AbbVie Announces Positive Topline Results from the Phase 3 CERVINO Trial for Etentamig in Relapsed/Refractory Multiple Myeloma

AbbVie's Etentamig Achieves Dual Primary Endpoints in RRMM

AbbVie announced positive topline results from the Phase 3 CERVINO trial, demonstrating that investigational etentamig significantly improved objective response rate (ORR) and progression-free survival (PFS) in 393 patients with triple-class exposed relapsed/refractory multiple myeloma. Etentamig achieved an ORR of 74% and reduced the risk of disease progression or death by 60% (HR 0.40) compared to standard available therapies. The drug also showed a manageable safety profile with low rates of cytokine release syndrome (28.3%, predominantly Grade 1) and a monthly dosing schedule, supporting its potential for broader access in various treatment settings.

• Etentamig achieved statistically significant and clinically meaningful improvements in both primary endpoints. The objective response rate was 74.0% (95% CI, 67.25–79.97) for etentamig versus 45.7% (95% CI, 38.59–52.91) for standard therapies (P<0.0001). Progression-free survival was also significantly improved, with a hazard ratio of 0.40 (95% CI, 0.29–0.54; P<0.0001), indicating a 60% reduction in the risk of disease progression or death.
• The trial demonstrated a manageable safety profile for etentamig, characterized by a low incidence of cytokine release syndrome (28.3%, predominantly Grade 1) and no Grade 3 or higher events. Grade 5 infections were lower with etentamig (1.5%) compared to standard therapies (3.1%). The optimized dosing strategy, involving a single step-up dose followed by monthly (Q4W) administration, aims to provide a convenient treatment option with potential for use in outpatient and community-based care settings.
• These positive results support etentamig's potential as a differentiated BCMA-targeted bispecific treatment option for heavily pre-treated, triple-class exposed relapsed/refractory multiple myeloma patients. Its manageable safety profile and convenient dosing schedule may address current limitations of other BCMA-directed therapies, such as CAR-T and other bispecific antibodies, by enabling treatment beyond specialized centers and into community settings, thereby expanding patient access.

Addressing the Critical Unmet Need in Triple-Class Exposed RRMM

Despite significant therapeutic advances, relapsed/refractory multiple myeloma (RRMM) continues to present substantial clinical and systemic challenges, particularly as patients progress through successive lines of therapy. The emergence of triple-class exposed (TCE) and penta-exposed (PE) populations has sharpened the focus on unmet needs in terms of both efficacy and healthcare burden.

• Triple-class exposed and penta-exposed patients face poor survival outcomes. Among 221 TCE patients in the Alberta Health System, median overall survival (OS) from first subsequent line of therapy (LOT) was 18.7 (95% confidence interval: 16.0–24.3) months, with a median time to next treatment or death of 10.1 (95% confidence interval: 8.4–13.3) months and an attrition rate of 32% after first LOT. In a Medicare population, median OS ranged from 13.0 months (triple-class refractory [TCR]) to 15.9 months (penta-exposed [PE]), with median time to discontinuation ranging from 4.2 (PE-TCR) to 6.9 (TCE) months — underscoring the limited effectiveness of available regimens in these populations.

• No standard of care exists for TCE and PE patients, with heterogeneous treatment patterns. In the Medicare cohort, pomalidomide was the most frequently used medication for the index LOT across all cohorts (32.6% [PE-TCR] to 43.3% [TCR]), yet regimen selection varied widely — pomalidomide plus daratumumab for TCE (17.2%) and PE (7.0%), pomalidomide plus carfilzomib for TCR (10.3%), and pomalidomide plus elotuzumab for PE-TCR (7.4%) — reflecting the absence of a defined therapeutic standard.

• Healthcare resource utilization in TCE patients is substantial. Within the first year of subsequent LOT, TCE patients in the Alberta cohort had a median of 1 emergency department visit, 1 hospitalization, 33 clinic visits, 4 infusion appointments, 37 unique healthcare encounters, and a mean of 32 days spent on laboratory tests. In the Medicare population, mean monthly healthcare costs ranged from $23,091 (TCE) to $24,412 (PE-TCR), with MM medications representing 66.2% (PE-TCR) to 72.8% (TCE) of total costs.

