IMS Day 1 Recap: Bispecific and CAR T Data Shape Myeloma Treatment

The combination of the CELMoD mezigdomide with the BCMA/CD3 bispecific antibody elranatamab (Elrexfio) produced responses in all 13 evaluable patients with relapsed/refractory multiple myeloma (R/R MM) in part 1 of the phase 1/2 MELT-MM study (NCT06645678), according to data presented at the 23rd International Myeloma Society (IMS) Annual Meeting.¹ The findings were among several T-cell–redirecting updates presented on day 1 of the meeting.

Also presented were extended follow-up data for the FcRH5/CD3 bispecific antibody cevostamab plus pomalidomide (Pomalyst) and dexamethasone, a matching-adjusted indirect comparison (MAIC) of 2 B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies, and updated results for linvoseltamab (Lynozyfic) in high-risk smoldering multiple myeloma (HR-SMM).^2-4

MELT-MM: Mezigdomide Plus Elranatamab in R/R MM

MELT-MM is an ongoing, open-label, multinational phase 1/2 study evaluating mezigdomide (CC-92480) with elranatamab (Elrexfio).¹ Mezigdomide is a novel CELMoD that rapidly degrades Ikaros and Aiolos. Preclinical data presented with the study showed that high tumor burden limits elranatamab's cytotoxicity, and that mezigdomide rescues this by augmenting T-cell effector function and attenuating PD-1 and TIGIT upregulation.

After an elranatamab lead-in (cycle 0), patients received elranatamab weekly in cycles 1 through 6, biweekly in cycles 7 through 12 for those with a partial response or better, and monthly in cycles 13 through 24 for those with a complete response (CR) or better. Mezigdomide was given on days 1 through 21 of each 28-day cycle at 0.3 mg or 0.6 mg. Eligible patients were anti-BCMA–naive and had received at least 2 prior lines of therapy, including a proteasome inhibitor and lenalidomide (Revlimid).

As of the April 2026 data cutoff, at a median follow-up of 10 months, 13 of 15 enrolled patients were evaluable. Seven received the 0.3-mg dose and 6 received the 0.6-mg dose. The median age was 69 years (range, 51–76), and patients had received a median of 4 prior lines (range, 2–7). Overall, 53.8% had prior anti-CD38 antibody exposure, 30.8% had prior non-BCMA bispecific antibody exposure, and 30.8% had extramedullary disease.

The overall response rate (ORR) was 100% (13/13), and 92.3% (12/13) of patients achieved a CR or better. Responses were consistent across mezigdomide dose levels and prior treatment exposure. Among 8 patients with a stringent CR and available minimal residual disease (MRD) data, 87.5% (7/8) were MRD negative. The median time to first response was 17 days (range, 14-45), and the median progression-free survival (PFS) was not reached.

Cytokine release syndrome (CRS) occurred in 76.9% of patients, all grade 1 or 2, and no immune effector cell–associated neurotoxicity syndrome (ICANS) was observed. There were no febrile neutropenia events. Fatigue was the most common nonhematologic adverse event (AE), at 84.6% any grade and 7.7% grade 3 or 4. Infections of any grade occurred in 46.2% of patients, including cytomegalovirus disease in 2 patients. Two reversible dose-limiting toxicities occurred in the 0.6-mg cohort: grade 4 thrombocytopenia and grade 3 acute kidney injury.

Both doses were selected as recommended phase 2 doses. Part 2 will randomly assign patients 1:1 to 0.3 mg or 0.6 mg of mezigdomide, stratified by IMWG frailty score.

MAIC: Anito-Cel vs Cilta-Cel in 4L+ R/R MM

An unanchored MAIC found no statistically significant differences in efficacy between anitocabtagene autoleucel (anito-cel; formerly CART-ddBCMA) and ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with R/R MM after at least 3 prior lines of therapy. The analysis did find significantly lower rates of several toxicities with anito-cel.²

The analysis compared individual patient data from the phase 2 iMMagine-1 trial (NCT05396885; n = 117; median follow-up, 15.9 months) with published aggregate data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207; n = 97; median follow-up, 18 months). Efficacy was adjusted for extramedullary disease, cytogenetic risk, refractory status, R-ISS stage, and bone marrow plasma cell percentage. Safety was adjusted for ECOG performance status, bone marrow plasma cell percentage, age, and sex. Effective sample sizes were 103 (88%) for efficacy and 106 (91%) for safety.

