Tumor flare pain reaction during teclistamab step-up dosing with tocilizumab prophylaxis: An underrecognized toxicity in the outpatient setting

Abstract Background: Teclistamab is a BCMA-directed bispecific antibody approved for the treatment of relapsed and refractory multiple myeloma (RRMM). However, despite the deep and durable response rates achieved, concerns remain regarding the acute toxicity profile, particularly the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Interestingly, additional toxicities have been reported with teclistamab,notably bone pain, which occurred in 17.6% of patients in the MajesTEC-1 trial (grade ≥ 3: 3.6%). We observed a high frequency of severe bone pain in our cohort of patients treated with teclistamab, particularly during the step-up dosing phase. This raised concerns about a tumor flare pain reaction. Thus, this study aimed to assess the safety of outpatient teclistamab administration with tocilizumab prophylaxis during the step-up dosing phase. Methods: We retrospectively evaluated all patients with RRMM who completed cycle 1 of teclistamab therapy initiated in an outpatient setting. All patients received tocilizumab prophylaxis (8mg/kg) at cycle 1, day 1, with an accelerated step-up dosing at day 1, day 3, and day 5, followed by a weekly dose. Other premedications consisted of dexamethasone (16 mg), acetaminophen (975 mg) and cetirizine (10 mg) for the first three doses. To receive outpatient teclistamab step-up dosing, patients were required to stay within 60 minutes of the hospital and have access to a 24-hour caregiver support. During the first 7 days, subjects were contacted by telephone or videoconference 4 times daily. CRS and ICANS were graded according to ASTCT guidelines. Tumor flare pain reaction was described as acute and severe bone pain without evidence of progressive disease or pseudo-progression. Results: Between July 2023 and July 2025, 34 subjects received at least five doses of teclistamab. Median age was 70 years (range 31-91), 53% were male, and 41% had extramedullary disease. The median number of prior lines of therapy was 3. The overall response rate of the global cohort was 74%. Adverse events included CRS in 9% and ICANS in 3% of patients, all grade 1. Two patients received dexamethasone and one other patient received tocilizumab for the management of CRS. Additionally, one patient required dexamethasone for ICANS management. No patients required hospitalization for CRS or ICANS management. Moreover, 6 patients (18%) presented with tumor flare pain reaction, and two of them required hospitalization for symptom management. All of whom received opioid analgesia, and all experienced rapid relief following dexamethasone administration. Two patients’ PET-CT showed moderate to high FDG uptake in the axial and proximal appendicular skeleton without corresponding lesions on CT or biological signs of progression. For the other four patients, only one imaging study (MRI or CT scan) showed pseudo-progression. For three patients, a broad cytokine panel was done during the pain episode, cytokine analysis revealed that most values were within normal limits, except for IL-2 (approximately twice above normal), soluble IL-2 receptor (1.5 to 3 times above the upper limit of normal), IL-10 (25 to 50 times above normal), and IL-6 (>100 times above normal). Conclusions: Our results support that outpatient administration with tocilizumab prophylaxis is a safe and feasible option for teclistamab step-up dosing. Prophylactic use of tocilizumab reduces both CRS incidence and severity with a very low rate of admission. Tumor flare pain reaction seems to be an under-recognized yet clinically significant adverse event occurring during teclistamab step-up dosing, often presenting as acute and severe bone pain with or without pseudo-progression. Tocilizumab may block the classical IL-6 signaling pathway while paradoxically enhancing a trans-signaling pathway, activating sensory neurons via GP130 and promoting pain through the JAK2/STAT3 pathway. Though speculative, this hypothesis has not been reported previously in studies evaluating prophylactic tocilizumab and warrants further investigation.

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