IMS 2026 Day 3 Recap: Etentamig Outperforms Standard Therapy in R/R MM Trial

Etentamig (ABBV-383) significantly improved response and survival compared with investigator's choice of standard available therapy (SAT) in patients with triple-class–exposed relapsed/refractory multiple myeloma (R/R MM), according to primary results from the phase 3 CERVINO trial (NCT06158841). These findings were presented on day 3 of the 23rd International Myeloma Society (IMS) Annual Meeting and Exposition, held September 23-26, 2026, in Glasgow, Scotland.¹ Additional day 3 data addressed measurable residual disease (MRD)-adapted deferral of autologous stem cell transplantation (ASCT) in newly diagnosed MM (NDMM), patient-reported outcomes with subcutaneous isatuximab, and an indirect comparison of anitocabtagene autoleucel (anito-cel) against 2 B-cell maturation antigen (BCMA)- and GPRC5D-targeting bispecific antibodies.

Etentamig Significantly Improves Response, PFS vs Standard Therapy in CERVINO

CERVINO is a global, multicenter, randomized, open-label phase 3 trial comparing etentamig, a second-generation BCMA × CD3 bispecific T-cell engager, with investigator's choice of SAT (carfilzomib [Kyprolis] plus dexamethasone; elotuzumab [Empliciti] plus pomalidomide [Pomalyst] and dexamethasone; or selinexor [Xpovio] plus bortezomib [Velcade] and dexamethasone) in patients with triple-class–exposed R/R MM who had received 2 or more prior lines of therapy and were naive to anti-BCMA therapy. Etentamig is designed with a low-affinity CD3-binding domain intended to reduce the risk of cytokine release syndrome (CRS), a high-avidity bivalent BCMA-binding domain, and retained FcRn binding that supports dosing once every 4 weeks after a single step-up dose.¹

At the prespecified interim analysis, 393 patients (etentamig, n = 196; SAT, n = 197) had been randomly assigned, with a median follow-up of 11.4 months. The median patient age was 70 years, and patients had received a median of 3 prior lines of therapy; disease was triple-class refractory in 51.9% of patients and refractory to anti-CD38 monoclonal antibody therapy in 86.0%.

The overall response rate (ORR) was significantly higher with etentamig than with SAT, at 74.0% (95% CI, 67.25%-79.97%) vs 45.7% (95% CI, 38.59%-52.91%; P < .0001). Progression-free survival (PFS) was also significantly improved with etentamig (HR, 0.40; 95% CI, 0.29-0.54; P < .0001); median PFS was not reached (95% CI, 14.55-not estimable) with etentamig vs 6.2 months (95% CI, 4.63-7.26) with SAT, and the benefit held across all prespecified subgroups. Twelve-month overall survival (OS) favored etentamig at 87.9% vs 72.0% with SAT (HR, 0.48; 95% CI, 0.29-0.77; nominal P = .0012), though the prespecified OS efficacy boundary had not been crossed at this cutoff.

Treatment-emergent adverse events (TEAEs) occurred in 97.9% of etentamig-treated patients vs 95.3% with SAT; grade 3/4 TEAEs occurred in 73.3% vs 64.2%, and serious TEAEs in 51.8% vs 40.4%. Etentamig was associated with fewer TEAE-related discontinuations (3.6% vs 9.6%) and fewer fatal TEAEs (2.6% vs 5.7%) than SAT. Grade 3/4 infections occurred in 27.7% of etentamig patients vs 19.2% with SAT (grade 5, 1.5% vs 3.1%). Among etentamig-treated patients, CRS occurred in 39.5% (mostly grade 1/2; grade 3 in ≤ 1%; no grade 4/5), and immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 3.6%. Among patients who received a single step-up dose, CRS occurred in 28.3% (grade 1, 23.9%; grade 2, 4.4%; no grade ≥ 3) and ICANS in 0.9% (1 patient; grade 1).