After adjustment, the ORR was 96% with anito-cel vs 98% with cilta-cel (OR, 0.34; 95% CI, 0.06–1.89), and the CR or better rate was 74% vs 80% (OR, 0.66; 95% CI, 0.34–1.30).

Anito-cel was associated with significantly lower rates of the following:

• any-grade CRS: 85% vs 95% (OR, 0.33; 95% CI, 0.11–0.94)
• any-grade ICANS: 8% vs 23% (OR, 0.28; 95% CI, 0.12–0.67)
• grade 3 or 4 infections: 9% vs 23% (OR, 0.28; 95% CI, 0.12–0.66)
• nonrelapse mortality: 3% vs 11% (OR, 0.20; 95% CI, 0.06–0.68)

No non-ICANS neurotoxicity events were observed in iMMagine-1, compared with 12 in CARTITUDE-1, including 5 cases of parkinsonism. Rates of grade 3 or higher CRS and ICANS were comparable, with 1 event each in iMMagine-1 vs 5 and 3, respectively, in CARTITUDE-1. Any-grade infection rates were also comparable, and results were consistent across sensitivity analyses.

“In this matched, adjusted, indirect comparison using variables that were identified from an expert panel, anito-cel had a superior safety profile in terms of all-grade CRS, all-grade ICANS, nonrelapse mortality, and severe infections. Very importantly, there were no cases of non-ICANS neurotoxicity seen with anito-cel,” said Surbhi Sidana, MD, associate professor of medicine at Stanford University, during a presentation of the poster.

Because the comparison is unanchored and relies on aggregate data from the comparator trial, it can adjust only for reported baseline factors. Anito-cel remains investigational. Its biologics license application for fourth-line R/R MM carries a Prescription Drug User Fee Act target action date of December 23, 2026.⁵

LINKER-SMM1: Linvoseltamab in High-Risk Smoldering Myeloma

Updated results from the phase 2 LINKER-SMM1 study (NCT05955508) showed that linvoseltamab monotherapy maintained a 100% ORR with deepening responses and no progression to active MM in patients with HR-SMM.³ Linvoseltamab is approved in the US for patients with R/R MM after at least 4 prior lines of therapy.

High-risk features were defined by the Mayo 2018 "20-2-20" or PETHEMA criteria. After 3 weeks of step-up dosing, patients received linvoseltamab 200 mg weekly in cycle 1, every 2 weeks in cycles 2 through 5, and every 4 weeks in cycles 6 through 24. The primary end points were safety in part 1, the safety run-in, and CR rate and MRD negativity at 12 and 24 months in part 2, the expansion.

As of December 24, 2025, 36 patients were enrolled. The median age was 61 years (range, 39–84), and 94% had an ECOG performance status of 0. The median follow-up was 8.6 months (range, 0-20).

Among 32 patients who completed at least 1 cycle, the ORR was 100%, including a VGPR or better rate of 97% and a CR or better rate of 69%. All responses were ongoing at the data cutoff. Among patients with a VGPR or better who were evaluable for MRD, 100% were MRD negative at 10⁻⁵ (n = 21/21) and 10⁻⁶ (n = 19/19; 2 indeterminate) sensitivity.

Grade 3 or higher treatment-emergent AEs occurred in 64% of patients, with no grade 5 events. Neutropenia was the only grade 4 event (n = 5). CRS occurred in 42% of patients, all grade 1 except for a single grade 2 event, and no ICANS was reported. Infections occurred in 92% of patients, including grade 3 infections in 19%, all of which resolved with routine care. All patients received IVIG replacement and pneumocystis pneumonia and antiviral prophylaxis. A phase 3 registrational study is ongoing.

