Elranatamab Phase 3 PFS Win Upgrades Evidence But Payer Bar Remains Unmet

Pfizer's ELREXFIO Meets Primary Endpoint in Phase 3 RRMM Study

Pfizer announced positive topline results from the Phase 3 MagnetisMM-32 study, demonstrating that ELREXFIO (elranatamab) monotherapy met its primary endpoint of progression-free survival (PFS) in adults with relapsed or refractory multiple myeloma (RRMM). The study showed a statistically significant and clinically meaningful reduction in the risk of disease progression or death compared to investigator’s choice of three standard-of-care regimens. More than 75% of ELREXFIO patients had not experienced disease progression or death at the time of analysis, with an estimated 68% PFS at 18 months. The safety profile was consistent with known data, with infection prophylaxis mitigating risks.

• The Phase 3 MagnetisMM-32 trial demonstrated that ELREXFIO significantly reduced the risk of disease progression or death, meeting its primary endpoint of progression-free survival (PFS) as assessed by BICR. This benefit was observed against a broad set of standard-of-care comparators, including elotuzumab, pomalidomide and dexamethasone (EloPd); pomalidomide, bortezomib and dexamethasone (PVd); or carfilzomib and dexamethasone (Kd), highlighting ELREXFIO's superior efficacy in this challenging patient population.
• ELREXFIO's safety profile in MagnetisMM-32 was consistent with previous findings, with no new safety signals identified. Importantly, proactive infection prophylaxis measures implemented from the study's outset effectively mitigated infection risk, including Grade 3 or higher infections, which were observed in 27.5% of ELREXFIO patients versus 18.1% in the comparator arm, and Grade 5 infections in 0.8% vs 1.6% respectively.
• The study focused on adults with relapsed or refractory multiple myeloma who had received at least one prior line of treatment with anti-CD38 therapy and lenalidomide. This patient group often faces limited treatment options and poorer outcomes, making ELREXFIO's demonstrated PFS benefit and encouraging safety profile particularly impactful for addressing a significant unmet medical need in this evolving treatment landscape.

Addressing Unmet Needs in Post-Anti-CD38/Lenalidomide RRMM

Recent literature on relapsed or refractory multiple myeloma (RRMM) centers on heavily pretreated populations with resistance to multiple drug classes and poor survival. Retreatment remains part of standard of care with heterogeneity in regimens suggesting no standard of care, underscoring need for novel efficacious therapies.

• Double-class refractory, triple-class refractory (TCR), triple-class exposed (TCE) and penta-refractory / penta-exposed (PE) disease: Patients with RRMM resistant to multiple drug classes remain a high unmet need population. Reported median overall survival (OS) was 22.3 and 11.6 months for double-class refractory and triple-class refractory patients, respectively; 21 months for a global post-daratumumab cohort but decreased to 14 months for triple-class refractory patients and 5 months for penta-refractory patients; and OS ranged from 13.0 (TCR) to 15.9 (PE) months in Medicare TCE, TCR, PE and PE-TCR cohorts, with median time to discontinuation (TTD) ranging from 4.2 (PE-TCR) to 6.9 (TCE) months.

• Lenalidomide-refractory and anti-CD38 monoclonal antibody-refractory disease after early proteasome inhibitor (PI) and immunomodulatory drug (IMiD) exposure: Use of PI and lenalidomide (Len) in early lines has resulted in a high proportion of RRMM being Len-refractory, associated with inferior outcomes. In RRMM previously exposed to PI and Len during 1-3 prior lines, median progression-free survival was 13.6 months in Len-refractory versus 14.9 months in Len non-refractory patients, median OS was 20.3 months in Len refractory and not reached in Len non-refractory patients, with overall response rates of 58.8% and 61.7%, respectively; in lenalidomide and anti-CD38 mAb previously treated registries, ≥ 93% were triple-class exposed, with median PFS of 5.2, 4.4 and 5.3 months and median OS of 19.3, 14.2 and 23.1 months in PREAMBLE, Connect MM and Flatiron Health, respectively.

• Relapse after BCMA-directed CAR T-cell therapy and need for mechanism-guided salvage: Despite astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for RRMM, most patients eventually relapse, which currently represents an unmet clinical need. Median time to relapse after CAR T-cell therapy was 5 months, 53% had extramedullary disease (EMD) at relapse associated with dismal post-relapse outcome, with salvage overall response of 79% and 39% complete response for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others.

