20 of 20 MRD Negative but Single-Arm Data Cannot Carry Frontline Approval

J&J's Ramantamig Shows Strong Early Data in Multiple Myeloma

Johnson & Johnson is advancing its trispecific antibody, ramantamig, for multiple myeloma, with promising early mid-stage trial data to be presented at the American Society of Hematology (ASH) meeting. The drug, which targets CD3, BCMA, and GPRC5D, was evaluated as an induction treatment in newly diagnosed multiple myeloma patients eligible for bone marrow transplants. All 20 evaluable patients achieved minimal residual disease negativity after three cycles, demonstrating strong initial efficacy.

• Ramantamig represents a new generation of cancer therapy as a trispecific antibody, designed to simultaneously engage three distinct targets: CD3 on immune cells and both BCMA and GPRC5D on multiple myeloma cells. This innovative three-pronged binding strategy aims to enhance anti-tumor activity and potentially overcome resistance mechanisms observed with bispecific approaches.
• In a mid-stage clinical trial, ramantamig, administered as an induction treatment alongside Darzalex and Revlimid, achieved minimal residual disease (MRD) negativity in 100% of the 20 evaluable newly diagnosed multiple myeloma patients eligible for bone marrow transplants after just three cycles. This outcome suggests a deep and rapid response to treatment.
• The strong early data for ramantamig positions it as a potentially significant addition to Johnson & Johnson's already broad multiple myeloma treatment portfolio. Its development as an induction therapy in combination with existing agents underscores a strategic effort to improve initial treatment outcomes and potentially extend remission for patients.

Trispecific Antibodies: A New Frontier in Multiple Myeloma

Dual antigen recognition through T-cell-engaging trispecific antibodies targeting B-cell maturation antigen (BCMA) and G-protein-coupled receptor class 5 member D (GPRC5D) alongside CD3 has emerged as a strategy to enhance tumor binding through increased avidity, resulting in efficient depletion of malignant clonal populations, targeting of tumor heterogeneity, and prevention of tumor antigen loss mediated resistance. Ramantamig (JNJ-79635322) is a trispecific antibody targeting BCMA and GPRC5D, both of which are highly expressed on plasmablasts and plasma cells in myeloma patient samples. At sub nM ranges, ramantamig induced potent cytotoxicity in cancer cell lines with concomitant T-cell activation and efficiently depleted both dual and single target-expressing MM cell lines.

Ramantamig induced dose-dependent depletion of malignant plasma cells both in MM patient samples in an ex-vivo T-cell co-culture assay and in healthy fresh whole blood co-cultured with H929 MM cells to mimic physiological conditions. Ramantamig exhibited potent antitumor activity in a murine xenograft prevention model (single-target-expressing clonal cells) and two tumor regression models. Phase 1 clinical trials are ongoing for patients with relapsed/refractory MM (NCT05652335, NCT06768489). A second construct, YMN-V115, was designed in a 1+1+1 format with one binding site each for BCMA, GPRC5D, and CD3 to maximize tumor-specific T cell engagement through dual-antigen targeting while minimizing the risk of CD3-mediated off-tumor toxicity.

YMN-V115 exhibited superior cytotoxic activity against MM cells in both in vitro and in vivo models, outperforming its bispecific counterparts. Its efficacy was maintained under soluble BCMA-saturated conditions, demonstrating resistance to decoy inhibition. Moreover, YMN-V115 effectively addressed antigenic heterogeneity by targeting both BCMA and GPRC5D tumor subsets, resulting in enhanced T-cell activation and durable tumor control. Early-phase data from emerging trispecific antibodies, such as ISB 2001, show ORRs as high as 75% and deep responses, including stringent complete responses (sCR) and minimal residual disease (MRD) negativity.

ASH Highlights: Early Data for J&J's Ramantamig and AbbVie's ABBV-2001

Recent studies in multiple myeloma have evaluated quadruplet and T-cell redirecting regimens in newly diagnosed and relapsed/refractory settings. Efficacy was commonly assessed by overall response rate, MRD negativity, and progression-free survival, with safety focused on cytopenias, infections, and cytokine release syndrome.

• The MANHATTAN Nonrandomized Clinical Trial evaluated carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy in 41 evaluable patients with newly diagnosed multiple myeloma: MRD negativity (10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), overall response rate was 100% (41 of 41 patients) and very good partial response or complete response rate was 95% (39 of 41 patients), 1-year PFS rate was 98% (95% CI, 93%-100%) and OS rate was 100%, with grade 3 or 4 neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]) and no deaths.

• Real-World Experience of Weekly Carfilzomib in Combination with Cyclophosphamide and Dexamethasone evaluated weekly carfilzomib, cyclophosphamide, and dexamethasone (KCd) in 33 patients with relapsed or refractory multiple myeloma previously treated with both bortezomib- and lenalidomide-containing regimens: overall response rate was 66.7%, including complete response or better in 15.1% and very good partial response or better in 42.4%, median progression-free survival (PFS) was 13.5 months (95% CI, 11.47-15.53) with median overall survival (OS) not reached, and most common grade ≥3 adverse event was neutropenia (15.2%).