CAMMA 1: Cevostamab Plus Pom-Dex in BCMA-Naive R/R MM

Cevostamab (RG6160; BFCR4350A) combined with pomalidomide and dexamethasone induced durable remissions in BCMA-naive patients with R/R MM. The data come from extended follow-up of arm B of the phase 1b CAMMA 1 study (NCT04910568).⁴ FcRH5 is expressed on myeloma cells regardless of BCMA or GPRC5D expression. Cevostamab monotherapy previously showed activity in late-line R/R MM in a phase 1 study (NCT03275103), with more pronounced responses in BCMA-naive patients.

Arm B enrolled patients who had received at least 1 prior immunomodulatory drug and at least 1 prior proteasome inhibitor as part of at least 1 prior line of therapy. Patients were randomly assigned 1:1 to cevostamab at 70 mg or 105 mg, given every 2 weeks in cycles 1 through 6 and every 4 weeks from cycle 7 onward. Pomalidomide 2 mg was given on days 1 through 21 and dexamethasone 20 mg on days 1, 8, 15, and 22 of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity.

As of January 23, 2026, 29 patients were enrolled in the 70-mg cohort and 25 in the 105-mg cohort. The median age in both cohorts was 65 years, and the median number of prior lines was 2. In the 70-mg vs 105-mg cohorts, respectively:

• 72.4% vs 56.0% were triple-class exposed
• 72.4% vs 68.0% were refractory to their last line
• 10.3% vs 32.0% had high-risk cytogenetics
• 13.8% vs 12.0% had extramedullary disease

At a median time on study of 16.0 months in the 70-mg cohort and 15.8 months in the 105-mg cohort, the ORRs were 86.2% and 88.0%, respectively. VGPR or better rates were 75.9% and 76.0%. Median DOR and PFS were not estimable at the data cutoff. The 12-month DOR rates were 87.2% and 77.3%, and the 12-month PFS rates were 78.6% and 75.1%.

Among MRD-evaluable patients with a CR, 92.3% (12/13) in each cohort achieved MRD-negative CR at 10⁻⁵ sensitivity at any time. Among all efficacy-evaluable patients, the MRD-negative CR rates were 41.4% (12/29) and 48.0% (12/25), respectively.

Grade 3 or 4 AEs occurred in 82.8% of patients in the 70-mg cohort and 96.0% in the 105-mg cohort. Grade 3 or 4 AEs occurring in at least 15% of patients in either cohort were:

• neutropenia: 75.9% and 80.0%
• anemia: 24.1% and 20.0%
• thrombocytopenia: 10.3% and 24.0%
• lymphopenia: 3.4% and 16.0%

Grade 3 or 4 infections occurred in 17.2% and 36.0% of patients, and grade 3 or 4 rash in 10.3% and 4.0%. Among the 26 patients who started cevostamab with triple step-up dosing, CRS was limited to grade 1 (53.8%) or grade 2 (7.7%). Grade 1 and grade 2 ICANS occurred in 1 patient each in the 105-mg cohort. One grade 5 AE excluding disease progression occurred in each cohort: septic shock in the 70-mg cohort and intracranial hemorrhage in the 105-mg cohort. Updated data will be presented at the meeting.

REFERENCES

1. Ja Min Byun et al. Mezigdomide plus elranatamab in relapsed/refractory multiple myeloma: results from part 1 of the phase I/II MELT-MM study. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.

2. Sidana S et al. Matching-adjusted indirect comparisons (MAICs) of efficacy and safety outcomes for anitocabtagene autoleucel versus ciltacabtagene autoleucel in 4L+ relapsed and/or refractory multiple myeloma (RRMM). Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; September 23-26, 2026; Glasgow, Scotland.

3. Rodríguez-Otero P et al. Updated safety and efficacy results for linvoseltamab (LINVO) in patients (pts) with high-risk smoldering multiple myeloma (HR-SMM): phase 2 LINKER-SMM1 trial. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.

4. Spencer A et al. Cevostamab plus pomalidomide (pom) and dexamethasone (dex) induces durable remissions in BCMA-naïve patients with relapsed/refractory multiple myeloma (RRMM): CAMMA 1 arm B extended follow-up data. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.