Linvoseltamab Expands Treatment Options for Relapsed/Refractory MM

Background

Multiple myeloma (MM) is an incurable B-cell malignancy characterized by the proliferation of monoclonal plasma cells in the bone marrow and extramedullary sites. Immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, and T-cell redirecting therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell–engaging (BTCE) antibodies have transformed the MM treatment landscape. B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is highly expressed on malignant plasma cells, making it an attractive target for the treatment of patients with MM.¹ Several BCMA-directed therapies, including idecabtagene vicleucel (ide-cel; Abecma; Bristol Myers Squibb), ciltacabtagene autoleucel (cilta-cel; Carvykti; Janssen Biotech, Inc/Legend Biotech), teclistamab-cqyv (Tecvayli; Janssen Biotech, Inc), and elranatamab-bcmm (Elrexfio; Pfizer Inc), have shown high overall response rates in clinical trials and are approved for the management of relapsed or refractory MM (RRMM).^2-6

On July 2, 2025, the FDA granted accelerated approval to linvoseltamab-gcpt (Lynozyfic; Regeneron Pharmaceuticals, Inc) for the treatment of adults with RRMM who have not had success with at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. The approval was based on the agent demonstrating deep, long-lasting responses in heavily pretreated patients, making linvoseltamab the fourth BTCE antibody approved for the management of RRMM.⁷

Mechanism of Action

Linvoseltamab is a recombinant immunoglobulin (Ig) G4 BTCE antibody against BCMA expressed on the surface of multiple myeloma cells and the CD3 receptor expressed on the surface of T cells. The binding of CD3 and BCMA leads to T-cell activation, resulting in cytokine release and tumor cell death.⁸

Dosing and Administration

Like all bispecific T-cell engagers on the market, linvoseltamab requires a step-up dosing schedule and premedications to reduce the incidence and severity of cytokine release syndrome (CRS). Table 1 shows the dosing schedule, recommended monitoring, premedications, and infusion durations.⁸ A few key differences compared with other BTCEs for RRMM are linvoseltamab’s intravenous (IV) route of administration, the higher dose of dexamethasone used as a premedication (40 mg), and the ability to space out dosing to monthly as early as week 24.^8,9

Clinical Data for Linvoseltamab

Linvoseltamab received accelerated FDA approval based on findings from the LINKER-MM1 trial (NCT03761108).¹⁰ This phase 1/2, open-label, multicenter, multicohort trial included adult patients with RRMM who had not had success with at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody. Patients had to have an ECOG performance status of 0 or 1 and were allowed to have received a BCMA-directed antibody-drug conjugate (ADC), but were excluded if they had received other BCMA-directed immunotherapies. Patients were also excluded if they had known central nervous system involvement of MM, plasma cell leukemia, or primary systemic light-chain amyloidosis.⁹

The phase 1 dose escalation followed a modified 3 + 3 dose escalation design, and the phase 2 portion of the study evaluated 2 full doses of 50 mg and 200 mg. For both treatment groups, step-up doses of 5 mg (cycle 1, day 1; C1D1) followed by 25 mg (C1D8) were given weekly, with the first treatment dose given the following week (C1D15). Weekly dosing was continued from weeks 3 through 14, followed by every-other-week dosing (biweekly) from weeks 16 through 24. The 200-mg group was allowed to transition to monthly dosing at week 24 if they had achieved at least a very good partial response (VGPR) or better and had been on therapy for a minimum of 24 weeks. Patients receiving the 50-mg dose who had progressed after weeks 4 through 14 on treatment were allowed to be escalated to 200 mg. Treatment was continued until disease progression, withdrawal of consent, or physician decision.⁹

The primary end point in the phase 2 portion of LINKER-MM1 was overall response rate (ORR) determined by an independent review committee. Secondary end points included duration of response, progression-free survival (PFS), overall survival (OS), rate of minimal residual disease (MRD) negativity (negative threshold of 10^–5), and safety. A total of 282 patients were enrolled and treated with linvoseltamab between January 23, 2019, and October 18, 2022. A total of 117 patients were treated with 200 mg, and 104 were treated with 50 mg. Those who received 200 mg had a median age of 70 years (range, 37-91), with a median of 5 prior lines of therapy (range, 2-16), including 39.3% with high-risk cytogenetics, 16.2% with extramedullary disease, and 28.2% who were at least penta-refractory.⁹