• Novel mechanistic targets — particularly GPRC5D and BCMA — are being actively pursued to address resistance and antigen escape. GPRC5D has emerged as a promising immunotherapeutic target due to its high and selective expression in MM cells and minimal presence in normal tissues. Therapeutic strategies targeting GPRC5D, including bispecific antibodies, CAR T cells, and antibody-drug conjugates, have demonstrated encouraging efficacy in RRMM. Talquetamab, the only approved GPRC5D-targeted therapy, showed overall response rates of >71% in triple-class exposed patients with relapsed/refractory MM in the MonumenTAL-1 study, though GPRC5D-targeted therapies also pose significant toxicity risks including oral, skin, nail, and cerebellar toxicity.

• CAR-NK cell therapy represents an emerging platform targeting the limitations of CAR-T approaches. NK cells offer innate antitumor activity, a reduced risk of graft-versus-host disease (GvHD), and the feasibility of "off-the-shelf" allogeneic production. CAR-NK strategies in RRMM are targeting antigens such as BCMA, NKG2D, CD38, CD70, SLAMF7, CD138, and GPRC5D, with preclinical and early clinical studies demonstrating potent cytotoxicity and favorable safety profiles. Emerging clinical data suggest that CAR-NK cell therapy may combine the specificity of CAR recognition with the inherent safety and versatility of NK biology.

• Multi-targeting strategies are being explored to prevent antigen escape and resistance. Newer trials are exploring more aggressive approaches combining multiple immunotherapy targets within a single line to prevent resistance and potentially achieve a cure. Key challenges such as antigen escape and the need for optimized combination strategies remain central to the field's development agenda.

CERVINO: Etentamig's Efficacy and Safety in RRMM

Several recent clinical studies have evaluated novel immunotherapy approaches in relapsed/refractory multiple myeloma (RRMM), yielding meaningful efficacy and safety data across distinct therapeutic modalities.

The MagnetisMM-1 trial investigated elranatamab, a BCMA×CD3 bispecific antibody, in 88 patients with relapsed/refractory MM, of whom 55 received elranatamab at efficacious doses. Patients were heavily pretreated, with a median of five prior regimens; 90.9% were triple-class refractory and 23.6% had received prior BCMA-directed therapy. With a median follow-up of 12.0 months, the overall response rate (ORR) was 63.6%, with 38.2% achieving complete response or better. The median duration of response (DOR) was 17.1 months, median progression-free survival (PFS) was 11.8 months, and median overall survival (OS) was 21.2 months. All 13 patients evaluable for minimal residual disease achieved negativity. Key adverse events included cytopenias and cytokine release syndrome (CRS), with no dose-limiting toxicities observed during dose escalation.

The MajesTEC-1 study and its associated pooled analysis evaluated teclistamab, the first approved BCMA×CD3 bispecific antibody, across a Global Trial cohort of 217 patients with triple-class exposed relapsed/refractory MM. With a median follow-up of 29.5 months, the ORR was 66.4%, with ≥complete response (CR) achieved in 50.2% of patients. Median PFS was 15.6 months and median OS was 29.1 months, with median DOR not reached. A separate systematic review and meta-analysis encompassing 34 studies and 4,064 patients confirmed teclistamab's superior OS compared to existing RRMM treatments (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.54–0.89; p = 0.037), with real-world ORR of 62% (95% CI: 58%–66%). The most common adverse events across both analyses were cytopenias, CRS, and infections, with infection management noted to improve over time with increased immunoglobulin use.

A phase 1 single-center trial assessed a novel BCMA/GPRC5D bispecific CAR T-cell therapy in 9 evaluable patients with RRMM and extramedullary disease, a particularly high-risk population. All patients achieved partial response or better, with 44.4% achieving complete response. The 1-year OS and PFS rates were 60% and 63%, respectively, with median OS and PFS not reached at a median follow-up of 6.08 months. CRS occurred in 66.7% of patients, all grade 1–2, and no neurotoxicity (ICANS) was observed. Common hematological toxicities included anemia, leukopenia, and thrombocytopenia.

