Goodman, Stacey

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

8515 Background: AL is a clonal plasma cell (PC) disorder causing multiorgan dysfunction from amyloid fibril deposition. While bortezomib (B) induction has been used prior to AHCT recently, AHCT without prior induction has been a common practice. The primary objective of this study was to compare outcomes of AL patients who proceeded to AHCT without induction to those receiving pre-AHCT induction with B. Methods: Outcomes of 426 systemic AL AHCT recipients between 2014-2018 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were reviewed. Patients receiving induction with therapy other than B, AHCT occurring > 9 months after diagnosis, no documented AL end-organ involvement, myeloma-defining events and conditioning other than melphalan (MEL) monotherapy were excluded. Multivariate analysis (MVA) was conducted to identify prognostic factors associated with relapse, PFS and overall survival (OS). Results: 286 patients received B induction therapy vs 140 patients receiving no induction. Age, gender, number and type of organs involved, and AL AHCT center volume were similar between the groups. Patients receiving induction had greater PC burden compared with no induction (PC ≥ 10%, 41% vs 11%, p < 0.01). Induction was B, cyclophosphamide and dexamethasone (D) in 83% followed by B, lenalidomide and D (10%) or B+D (7%). Median follow-up was 24.9 months. At 2 years, B induction vs. no induction was associated with 13% (95% CI 10-17%) vs 22% (95% CI 15-30%) relapse risk (p = 0.03); 83% (95% CI 79-87%) vs 74% (95% CI 66-81%) PFS (p = 0.04); 93% (95% CI 90-95%) vs 94% (95% CI 89-97%) OS (p = 0.7). On MVA, the B induction group had improved PFS (HR 0.46, 95% CI 0.3-0.7, p < 0.001) with similar OS (HR 0.6, 95% CI 0.3-1.2, p = 0.1) compared with no induction. Creatinine < 2 mg/dl (HR 0.55, 95% CI 0.3-0.9, p = 0.02) and Karnofsky score ≥90 (HR 0.51, 95% CI 0.33-0.78, p < 0.01) were also associated with improved PFS. MEL dose < 180 mg/m2 was associated with inferior PFS (HR 2.17, 95% CI 1.31-3.61, p < 0.01) and OS (HR 3.6, 95% CI 1.5-8.6, p < 0.01). No deaths were seen in the first 100 days post-AHCT. At last follow-up, 32 deaths occurred, 26 (81%) due to AL. Conclusions: Compared with prior CIBMTR analyses, B induction use has increased in AL AHCT recipients and a higher PC burden was the only clinical determinant. Furthermore, B induction was associated with lower relapse and improved PFS at 2 years with no OS difference despite higher proportion of patients with > 10% PC, which has been associated with poor outcomes.