The ORR was 70.9% in the 200-mg group and 48.1% in the 50-mg group. Patients in the 200-mg group who achieved a complete response (CR) or better were evaluated for MRD negativity using clonoSEQ or EuroFlow tests. MRD negativity was achieved in 92.9% of patients. The ORR in the 200-mg group remained high across high-risk subgroups, with ORRs of 67.4% in patients with high-risk cytogenetics, 66.7% in those with penta-refractory disease, and 52.6% in those with extramedullary disease. Ten patients also had prior exposure to the anti-BCMA ADC belantamab mafodotin-blmf (Blenrep; GlaxoSmithKline LLC), with an ORR of 70.0%. Eight patients who progressed on the 50-mg dose escalated to 200 mg, with 75.0% having a VGPR.⁹

The time to response was rapid, with a median time to at least partial response (PR) of 1 month (range, 0.5-6.3), and deepened responses occurred over time. The median time to at least a CR was 8.5 months (range, 1.6-14.1). Of the 31 patients who changed to monthly dosing before achieving a CR or better, 64.5% deepened their response to CR or better. PFS and OS have not yet been reached, but the probability of attaining PFS at 12 months was 70.0%, and the likelihood of being alive at 12 months was 75.3%.⁹

Adverse Effects

The most common adverse effect (AE) during the step-up treatment period was CRS, which occurred in 54.8% and 46.2% of patients in the 50-mg and 200-mg groups, respectively, primarily at grade 1/2 (52.9% and 45.3%, respectively). Grade 3 CRS occurred in 2 patients (1.9%) in the 50-mg group and 1 patient (0.9%) in the 200-mg group. In the 200-mg group, the grade 3 event occurred with the first step-up dose. In the 50-mg group, one patient experienced a grade 3 event with the first step-up dose, and another patient with the second step-up dose. No grade 4 or 5 CRS events occurred. The median time to CRS onset was 11 hours (measured from the end of infusion; range, –1.1 to 183.6), and the median time to resolution was 15.6 hours (range, 1-96). Most CRS events occurred during the step-up dosing period. Thirty-eight percent occurred with the first step-up dose, followed by 17.0% with the second step-up dose, 10.0% with the first treatment dose, and 3.6% with the second treatment dose.⁹

Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 9 patients (7.7%) in the 200-mg group (2.6% each for grades 1, 2, and 3). No grade 4 ICANS events occurred. All patients except 1 had ICANS during step-up dosing, with all events occurring either with CRS or an infusion-related reaction. ICANS median time to onset was 1 day (range, 1-4), with a median time to resolution of 2 days (range, 1-11).⁹

The most common AEs observed after step-up dosing in the 200-mg group included myelosuppression, hepatotoxicity, and infections (Table 2).⁹ Infections in the RRMM patient population are well known. Prophylactic strategies should include protection against varicella zoster, most commonly with acyclovir or valacyclovir, and protection against Pneumocystis jirovecii, most commonly with sulfamethoxazole-trimethoprim.¹¹ There were 3 treatment-related deaths due to infections, 1 each from P jirovecii pneumonia (PJP), progressive multifocal leukoencephalopathy, and pseudomonal sepsis. The most frequent opportunistic infection was PJP (4.3%), and all cases occurred before the PJP prophylaxis was started. After instituting PJP prophylaxis, no additional cases of PJP occurred, underscoring the importance of prophylaxis in this patient population. IV Ig (IVIG) use was at the treating provider’s discretion, with 64.1% of patients receiving at least 1 dose.⁹

Linvoseltamab’s Place in Therapy

Linvoseltamab joins a competitive market for BTCEs in the RRMM space. Teclistamab and elranatamab target BCMA, and talquetamab targets GPRC5D.^2-4 Linvoseltamab is the only FDA-approved BTCE administered via IV, with the option to switch to monthly dosing as early as 6 months; by contrast, elranatamab does not switch to monthly dosing until 1 year.^3,9