MRD-Guided ASCT Deferral Feasible in NDMM, MILESTONE Study Shows

The phase 2 MILESTONE study (NCT04991103) prospectively evaluated whether postinduction MRD status could guide deferral of up-front ASCT in transplant-eligible patients with NDMM. Patients received 6 cycles of quadruplet induction with daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, after which ASCT was deferred in patients who achieved postinduction MRD negativity. The primary end point was the rate of ASCT deferral based on postinduction MRD status by next-generation sequencing (clonoSEQ) at a 10⁻⁵ threshold. Longitudinal immune phenotyping and cytokine analyses were performed across treatment phases to identify biomarkers associated with MRD kinetics.²

Twenty patients were enrolled between November 2021 and May 2023 (median age, 69 years; 50% male; 45% from racial and ethnic minority groups). Overall, 15% had high-risk fluorescence in situ hybridization abnormalities, including t(4;14), t(14;16), and del(17p). Five patients (25%) achieved MRD negativity (< 10⁻⁵) after induction and deferred ASCT per protocol. At a median follow-up of 42.3 months, disease had progressed in 2 patients, and no deaths had occurred. Over the course of the study, the cumulative MRD-negative complete response rate was 85% at less than 10⁻⁵ and 55% at less than 10⁻⁶, and sustained MRD negativity was achieved in 60% of patients at less than 10⁻⁵ and 35% at less than 10⁻⁶.

MRD negativity was associated with broad remodeling of the immune microenvironment. The baseline serum BCMA (sBCMA)/BAFF ratio at screening correlated with bone marrow plasma cell burden and outperformed either cytokine measured alone, whereas an increasing CXCL9/sBCMA ratio after consolidation was associated with lower MRD burden after ASCT. Expansion of CD57⁺PD-1⁻ effector memory CD8⁺ T cells between screening and maintenance correlated with lower MRD levels, whereas expansion of PD-1⁺ or CD11c/CD16-defined EMRA CD8⁺ subsets correlated with higher residual disease burden. Favorable MRD responses were also associated with downmodulation of classical monocytes, shifts in naive and transitional B-cell populations, and expansion of CD11c⁺CD57⁻CD56^bright natural killer cell subsets.

The authors concluded that MILESTONE demonstrates the feasibility of using postinduction MRD status to guide ASCT deferral in NDMM, with the randomized phase 2 MASTER-2 trial now testing this MRD-adapted approach alongside comprehensive immune profiling.

Patient Satisfaction, Perceived Benefit Favor Subcutaneous Isatuximab Delivery

The phase 3 IRAKLIA trial (NCT05405166) previously established that subcutaneous (SC) isatuximab-irfc (Sarclisa) delivered via an on-body injector (OBI) was noninferior to intravenous (IV) isatuximab, each combined with pomalidomide and dexamethasone (Pd), in patients with R/R MM. A new patient-reported outcomes analysis examined experiences among satisfied and neutral patient subgroups in both arms, along with perceived treatment benefit and willingness to continue therapy at the end of treatment (EOT).³

The trial randomly assigned 531 patients 1:1 to SC isatuximab via OBI (n = 263) or IV isatuximab (n = 268), each with Pd. Four patients did not receive treatment. Isatuximab was dosed at a fixed 1400 mg for SC administration or 10 mg/kg for IV administration, weekly in cycle 1 and every 2 weeks thereafter. The satisfied subgroup comprised patients who reported being "satisfied" or "very satisfied" with their injection method at cycle 5, day 15 on the Patient Experience and Satisfaction Questionnaire Follow-Up, and the neutral subgroup comprised those who reported being "neither satisfied nor dissatisfied." Perceived benefits and disadvantages, as well as willingness to continue treatment, were assessed at EOT using the Patients' Assessment of Treatment (PAT) questionnaire.

Among satisfied patients at cycle 5, day 15 (SC arm, n = 183; IV arm, n = 143), more patients in the SC arm disagreed or strongly disagreed that the injection method was uncomfortable (78.7% vs 64.3%) or painful (89.1% vs 72.0%) compared with the IV arm, and more reported fewer perceived medication adverse effects (73.2% vs 55.9%). Trends were similar among neutral patients. Of patients who completed the PAT at EOT (SC arm, n = 77; IV arm, n = 70), a slightly higher proportion in the SC arm reported high benefits and low disadvantages (45.5% vs 40.0%), and more patients in the SC arm both expressed willingness to continue treatment and felt that benefits outweighed disadvantages (50.7% vs 31.4%).

