When CRS Strikes Late: An Unusual Presentation of Elranatamab Toxicity in Refractory Multiple Myeloma: A Case Report

Cytokine release syndrome (CRS) is an early-onset complication of bispecific T-cell engagers such as elranatamab, a BCMA-directed CD3 bispecific antibody recently approved for relapsed/refractory multiple myeloma. Nearly all cases of CRS occur within the first two weeks of therapy. The MagnetisMM-9 trial in 2024 demonstrated only 1 of 85 patients who developed CRS beyond the fourth dose, while none had experienced grade 3+ CRS. We report what is, to our knowledge, the first published case of Grade 3 CRS occurring four months into elranatamab therapy, marking an exceptionally rare deviation from typical toxicity patterns.

A 39-year-old female with POEMS syndrome secondary to light chain-predominant multiple myeloma was treated with multiple prior regimens, including D-KPd, DPd, and DPd with bortezomib. Due to incomplete disease response, she began weekly subcutaneous elranatamab in June 2024. After four months of therapy, she experienced chest pain, tachycardia, vomiting, and cough three days following her October 24th injection. Imaging revealed diffuse bilateral pulmonary ground-glass opacities with foci of consolidation. Despite broad-spectrum antibiotics, antivirals, and corticosteroids, her condition worsened. She was sent to the ICU for worsening respiratory distress, requiring approximately 60 liters of 90% FiO2 high flow nasal cannula, consistent with Grade 3 CRS. Tocilizumab was initiated one week into hospitalization, and within 48 hours, the patient showed gradual respiratory improvement. Six days post-tocilizumab, she tolerated low-flow nasal cannula and was eventually discharged twelve days after on room air.

Delayed-onset CRS of this severity associated with elranatamab is not well known, making this one of the few documented instances of Grade 3 CRS developing months into treatment. The delayed timeline poses a challenge, as clinicians typically attribute late symptoms to infection, disease relapse, or unrelated complications. This case challenges established guidelines about the course of CRS and long-term surveillance protocols in patients receiving bispecific therapies.