-2-20 criteria including serum M-protein ≥2 g/dL, bone marrow plasma cells ≥20%, and/or a free light chain ratio ≥ 20.

Fifty previously untreated high-risk smoldering myeloma patients were enrolled in ERASMM (EMN34) with median age 65, baseline disease characteristics included an M-protein level ≥2 g/dL in 84% of patients, bone marrow plasma cell infiltration ≥20% in 72%, and a free light chain ratio ≥20 in 66%. After 6 cycles, the objective response rate was 90%, with a complete response rate of 30%; at a median follow-up of 14 months, ORR reached 92% with a complete response rate of 72%, and undetectable MRD (10⁻⁶) in 90% of the 29 patients with evaluable samples. Safety data was notable for a 10% treatment discontinuation rate due to adverse events (including Guillain-Barré syndrome in one patient, who recovered and remained in stringent complete response), with no new safety signals compared to elranatamab's known profile in relapsed/refractory myeloma; CRS occurred in 70% of patients (mostly grade 1/2, 4% grade 3), and infections in 54% (14% grade 3, with grade 4/5 events reported in a small number).

These are striking response and MRD rates for smoldering disease, but the field remains genuinely divided on whether and how to treat high-risk smoldering myeloma at all as this is an asymptomatic cancer. This trial does not settle that debate but it does, however, demonstrate that elranatamab can produce deep, durable responses in this earlier disease state and is worth watching as longer follow-up accrues.

For Patients

For people with relapsed multiple myeloma, teclistamab (a bispecific antibody) showed a substantial survival benefit over standard combination chemotherapy when used earlier, after just one to three prior treatments, rather than being reserved for later in the disease course.

For people with more heavily pretreated relapsed myeloma, a new type of oral drug called mezigdomide, when added to standard therapy, meaningfully delayed disease progression and may be a particularly convenient option for patients who don't have easy access to specialized cellular therapy centers.

For people with heavily treated relapsed/refractory multiple myeloma, an early clinical trial of a new way to make CAR-T cells directly inside the body, rather than removing and re-engineering cells outside the body, showed 100% of patients responding to treatment. This is very early research but could eventually make CAR-T therapy faster and more widely available if it continues to show promise.

For people with high-risk smoldering multiple myeloma (an early, not-yet-symptomatic stage of the disease), treatment with the bispecific antibody elranatamab produced deep and durable responses in a clinical trial. Whether treating smoldering myeloma before it becomes symptomatic actually improves long-term outcomes remains a genuinely debated question in the field, so this is a decision to make carefully with your care team.

Key Takeaways

  • MajesTEC-9 showed teclistamab monotherapy reduced risk of progression or death by 71% versus investigator's choice in relapsed myeloma after 1-3 prior lines, supporting anti-BCMA T-cell redirecting therapy as early as second-line treatment.

  • SUCCESSOR-2 showed mezigdomide plus carfilzomib-dexamethasone reduced risk of progression or death by 52% versus carfilzomib-dexamethasone alone in heavily pretreated relapsed myeloma.

  • InMMyCAR, an early phase 1 trial of in vivo CAR-T (KLN-1010) requiring no ex vivo manufacturing or lymphodepletion, showed a 100% objective response rate, though in a very small number of patients.

  • ERASMM showed elranatamab monotherapy achieved a 92% objective response rate and 90% undetectable MRD in high-risk smoldering myeloma, though whether to treat smoldering disease at all remains unresolved.

References

  1. Touzeau C, et al. Teclistamab in multiple myeloma with one to three prior lines of therapy: MajesTEC-9. Presented by Mina R at: 2026 ASCO Annual Meeting; simultaneously published in the New England Journal of Medicine.

  2. Richardson P, et al. SUCCESSOR-2: mezigdomide plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in relapsed/refractory multiple myeloma. Presented at: 2026 ASCO Annual Meeting.

  3. Ho PJ, et al. InMMyCAR: a phase 1 study of KLN-1010, an in vivo CAR-T therapy, in multiple myeloma. Presented at: 2026 ASCO Annual Meeting.

  4. Touzeau C, et al. ERASMM (EMN34): a phase 2 study of elranatamab in high-risk smoldering multiple myeloma. Presented at: 2026 ASCO Annual Meeting.