Bispecifics in New Combos, New Uses, and Earlier Lines of Treatment in Myeloma

Maria-Victoria Mateos, MD, PhD, closed out the late-breaking session of the 67th American Society of Hematology (ASH) Annual Meeting with results that showed patients treated with 1 to 3 therapies for multiple myeloma (MM) had an 83% progression-free survival (PFS) advantage taking teclistamab (Tecvalyi) and daratumumab (Darzalex), both from Johnson & Johnson, compared with triplets that only recently became the standard of care.1

By the time Mateos, associate professor of medicine at the University of Salamanca, Spain, presented the stunning phase 3 data pairing teclistamab, a bispecific antibody, with daratumumab, a well-known anti-CD38 therapy, it was the pinnacle of a meeting that had already featured multiple abstracts supporting other novel uses for bispecifics in MM, including earlier lines of care.

Calling the results for the MajesTEC-3 trial (NCT05083169) “the greatest PFS treatment effect we've seen to date,” Mateos said the findings “suggest the potential for functional cure” as she went on to explain in a press briefing how early infection risk could be mitigated to support this combination as a new standard of care in relapsed/refractory MM.

These are developments with enormous implications for managed care: it could mean patients with MM—and there are more of them—will take fewer medications, which for some will mean less time in the clinic. But as Mateos acknowledged, the findings, coupled with other data presented during ASH, also raise new questions about how therapies for MM should be sequenced.

Patients were excluded from MajesTEC-3 if they had previously received B-cell maturation antigen–directed (BCMA-directed) therapy or were refractory to anti-CD38 monoclonal antibodies; such a population might be more challenging to enroll if they study launched today. Results were also published in The New England Journal of Medicine (NEJM).2

Just as MajesTEC-3 made the case that patients benefit when bispecifics move into earlier lines of care, so too did a phase 1/2 study that found compelling results with another bispecific, linvoseltamab (Lynozyfic; Regeneron), when used to treat patients newly diagnosed with MM.3

“As long as we're getting similar to higher overall and complete response [CR] rates, we always want to try to give myeloma patients the best therapy we can give up front, because the faster we reduce their disease burden, the better they're going to feel,” said Robert Z. Orlowski, MD, PhD, chairman and interim director of myeloma, and professor of medicine in the departments of Lymphoma/Myeloma and Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. Orlowski presented results of the LINKER-MM4 trial (NCT03761108), which found an overall response rate (ORR) of 86% in patients treated with doses of 200 mg or 50 mg, with a median time to partial response or better of 1.2 months (See related interview).3

“The deeper the response, the longer in remission they're going to stay. And especially if we're talking about transplant-ineligible patients, some of whom, unfortunately, because of other complications, don't get to second line or third line,” Orlowski said. “That's another rationale to try to give the best treatment up front.”

The FDA approved linvoseltamab in July 2025 for patients with MM who have had at least 4 prior lines of therapy.4

As Brooke Adams, PharmD, BCOP, a clinical pharmacist at Orlando Health Care Institute, shared at an event presented by The American Journal of Managed Care® on the eve of ASH, bispecifics offer new possibilities for patients with MM. But this means emergency physicians and community practices must be ready for a larger wave of patients to be treated with bispecifics. “Buckle up, it’s about to get more exciting,” she said.

Results for MajesTEC-3

The phase 3 study randomly assigned patients with 1 to 3 previous lines of therapy to receive combination therapy with teclistamab and daratumumab or daratumumab combined with dexamethasone plus the investigator’s choice of pomalidomide (DPd) or bortezomib (Velcade) (DVd); this was called the DPd or DVd group. The trial randomized 587 patients (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd).2 The primary end point was PFS, as assessed by an independent review committee. Data showed the following:

• At a median of 34.5 months, PFS was significantly longer with teclistamab-daratumumab than with DPd or DVd; the estimated 36-month PFS was 83.4% in the teclistamab–daratumumab group and 29.7% in the DPd or DVd group (HR, 0.17; 95% CI, 0.12 to 0.23; P < .001).2
• More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a CR or better (81.8% vs 32.1%), an overall response (89.0% vs 75.3%), and minimal residual disease (MRD) negativity (10-5; 58.4% vs 17.1%) (P < .001 for all comparisons).2
• Serious adverse events (AEs) occurred in 70.7% of the teclistamab-daratumumab group and in 62.4% of the DPd or DVd group; death from AEs occurred in 7.1% and 5.9%, respectively.1 In Mateos’ presentation and in the NEJM manuscript, authors noted that current guidelines call for prophylactic tocilizumab, which was not permitted in the trial. Events can be controlled with immunoglobulin therapy and infection prevention protocols, they wrote.2

Linvoseltamab With Anti-CD38 Therapy

Investigators presented data for a small number of patients in phase 1b of LINKER-MM2 (NCT05137054), who were treated with anti-CD38 therapy and with different dose levels of linvoseltamab. The poster included data for 42 patients, all who had progressed after 3 lines of therapy or 2 lines if they were a T-cell engager and double-class refractory. Prior treatment with daratumumab or isatuximab (Sarclisa; Sanofi) was permitted if previously tolerated at least 6 months or after a 3-month washout. Results showed the following5:

• Linvoseltamab doses began first, with step-up dosing and 2 full doses before anti-CD38 doses were added. Dexamethasone was given ahead of anti-CD38 medication per the label.
• Dose 1 of linvoseltamab was paired with daratumumab for 12 patients and isatuximab for 6 patients, dose 1b of linvoseltamab was paired with daratumumab for 6 patients and isatuximab for 8 patients, and dose 2 of linvoseltamab for 8 patients with daratumumab, and zero for isatuximab.
• Median follow-up was 14.8 months for dose 1, with 21.3 months for daratumumab and 11.3 months for isatuximab. The median follow-up was 7.6 months for dose 1b, with 13.5 months for daratumumab and 5.2 months for isatuximab, and the median follow-up was 5.9 months for dose 2, all daratumumab.
• The most common treatment-emergent AEs (TEAEs) were anemia of any grade, 48%, with grade 3 or 4, 26%; neutropenia, 41% for both; diarrhea, 38% and 2%, respectively; and thrombocytopenia, 38% and 17%.
• Cytokine release syndrome (CRS) was seen in 33% of patients, all grade 1 and 2, except 1 grade 3 event that resolved. No patient experienced immune-effector cell–associated neurotoxicity syndrome (ICANS). Infections were seen in 76%, with grade 3 or higher in 40% and 3 deaths.
• Among efficacy evaluable patients, ORRs were seen in 75% in dose 1, 93% in dose 1b, and 86% in dose 2. The 12-month duration of response (DOR) rate was 79%; median DOR not reached. The 12-month PFS rate was 73% (95% CI, 53%-86%); median PFS not reached). All patients were MRD negative to < 10-5.

Linvoseltamab as Immunoconsolidation Therapy

Attendees at ASH were buzzing about IMMUNOPLANT (NCT06376526), a phase 2 investigator-initiated study at the University of Miami Sylvester Comprehensive Cancer Center. Dickran Kazandjian, MD, presented data on patients with MM who had not achieved MRD negativity following treatment with initial combination therapy, a situation that can affect up to 50% of patients.6

For these patients investigators evaluated a treatment of 4 to 6 cycles of linvoseltamab as an immunoconsolidation strategy prior to standard management. All patients treated this way achieved MRD negativity by the time of data cutoff, investigators reported.5

“The primary objective is to determine MRD conversion rate after 4-6 cycles of [linvoseltamab],” the investigators wrote. Key secondary objectives included MRD status at 6, 12, and 24 months, as well as PFS and OS, plus safety.

Patients received 200-mg doses intravenously following 2 step-up doses weekly for cycles 1 to 3 followed by every 2 weeks starting with cycle 4. Bone marrow MRD is evaluated at cycle 4; if positive, patients receive cycles 5 and 6 before returning to standard management. Prophylaxis includes tocilizumab and dexamethasone. As of July 2025, the regimen had been given to 19 patients with the following results5:

• Median age of 60 years (range, 40-77); 26% of patients are female.
• Eleven percent of patients are Black and 47% are Hispanic, 32% have high-risk features, and 74% have an Eastern Cooperative Oncology Group score of 0.
• All patients were MRD positive at baseline, as measured by clonoSEQ. As of data cutoff, 14 patients received 4 cycles of linvoseltamab and underwent MRD assessment, with 100% achieving MRD negativity, as measured by clonoSEQ and flow cytometry.
• The 3 patients who reached the 6-month mark remained MRD negative, with no CRS or ICANS reported; 74% of patients had linvoseltamab-related AEs, including rash, upper respiratory infection, and bone pain. No serious AEs were reported.

References

1. Mateos MV, Phase 3 randomized study of teclisatamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib (DPd or DVd) in patients with relapsed refractory multiple myeloma (RRMM): results of MajesTEC-3. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract LBA-6.

2. Costa LJ, Bahlis NJ, Perrott A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. Published online December 9, 2025. doi:10.1056/NEJMoa2514663

3. Orlowski RK, et al. Safety and efficacy of linvoseltamab as a simplified monotherapy first-line regimen in NDMM: initial results from the window of opportunity phase 1/2 LINKER-MM4 trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Paper No. 697.

4. Klein HE. FDA approves linvoseltamab to treat R/R multiple myeloma. Am J Manag Care. 2025;31(spec 9):SP558-SP559.

5. Dimopoulos MA, Delimpasi S, Manier S, et al. Safety and efficacy of linvoseltamab combined with anti-CD38 monoclonal antibodies daratumumab or isatuximab in patients with relapsed/refractory multiple myeloma (RRMM): initial results from the multicohort phase 1b LINKER-MM2 trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Paper 2254.

6. Kazankjian D, Diamond B, Hoffman JE, et al. A phase 2 trial of abbreviated fixed-duration (default 4 cycles) linvoseltamab immunoconsolidation to deepen responses post newly diagnosed multiple myeloma combination therapy for minimal residual disease positivity (the IMMUNOPLANT study). Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Paper 0248.