CRS With Linvoseltamab Peaks 6 to 8 Hours After First Step-Up Dose

Cytokine release syndrome (CRS) associated with linvoseltamab-gcpt (Lynozyfic; Regeneron) occurred most frequently 6 to 8 hours after the first step-up dose and declined with subsequent administrations, according to a retrospective analysis of patient-level data from the phase 1/2 LINKER-MM1 trial (NCT03761108).¹

Among 117 patients receiving the 200-mg regimen, signs and symptoms of CRS occurred in 26.5% following the first step-up dose, 13.3% following the second step-up dose, and 2.7% following the first full dose. Nearly all events were grade 1 or 2. The findings were presented at the 23rd International Myeloma Society Annual Meeting.¹

LINKER-MM1 Supported Linvoseltamab Approval

Linvoseltamab is a B-cell maturation antigen–directed CD3 bispecific antibody that redirects T cells toward malignant plasma cells. LINKER-MM1 evaluated linvoseltamab in adults with relapsed or refractory multiple myeloma previously treated with an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients enrolled in phase 2 were required to have triple-class refractory disease.¹

Earlier results from the trial demonstrated an overall response rate of 71% with the 200-mg dose, including a complete response or better in approximately half of patients after longer follow-up. CRS occurred in 46% of the 117-patient population, including grade 1 events in 35%, grade 2 events in 10.3%, and grade 3 events in 0.9%.^1,2

The FDA granted linvoseltamab accelerated approval in July 2025 for adults with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Its prescribing information carries boxed warnings for serious or fatal CRS and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome.^3,4

CRS Concentrated After Initial Step-Up Dose

The updated analysis examined the timing, frequency, and severity of CRS during step-up dosing. Patients received 5 mg on day 1, 25 mg on day 8, and the first full 200-mg dose on day 15. Premedication was administered without prophylactic tocilizumab, and patients underwent 24-hour inpatient monitoring following each step-up dose. Events with missing start times were excluded from the timing analysis.¹

Following the first 5-mg dose, 31 patients experienced signs or symptoms of CRS. Grade 1 events occurred in 24 patients between 4 and 25 hours after administration. Six patients developed grade 2 CRS between 5 and 13 hours post dose. The single grade 3 event occurred during the seventh hour.¹

CRS frequency peaked between 6 and 8 hours after the first step-up dose. Three grade 2 events and intermittent grade 1 events occurred after this peak, showing that risk continued beyond the highest-incidence window.¹

Following the second step-up dose, 15 of 113 treated patients, or 13.3%, experienced CRS. Fourteen events were grade 1 and occurred between 4 and 21 hours after administration. Most were observed between hours 4 and 11. One grade 2 event occurred during the eighth hour, and no grade 3 events were reported.¹

Only 3 of 111 patients, or 2.7%, developed CRS after the first full dose. Two grade 1 events began during the fifth and seventh hours, whereas 1 grade 2 event began during the 10th hour. No grade 3 events followed the first full dose.¹

Findings Inform Monitoring and Intervention

Tocilizumab was administered to 22 patients, representing 18.8% of the full analysis population. Corticosteroids were used in 11.1%, oxygen support in 7.7%, and intravenous fluid boluses in 9.4%. One patient required vasopressor support.¹

The concentration of events after the first step-up dose helps define when clinical teams should maintain their highest level of vigilance. It does not support shortening observation independently of the prescribing information, which requires hospitalization for 24 hours after both the first and second step-up doses.⁴

For pharmacists, the results can inform staffing, bedside assessment, and readiness to administer supportive treatment. Baseline counseling should emphasize fever as a possible early sign of CRS and the need to report symptoms immediately. Teams must also remain prepared to distinguish CRS from infection, because heavily pretreated patients receiving BCMA-directed bispecific therapy face substantial infectious risk. Consensus guidance recommends structured infection screening, prophylaxis, immunoglobulin monitoring, and vaccination planning during bispecific-antibody treatment.⁵

The analysis shows that linvoseltamab-associated CRS is most likely to emerge several hours after initial exposure and becomes less frequent as dosing progresses. Adherence to step-up dosing and required observation remains essential despite the low incidence of severe events.

REFERENCES

1. Martínez-López J, Mateos MV, Rodríguez-Otero P, et al. Incidence and timing of cytokine release syndrome observed with linvoseltamab in LINKER-MM1 in patients with relapsed/refractory multiple myeloma. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Abstract PA-253.

2. 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

3. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. News release. FDA. July 2, 2025. Accessed September 28, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma

4. Lynozyfic (linvoseltamab-gcpt) injection, for intravenous use. Prescribing information. Regeneron Pharmaceuticals, Inc; 2025. Accessed September 28, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761400s000lbl.pdf

5. Ludwig H, Terpos E, van de Donk N, et al. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023;24(6):e255-e269. doi:10.1016/S1470-2045(23)00159-6