• Elderly, frail, and high-risk cytogenetics populations including del17p and 1q21+: Cohorts enriched with TCR, elderly and frail patients are specifically targeted with all-oral regimens, including 25 (41%) ≥75 years old, 26 (43%) frail, and 57% with high-risk cytogenetics (t(4;14), t(14;16), +1q21, del17p) with triple-class refractory rate of 39%. Gain/amplification of 1q21 (≥3 copies) can negatively affect prognosis due to involvement in resistance to anti-myeloma therapy and disease progression, while MM patients with del17p are deficient in TP53 and have a particularly poor prognosis.

ELREXFIO's Superior PFS in MagnetisMM-32 Against SOC

Bispecific antibodies have shown improved efficacy over physician-directed and real-world regimens in triple-class exposed/refractory multiple myeloma. In an unanchored matching-adjusted indirect comparison, elranatamab demonstrated significantly better objective response rate and progression-free survival (PFS) than teclistamab, and numerically better complete response, duration of response, and overall survival (OS). In phase II trials MajesTEC-1 and MagnetisMM-3, overall response rates of 63 and 61% were observed with teclistamab and elranatamab, respectively, in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). Compared with physician's choice of treatment (PCT) in LocoMMotion, elranatamab was associated with objective response rate (ORR) rate difference: 37.52; 95% CI 26.20-48.83; odds ratio: 4.85; 95% CI 2.85-8.23 and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84-52.74; odds ratio: 184.01; 95% CI 24.66-1372.86), longer PFS (HR 0.32; 95% CI 0.20-0.49), and OS (HR 0.62; 95% CI 0.40-0.94). Compared with PCT in MAMMOTH, elranatamab was associated with ORR rate difference: 28.14; 95% CI 16.77-39.52; odds ratio: 3.24; 95% CI 1.98-5.32 and ≥CR rate difference: 26.22; 95% CI 16.40-36.05; odds ratio: 5.48; 95% CI 2.88-10.44, PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71). In five UK centres, real-world outcomes were median PFS 3.71 months [95% confidence interval (CI) 2.73-4.73] and median OS 11.00 months [8.02-18.10], with unadjusted PFS difference in restricted mean survival time (dRMST) 6.95 months [4.08-9.61] and OS Hazard Ratio (HR) 0.66 [0.45-0.96] for elranatamab, and adjusted PFS dRMST 6.45 [3.05-9.45] and OS HR 0.75 [0.46-1.26].

B-cell maturation antigen-directed chimeric antigen receptor T-cell therapies demonstrated superior response and survival versus standard of care (SOC) and other comparators. Idecabtagene vicleucel and ciltacabtagene autoleucel were compared to SOC regimens in phase III trials KarMMa-3 and CARTITUDE-4, respectively, with both studies demonstrating significantly improved response rates, depth of response, and PFS compared to SOC. In CARTITUDE-4 in lenalidomide-refractory patients after one to three prior lines, median PFS was not reached (95% CI 34·5 months-not evaluable) versus 11·8 months (9·7-14·0) (HR 0·29 [95% CI 0·22-0·39]), and median OS was not reached (95% CI not evaluable) versus not reached (37·7 months-not evaluable) (HR 0·55 [95% CI 0·39-0·79]; p=0·0009). At median follow-up of 15.9 months, median PFS was not reached versus 11.8 months (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001), PFS at 12 months was 75.9% (95% CI, 69.4 to 81.1) versus 48.6% (95% CI, 41.5 to 55.3), overall response was 84.6% vs. 67.3%, complete response or better was 73.1% vs. 21.8%, and absence of minimal residual disease was 60.6% vs. 15.6%. In matching-adjusted indirect comparisons, cilta-cel had significant reductions in risk of progression or death of 64% versus elotuzumab + pomalidomide + dexamethasone (EloPd), 49% versus isatuximab + carfilzomib + dexamethasone (IsaKd), 69% versus isatuximab + pomalidomide + dexamethasone (IsaPd), and 62% versus selinexor + bortezomib + dexamethasone (SVd), with significant OS improvements of 52% versus EloPd, 58% versus IsaPd, and 60% versus SVd. Against idecabtagene vicleucel from KarMMa-3, cilta-cel was 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03-1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15-1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54-2.37]; p < 0.0001), with 49% reduction in risk of progression or death (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). Adjusted comparisons of CARTITUDE-1 versus LocoMMotion real-world clinical practice showed response rate, 3.12, 95% confidence interval [95% CI]: 2.24-4.00, PFS hazard ratio=0.15, 95% CI: 0.08-0.29, and OS hazard ratio HR=0.20, 95% CI: 0.09-0.41.