• The phase 2 GMMG-HD10/DSMM-XX (MajesTEC-5) study evaluated teclistamab/daratumumab/lenalidomide (Tec-DR) or Tec-DR with bortezomib (Tec-DVR) in 49 transplant-eligible patients with newly diagnosed multiple myeloma: MRD-negative CR rate was 91.8% (45/49), MRD negativity rate was 100% in evaluable samples at postinduction cycle 3 (1 × 10 (46/46)), cycle 6 (1 × 10 (46/46) and 1 × 10 (46/46)) and premaintenance (1 × 10 (40/40)), ORR was 100% (49/49), with grade 3 or 4 treatment-emergent AEs in 91.8% (45/49) including lymphopenia (59.2%; 29/49), neutropenia (59.2%; 29/49) and leukopenia (18.4%; 9/49), cytokine release syndrome in 67.3% (33/49) all grade 1 or 2, no treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) events, and any-grade and grade 3 or 4 infections in 81.6% (40/49) and 36.7% (18/49).

• A systematic review and meta-analysis of salvage outcomes with teclistamab after BCMA-directed therapy failure included 9 observational studies with 718 BDT-exposed patients with relapsed/refractory multiple myeloma: pooled ORR was 56% (95% CI: 50-63), CR rate was 22% (95% CI: 17%-27%), VGPR rate was 20% (95% CI: 15%-27%), median PFS was 101 days compared with 220 days in BDT-naive patients and median OS was 437 days in each group, with infections in 44.6%, any-grade CRS in 57.9% (grade ≥3, 1.3%), and neutropenia in 32.3%.

Trispecifics: Reshaping the Multiple Myeloma Treatment Landscape

In newly diagnosed multiple myeloma, CD38 monoclonal antibody-based quadruplet regimens were associated with a significantly higher rate of minimal residual disease negativity (pooled OR = 2.02, 95% CI: 1.41-2.88, P = 0.0001) and significantly improved progression-free survival (pooled HR = 0.74, 95% CI: 0.59-0.94, P = 0.01) compared to triplet regimens across nine randomized controlled trials comprising 4557 patients. Subgroup analyses revealed that the progression-free survival benefit was not significant for isatuximab-based quadruplet regimens (pooled HR = 1.04, 95% CI: 0.67-1.62, P = 0.84) or in transplant-ineligible patients (pooled HR = 0.79, 95% CI: 0.56-1.13, P = 0.19). In the Phase 3 IKEMA study at long-term follow-up (44.2 months), isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd achieved progression-free survival benefit in 1q21+ patients (HR 0.58, 95% CI: 0.37-0.92) and isolated 1q21+ patients (HR 0.49, 95% CI: 0.27-0.92), with median progression-free survival of 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+, and MRD negativity and complete response or better rates of 29.3% versus 15.4% in 1q21+ patients and 36.2% versus 12.9% in isolated 1q21+ patients.

Teclistamab monotherapy significantly improved outcomes compared with investigator's choice of pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received one, two, or three lines of therapy including an anti-CD38 monoclonal antibody and lenalidomide. At interim analysis with median follow-up of 17.3 months, estimated 18-month progression-free survival was 69.8% vs. 26.9% (hazard ratio for disease progression or death, 0.29; 95% confidence interval [CI], 0.23 to 0.38; P<0.001), complete response or better was 65.9% vs. 16.8% (P<0.001), and estimated 18-month overall survival was 79.2% vs. 68.6% (hazard ratio for death, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with grade 3 or 4 adverse events in 84.9% versus 76.3% and grade 3 or 4 infection in 41.6% versus 29.0%. In Japanese patients with relapsed or refractory disease progressing on or intolerant to ≥3 prior therapies, elranatamab monotherapy in MagnetisMM-2 (N = 4) and MagnetisMM-3 (n = 12) produced objective response rates of 50.0% (95% CI, 6.8-93.2) and 58.3% (95% CI, 27.7-84.8), with cytokine release syndrome in 100% (grade 3/4: 25.0%) and 58.3% (no grade 3/4), respectively, and no immune effector cell-associated neurotoxicity syndrome reported, while a multi-institutional real-world study of talquetamab in 114 triple-class refractory patients with median 6 prior therapies reported overall response rate of 73%, complete response in 26% and very good partial response in 26%, median progression-free survival of 10 months, and six-month progression-free and overall survival rates of 56 and 86% respectively.

Transplant-sparing quadruplet approaches without high-dose melphalan and autologous hemopoietic cell transplant have shown deep responses in newly diagnosed disease. In the MANHATTAN nonrandomized trial of carfilzomib-lenalidomide-dexamethasone-daratumumab in 41 evaluable patients, MRD negativity at 10-5 sensitivity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), overall response rate was 100% (41 of 41 patients) and very good partial response or complete response rate was 95% (39 of 41 patients), with 1-year progression-free survival rate of 98% (95% CI, 93%-100%) and overall survival rate of 100%. In a phase 2 measurable residual disease-adapted study of elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone without transplant intent in 46 patients, the rate of stringent complete response and/or MRD-negativity (10-5) after cycle 8 was 26 of 45 (58%), MRD-negativity (10-5) rate increased to 70% over time, and estimated 3-year progression-free survival was 72% overall and 92% for patients with MRD-negativity (10-5) at cycle 8. Route and sequencing comparisons showed comparable efficacy with differentiated tolerability: in MMY-3021, best response rate remained 52% in each arm for subcutaneous versus intravenous bortezomib, with time to progression median 9.7 vs. 9.6 months (hazard ratio 0.872, P=0.462), progression-free survival median 9.3 vs. 8.4 months (hazard ratio 0.846, P=0.319), overall survival at 1-year 76.4% vs. 78.0% (P=0.788), and significantly lower peripheral neuropathy rates with subcutaneous administration, while lenalidomide plus dexamethasone at first relapse versus later salvage showed median time to progression 17.1 vs. 10.6 months (P = 0.026), progression-free survival 14.1 vs. 9.5 months (P = 0.047), and overall survival median 42.0 vs. 35.8 months (P = 0.041).