Linvoseltamab also offers convenient flat dosing, mitigating concerns about drug waste and reimbursement.⁸ Like teclistamab, elranatamab, and talquetamab, it is approved for patients with RRMM who have not had success with at least 4 prior lines of therapy, including a PI, IMiD, and an anti-CD38 monoclonal antibody.^2-4,9 A key difference in sequencing is that, at this time, teclistamab, elranatamab, and talquetamab allow prior BCMA CAR-T cell therapy, whereas linvoseltamab does not, potentially limiting its role in patients whose disease has progressed on cilta-cel or ide-cel.^2-5,9

Clinical and Logistical Considerations

Because of the risk of CRS and ICANS with linvoseltamab, patients should be monitored in the inpatient setting for 24 hours after the first 2 doses.⁸ Some centers are well equipped to handle this specialized monitoring in the outpatient setting with home monitoring equipment and provider coverage after hours, whereas other institutions may prefer to partner with a hospital for inpatient observation for the first 2 doses. Compared with other BTCEs for RRMM, linvoseltamab has the shortest hospital monitoring recommendations (Table 3^2-4,9), and it can be given during an inpatient observation encounter and still billed as outpatient. If clinic chair time is not a concern, linvoseltamab can be given in the clinic, and the patient can then be admitted for observation.^2-4,9 Based on the LINKER-MM1 trial results, linvoseltamab has the lowest reported rates of CRS (Figure^2-4,9), likely due to the higher dose of dexamethasone given as a premedication, making outpatient administration an attractive option to consider; however, it does come with a longer chair time due to the infusion duration.⁹

Due to the risks of CRS and neurologic toxicity, including ICANS, linvoseltamab is available only through Lynozyfic REMS, a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Like other REMS programs for MM BTCEs, it requires facility enrollment, provider enrollment, and distribution of a wallet card to the patient to ensure proper patient and caregiver education.⁸

Conclusions

Linvoseltamab is finding its place within the crowded RRMM treatment paradigm, joining 2 other BCMA-targeting BTCEs already on the market and 1 targeting GPRC5D.^2-4,9 Linvoseltamab is the only IV BTCE for RRMM, and it can go to monthly dosing as early as week 24.⁸ Its use is technically limited after BCMA CAR T-cell therapy, given that these patients were excluded from the LINKER-MM1 trial. However, considering the response rates of the other BCMA-targeting BTCEs, there is no compelling reason it could not be used in this patient population in clinical practice. Some providers may select a different BTCE in this patient population until linvoseltamab gains this sequencing data, which will come with time. Linvoseltamab has the lowest CRS rate, likely due to the higher dexamethasone premedication dose prior to the step-up doses and its convenient flat dosing.⁸ All BTCEs in RRMM give patients high response rates, and the selection of the product will likely come down to the payer, facility formularies, patient preference, and provider preference.^2-4,9

REFERENCES

1. Parekh DS, Tiger YKR, Jamouss KT, Hassani J, Bou Zerdan M, Raza S. Updates on therapeutic strategies in the treatment of relapsed/refractory multiple myeloma. Cancers (Basel). 2024;16(17):2931. doi:10.3390/cancers16172931

2. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478

3. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9

4. Jakubowiak AJ, Anguille S, Karlin L, et al. Updated results of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma with prior exposure to T-cell redirecting therapies: results of the phase 1/2 MonumenTAL-1 study. Blood. 2023;142(suppl 1):3377. doi:10.1182/blood-2023-187242

5. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

6. Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8009. doi:10.1200/JCO.2023.41.16_suppl.8009

7. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed July 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma

8. Lynozyfic. Prescribing information. Regeneron Pharmaceuticals, Inc; 2025. Accessed July 5, 2025. https://www.regeneron.com/downloads/lynozyfic_fpi.pdf

9. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(22):2702-2712. doi:10.1200/JCO.24.01008

10. Phase 1/2 study of linvoseltamab in adult patients with relapsed or refractory multiple myeloma (LINKER-MM1). ClinicalTrials.gov. Updated September 3, 2025. Accessed September 21, 2025. https://clinicaltrials.gov/study/NCT03761108

11. Swan D, Murphy P, Glavey S, Quinn J. Bispecific antibodies in multiple myeloma: opportunities to enhance efficacy and improve safety. Cancers (Basel). 2023;15(6):1819. doi:10.3390/cancers15061819