Abstract
Background: The emergence of FDA approved bispecific antibodies for the treatment of relapsed and refractory multiple myeloma (RRMM) has significantly changed the treatment landscape. Early studies of teclistamab and elranatamab (BCMAxCD3) as well as talquetamab (GPRC5DxCD3) have shown high response rates at the expense of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and infections (Rodriguez-Otero et al. Lancet Oncol 2024). Sub-studies of larger trials have reported on the use of prophylactic tocilizumab prior to teclistamab (van de Donk et al. J Clin Oncol 2023) and the investigational bispecific antibody cevostamab (Trudel et al. Blood 2022). Limited real-world evidence is also emerging for prophylactic tocilizumab prior to teclistamab (Marin et al. Blood 2023; Kowalski et al. Blood 2023). To our knowledge there has not yet been any systematic study of this approach prior to elranatamab or talquetamab. We were motivated to administer prophylactic tocilizumab prior to the first step-up-dose for our patients treated with any of the three FDA approved bispecific antibodies.
Methods: This single-center study includes all RRMM patients treated outside the context of a clinical trial with a bispecific antibody at the University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center between the first FDA approval (October 25, 2022) and data cutoff (June 21, 2024). The primary aim was to investigate the effect on CRS mitigation which was assessed by the standard Lee ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Other adverse events were graded according to CTCAE V5.0.
Results: At the time of data cutoff 72 patients received prophylactic tocilizumab prior to bispecific antibody treatment. Of these patients, 36 were treated with teclistamab, 20 were treated with elranatamab and 16 were treated with talquetamab. The median age was 67 (range 40-84) and 21 (29%) patients were 75 or older. Forty-two (58%) of patients were female, 17 (24%) were Black and 25 (35%) were of Hispanic ethnicity. Fifty-five (76%) patients met at least one exclusion criteria for their respective drug's clinical trial. In this population we observed a low rate of CRS (14%; 95% CI: 7%-24%) and ICANS (8%; 95% CI: 3%-17%). The rate of CRS and ICANS for teclistamab, elranatamab, and talquetamab was 11% and 8%, 20% and 0%, and 13% and 19%, respectively. The rate of recurrence for CRS and ICANS was 0% and 1%. A single repeat dose of tocilizumab was given for ICANS and additional dexamethasone was given to 3 patients for ICANS. Among patients who experienced CRS, 9 of 10 events were grade 1 (teclistamab, elranatamab and talquetamab) and 1 was grade 2 (elranatamab). Among patients who experienced ICANS, 2 of 6 events were grade 1; 2 were grade 2 (teclistamab and talquetamab) and 2 were grade 3 (talquetamab). One of the suspected grade 3 ICANS events (decreased ICE score with possible seizure) occurred in a patient with known CNS myeloma and intra-cranial hemorrhage. The second suspected grade 3 ICANS event (seizure) occurred in a patient with plasma cell leukemia who required ICU care due to pneumonia, dialysis dependence, and suspected disseminated VZV. The complexity of these cases illustrates the real-world experience; in each case, ICANS could not be excluded. A serum IgG <400 mg/dL occurred in 59 (82%) patients and infections occurred in 34 (47%) patients. Grade 3 or higher neutropenia occurred in 38 (53%) patients within a median of 13 (range: 1-123) days. Among the 68 response evaluable patients, the overall response rate (ORR) was 45/68 (66%; 95% CI: 54-77%) in total and was 57%, 71% and 81% for teclistamab, elranatamab and talquetamab, respectively. The best objective response was complete response in 26 patients (38%; 95% CI: 27%-51%), partial response in 12 (18%; 95%CI: 9%-29%), stable disease in 13 (19%: 95% CI: 11%-30%), and progressive disease in 10 (15%: 95% CI: 7%-25%). Median follow up was 151.5 days (8-522) and among responders, the median duration of response was not reached. At the time of data cutoff, 38 (53%) patients remain on bispecific antibody therapy.
Conclusions: Our findings build on previous evidence that tocilizumab may be effective as a preventative, rather than reactive, measure for patients treated with a bispecific antibody for RRMM. Larger randomized studies are needed to confirm and expand on our results.
Kowalski:Pfizer: Consultancy. Diamond:Janssen: Honoraria. Maura:Sanofi: Consultancy, Honoraria; Medidata: Consultancy, Honoraria. Hoffman:Syndax: Other: stock and other ownership interests. Kazandjian:MJH Life Sciences: Honoraria; BMS: Honoraria; Alphasights: Consultancy; Curio Science: Honoraria; Karyopharm Therapeutics: Honoraria, Research Funding, Speakers Bureau; Bridger Consulting Group: Consultancy; MJH Life Sciences: Honoraria; Arcellx: Honoraria, Other: served on independent data monitoring committees (IDMC); Aperture Medical Technologies: Honoraria, Other: served on independent data monitoring committees (IDMC); Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magnolia: Honoraria; NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, BMS/Celgene, Janssen,: Research Funding; Aptitude Health: Honoraria; MMRF: Honoraria; Dedham Group: Consultancy; Plexus: Honoraria. Landgren:Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.
Tocilizumab for the prevention of cytokine release syndrome