Etentamig's Differentiated Profile for Broader RRMM Access

BCMA-directed immunotherapies have been evaluated against standard-of-care (SOC) regimens in pivotal clinical trials, with CAR-T cell therapies demonstrating particularly compelling efficacy advantages. Idecabtagene vicleucel and ciltacabtagene autoleucel (cilta-cel) were compared to SOC regimens in the phase III trials KarMMa-3 and CARTITUDE-4, respectively, both of which demonstrated significantly improved response rates, depth of response, and progression-free survival compared to SOC. In a large real-world CIBMTR registry study of 595 cilta-cel-treated patients — who had received a median of 7 prior lines of therapy — the best overall response rate was 87%, with ≥very good partial response in 75% and ≥complete response in 35%. Estimated 12-month progression-free and overall survival were 73% (95% CI: 68–77%) and 85% (95% CI: 81–88%), respectively. In the real-world IMMPACT-MM study evaluating cilta-cel after 1–3 prior lines of therapy, the overall response rate was 98.0% among patients with a response assessment, with 72.4% achieving complete response and MRD negativity (10⁻⁵) in 97.2% of 36 MRD-evaluable patients.

Bispecific antibodies (BsAbs) teclistamab and elranatamab have been evaluated in heavily pretreated populations, where direct SOC comparisons were not the study design, but efficacy benchmarks remain clinically meaningful. In the phase 1–2 MajesTEC-1 trial, teclistamab — administered as a weekly subcutaneous injection at 1.5 mg per kilogram following step-up doses — achieved an overall response rate of 63.0% in patients with a median of five prior therapy lines, 77.6% of whom had triple-class refractory disease. A complete response or better was achieved in 39.4% of patients, with a median duration of response of 18.4 months (95% CI, 14.9 to not estimable) and median progression-free survival of 11.3 months (95% CI, 8.8 to 17.1). In the MagnetisMM-1 phase 1 trial, elranatamab monotherapy in 55 patients at efficacious doses yielded an overall response rate of 63.6%, with 38.2% achieving complete response or better, a median duration of response of 17.1 months, median progression-free survival of 11.8 months, and median overall survival of 21.2 months at a median follow-up of 12.0 months.

Safety profiles across both CAR-T and BsAb modalities are characterized by cytokine release syndrome (CRS), cytopenias, infections, and neurotoxicity, though the severity distributions differ. In the CIBMTR cilta-cel study, CRS occurred in 80% of patients (≥grade 3: 4%), immune effector cell-associated neurotoxicity syndrome (ICANS) in 22% (≥grade 3: 4%), and non-ICANS neurotoxicity in 5%, including Parkinsonism in 2.7% and cranial nerve palsies in 2.5%. Treatment-related mortality was 5%. With teclistamab in MajesTEC-1, CRS occurred in 72.1% (grade 3: 0.6%; no grade 4), neutropenia in 70.9% (grade 3 or 4: 64.2%), and infections in 76.4% (grade 3 or 4: 44.8%). Real-world teclistamab data further indicated that primary prophylaxis with intravenous immunoglobulin was associated with a significantly lower infection risk on multivariate analysis (hazard ratio 0.33; 95% CI 0.17, 0.64; p = 0.001). Operational challenges and access limitations — particularly for CAR-T therapies, which require specialized institutional infrastructure — remain important considerations in the broader clinical deployment of these agents.

Etentamig's Phase 3 Success: A New Horizon for RRMM

The recent announcement regarding etentamig's positive Phase 3 CERVINO trial results marks a pivotal moment for patients battling triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). With an impressive 74% objective response rate and a 60% reduction in the risk of disease progression or death, etentamig demonstrates a compelling efficacy profile in a patient population where treatment options, while expanding, still leave significant unmet needs.

This data positions etentamig as a formidable contender in the rapidly evolving landscape of multiple myeloma therapies, particularly among bispecific antibodies (bsAbs). While agents like linvoseltamab have shown superior outcomes compared to real-world standard-of-care in TCE RRMM, and other approved bsAbs like teclistamab are demonstrating strong efficacy, etentamig's profile offers distinct advantages. Notably, its manageable safety, characterized by a low rate of predominantly Grade 1 cytokine release syndrome (CRS), could differentiate it significantly. CRS is a known concern with T-cell engaging therapies, and a more favorable safety profile could facilitate broader adoption and potentially enable treatment in a wider range of clinical settings.

Furthermore, a monthly dosing schedule represents a substantial convenience factor for patients and healthcare providers, potentially improving adherence and quality of life. This combination of robust efficacy, a favorable safety profile, and convenient administration could establish etentamig as a new standard or a highly preferred option for this heavily pretreated patient group. However, the competitive landscape remains intense, with numerous bsAbs in various stages of development. Long-term safety data, particularly concerning infections and the inevitable emergence of resistance mechanisms, will be crucial for sustained success. Additionally, real-world effectiveness and market access strategies will be key determinants of its ultimate impact.