The findings add to prior IRAKLIA reporting of higher overall satisfaction with isatuximab SC OBI vs IV at cycle 5, day 15 (96.8% vs 70.8%) among questionnaire completers. IRAKLIA supported the FDA's July 2026 approval of SC isatuximab-irfc (Sarclisa Escena), delivered via the CirCLIQ on-body delivery system, across all previously approved IV isatuximab indications.⁴

Anito-Cel Shows Higher Response, Favorable Safety vs Bispecifics in Matching-Adjusted Indirect Comparisons

Unanchored matching-adjusted indirect comparisons compared the BCMA-directed chimeric antigen receptor T-cell therapy anitocabtagene autoleucel (anito-cel) with the bispecific antibodies teclistamab-cqyv (Tecvayli) and talquetamab-tgvs (Talvey) in patients with R/R MM who had received 3 or more prior lines of therapy. The analyses used individual patient-level data from the phase 2 iMMagine-1 trial (NCT05396885; efficacy-evaluable population, n = 117; median follow-up, 15.9 months) and aggregate data from MajesTEC-1 (NCT03145181, NCT04557098; n = 165; median follow-up, 14.1 months) and MonumenTAL-1 (NCT03399799, NCT04634552; 0.4-mg cohort, n = 143; median follow-up, 18.8 months; 0.8-mg cohort, n = 145; median follow-up, 12.7 months). Efficacy comparisons were adjusted for extramedullary disease, cytogenetic risk, refractory status, Revised International Staging System stage, and bone marrow plasma cell percentage, and safety comparisons were adjusted for ECOG performance status, bone marrow plasma cell percentage, age, and sex. Sensitivity analyses used the iMMagine-1 enrolled population (n = 129).⁵

After adjustment, anito-cel showed significantly higher odds of ORR than teclistamab (OR, 8.74; 95% CI, 2.88-26.56), talquetamab 0.4 mg (OR, 4.14; 95% CI, 1.22-14.06), and talquetamab 0.8 mg (OR, 4.49; 95% CI, 1.33-15.14), with similarly higher odds for more stringent response outcomes and overall MRD negativity at a 10⁻⁵ threshold; findings were consistent across sensitivity analyses.

Key toxicities, including grade 3/4 or higher CRS, did not differ significantly between anito-cel and either comparator. Grade 3/4 or higher ICANS was not significantly different vs teclistamab but was significantly lower with anito-cel vs talquetamab 0.4 mg (OR, 0.15; 95% CI, 0.07-0.34) and 0.8 mg (OR, 0.24; 95% CI, 0.11-0.53). Anito-cel was also associated with significantly lower odds of grade 3/4 infections vs teclistamab (OR, 0.11; 95% CI, 0.05-0.22) and talquetamab 0.4 mg (OR, 0.32; 95% CI, 0.14-0.72), and of grade 3/4 or higher infections vs talquetamab 0.8 mg (OR, 0.46; 95% CI, 0.215-0.996), along with lower odds of nonrelapse mortality vs teclistamab (OR, 0.18; 95% CI, 0.06-0.56) and talquetamab 0.4 mg (OR, 0.25; 95% CI, 0.08-0.81).

Anito-cel remains investigational; the FDA accepted its biologics license application for fourth-line R/R MM in February 2026, with a Prescription Drug User Fee Act action date of December 23, 2026.⁶

REFERENCES

1. Voorhees P, Mateos MV, Costa L, et al. CERVINO: phase (Ph) 3 results of etentamig vs investigator's choice of standard available therapies (SAT) in patients (pts) with triple-class exposed relapsed or refractory multiple myeloma (RRMM). Presented at: 23rd IMS Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland.

2. Bal S, Zumaquero E, Ravi G, et al. Feasibility of MRD-adapted deferral of autologous stem cell transplantation in newly diagnosed multiple myeloma: clinical and translational results from the phase II MILESTONE study. Presented at: 23rd IMS Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland.

3. Ling S, Špička I, Oriol A, et al. Evaluation of patient-reported outcomes and subgroup analysis with subcutaneous isatuximab delivered via on-body injector compared with intravenous delivery from the phase 3 IRAKLIA trial. Presented at: 23rd IMS Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland.

4. FDA approves isatuximab-irfc for subcutaneous injection for multiple myeloma indications. FDA. Updated July 10, 2026. Accessed September 25, 2026. https://tinyurl.com/39587f3c

5. Patel K, Hungria V, Hasegawa K, et al. Matching-adjusted indirect comparisons (MAICs) of anitocabtagene autoleucel (anito-cel) versus teclistamab and talquetamab for the treatment of 4L+ relapsed and/or refractory multiple myeloma (RRMM). Presented at: 23rd IMS Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland.

6. Gilead Sciences to acquire Arcellx to maximize long-term potential of anito-cel. News release. Gilead Sciences. February 23, 2026. Accessed September 25, 2026. https://tinyurl.com/5xzzpvzt