A phase I/II, open label, Study to evaluate safety, tolerability and efficacy of elranatamab in patients with relapsed or refractory AL amyloidosis: Interim report of phase I results

Abstract Background: Rapid and deep normalization of involved free light chains (iFLC) is necessary for organ response and attendant survival in AL amyloidosis patients. There are no FDA-approved treatment options for relapsed patients. Elranatamab, a bispecific T-cell redirecting antibody targeting B-cell maturation antigen (BCMA), is FDA-approved in relapsed and refractory multiple myeloma (MM) but has not been prospectively evaluated in AL amyloidosis patients. A retrospective case series demonstrated 100% overall response rate (ORR), including 65% complete responses (CR) and cardiac and renal responses. Herein, we report the interim results of the phase I portion of a multicenter, open-label, single-arm phase I/II clinical trial of elranatamab in relapsed AL amyloidosis patients (NCT06569147). Methods: Adult patients with AL amyloidosis based on consensus criteria and without overlapping MM who had progressed after or were refractory to 1+ prior line, inclusive of daratumumab and cyclophosphamide/bortezomib/dexamethasone, alone or in combination, were eligible. Patients with Mayo 2004 with European modification stage IIIB at the time of screening were excluded. No prior BCMA-targeting therapies were allowed, except for belantamab mafodotin, if it was not the last line of therapy before enrollment. Disease progression was defined as a difference between involved and uninvolved FLC (dFLC) of at least 20 mg/L after at least 2 cycles of therapy. In phase I, patients are administered two step-up doses, 12mg SQ and 32mg SQ on Day 1 (D1) and D4, respectively, followed by weekly 76mg SQ doses (Dose Level 0). For patients who achieve a very good partial response (VGPR) or better after 2 cycles, schedule is modified to elranatamab on D1 and D15 starting with Cycle 3. Patients received fixed-duration treatment consisting of 6 cycles, followed by observation. During phase I, patients are staggered every 28 days to allow for monitoring of dose-limiting toxicities. The primary objective of Phase I is to determine the recommended Phase II dose. Results: At a median 5.5 (range, 3–7.8) months follow-up, 6 patients were enrolled in this study. The median age of patients was 67.5 years (range, 58–70) with 4 patients ≥65 years old. The median time since diagnosis was 26 months (range, 11–66). At time of enrollment, 5 patients (83.3%) had Mayo 2004 with European Modifications Cardiac Stage I disease, and one patient had Stage IIIA (16.7%). The median NT-proBNP was 713 ng/L (range, 308–3512) and median high-sensitivity troponin T of 21 pg/mL (range, 10–103). Patients had a mean dFLC of 29.8 mg/L (std, 17.6). The median prior lines of therapy were 1.8 (range, 1–3) with all patients having previous daratumumab and bortezomib therapy. Cyclophosphamide was administered in 83.3% of patients and 66.7% had previous pomalidomide therapy. Cytokine release syndrome (CRS) occurred in 4 patients: one grade 1 (16.7%) and three grade 2 (50%). The median time to CRS was 1.5 days (range, 1–2) and median time to resolution 1 day (0–9). Tocilizumab was administered in 2 patients, dexamethasone in 1 patient and supplemental oxygen in 2 patients. No patient required vasopressor support. There were no occurrences of Immune Cell-Effector Associated Neurotoxicity Syndrome (ICANS) or other neurotoxicity. Hematological adverse events occurred in all patients: anemia (all grade=100%, ≥grade 3=16.7%), neutrophil count decrease (all grade=50%, ≥grade 3=16.7%), and platelet count decrease (all grade=50%, ≥grade 3 =0). Upper respiratory tract infections occurred in 3 patients (all grade=50%, ≥grade 3=0), and urinary tract infections occurred in 1 patient (all grade=16.7%, ≥grade 3=0). There have been no deaths, and no patients discontinued treatment. The ORR was 100%. All patients (100%) achieved a ≥ VGPR and 60% achieved a CR. All patients (100%) achieved dFLC<10 mg/L and iFLC<20mg/L by C2D1 (median time=15 days, range, 8-18). The median number of elranatamab doses received is 13 (8–17). Two of three patients evaluable for cardiac response achieved a carPR (66.6%) at 3 and 6 months, respectively. Conclusion: In this interim report of a phase I/II prospective study in patients with relapsed AL amyloidosis, elranatamab has demonstrated no new safety signals while showing promising efficacy. Data regarding longevity and predictive biomarkers of response stemming from correlative studies are highly anticipated. Data will be updated at the time of ASH meeting.