Combination regimens containing newer agents also prolonged survival versus established triplets. In DREAMM-7, belantamab mafodotin, bortezomib, and dexamethasone (BVd) versus daratumumab, bortezomib, and dexamethasone (DVd) after at least one line yielded median PFS of 36.6 months (95% CI, 28.4 to not reached) versus 13.4 months (95% CI, 11.1 to 17.5) (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001), OS at 18 months of 84% versus 73%, and complete response or better plus MRD-negative status in 25% versus 10%. With extended follow-up, median OS was not reached (NR; 95% CI NR-NR) versus NR (41.0 months-NR) (hazard ratio [HR] 0·58; 95% CI 0·43-0·79; p=0·0002), with median duration of response of 40·8 months [95% CI 30·5 months-NR] versus 17·8 months [13·8-23·6]. In SUCCESSOR-2, mezigdomide-carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with at least one previous regimen including anti-CD38 antibodies and lenalidomide improved PFS (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001).

ELREXFIO's Consistent Safety and BCMA-Directed Mechanism

Elranatamab, a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, showed a manageable safety profile in the phase 2 MagnetisMM-3 trial in patients with relapsed or refractory multiple myeloma. In cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123), common adverse events (any grade; grade 3-4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%, and fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. In Japanese patients receiving elranatamab monotherapy in MagnetisMM-2 (N = 4) and MagnetisMM-3 (n = 12), all patients experienced treatment-emergent adverse events in MagnetisMM-2 (grade 3/4: 75.0%) and MagnetisMM-3 (grade 3/4: 100%); cytokine release syndrome occurred in 100% (grade 3/4: 25.0%) and 58.3% (no grade 3/4) of patients, respectively. Neither study reported immune effector cell-associated neurotoxicity syndrome.

Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remain the key tolerability considerations, with dosing and prophylaxis influencing incidence and severity. The maximum elranatamab serum concentration on day 1 was positively associated with any-grade and grade ≥ 2 cytokine release syndrome, and based on the incidence, severity, and predictable profile of cytokine release syndrome, the 12/32-mg priming-dose regimen with premedication was determined to be the optimal regimen before the first full dose of 76 mg on day 8. An exposure-safety analysis across MagnetisMM-1, 2, 3, and 9 showed no statistically significant relationship between elranatamab exposure and the incidence of grade ≥3 infections, neutropenia, anemia, and thrombocytopenia, with a flat exposure-safety relationship supporting the 76-mg once-weekly (QW) regimen compared with lower doses within the efficacious dose range (215-1000 µg/kg, equivalent to 16-76 mg). In real-world prophylaxis with a single dose of tocilizumab prior to the first dose of bispecific antibodies, the CRS rate was 8.9%, 12.5%, 0%, and 13% for teclistamab, elranatamab, linvoseltamab and talquetamab individually, with an overall CRS rate of 10.1% and overall ICANS of 5.9%.

Infections, cytopenias, and rare severe neurologic and viral events further define tolerability across settings. In a multinational real-world propensity score-matched study (188 patients in each group), cytokine release syndrome occurred more often with elranatamab (45.2% vs 27.1%; p < 0.001), whereas grade ≥ 3 neutropenia was more frequent with teclistamab (84.6% vs 74.5%; p = 0.015), and the immune effector cell-associated neurotoxicity syndrome and infection rates were comparable. A systematic review and meta-analysis of BCMA-directed bispecific antibodies in relapsed/refractory systemic light chain (AL) amyloidosis (8 independent cohorts, 80 patients treated with teclistamab or elranatamab) reported cytokine release syndrome in 60% and immune effector cell-associated neurotoxicity syndrome in 7%, while Grade ≥ 3 infections were observed in 25%. Individual reports describe the first case of grade 4 ICANS presenting alongside grade 1 cytokine release syndrome requiring high-dose methylprednisolone therapy, hepatitis B virus reactivation with HBV DNA increased to 3.6 log10 IU/mL requiring tenofovir alafenamide 25 mg once daily, and grade 1-2 cytokine release syndrome, cytopenias, CMV reactivation and hypo-gammaglobulinemia with one patient experiencing grade 3 neurological toxicity.