Intensity of Cyclophosphamide-Based Bridging Therapy Before Chimeric Antigen Receptor T Cell Therapy in Myeloma

Abstract

Patients receiving autologous chimeric antigen receptor T-cell (CAR-T) therapies for multiple myeloma (MM) may require bridging therapy (BT) before CAR-T infusion to maintain some level of disease control. Alkylators such as cyclophosphamide (Cy) are often used as parts of BT regimens, either in high-intensity regimens such as modified hyperCVAD or once-weekly regimens such as KCd. However, there is no consensus around the optimal BT alkylator dose intensity in MM. We performed a single-center analysis of all instances of BT before planned autologous CAR-T for MM during a 5-year period ending April 2022. We classified bridging regimens into three cohorts: (1) hyperfractionated Cy (HyperCy) with inpatient Cy every 12-24 hours or as continuous intravenous infusions, (2) less intensive Cy dosing (WeeklyCy) such as KPd or KCd, and (3) NonCy, where no alkylators were used in BT. Demographic, disease-related, and treatment-related characteristics were collected for all patients. The three BT cohorts were compared using Fisher's exact tests, Kruskal-Wallis tests, and log-rank tests where appropriate. We identified 70 discrete BT instances among 64 unique patients: 29 (41%) with HyperCy, 23 (33%) with WeeklyCy, and 18 (26%) with NonCy. Median total levels of Cy dosing during BT were 2100 mg/m2, 615 mg/m2, and 0 mg/m2 respectively. Age, number of prior lines, triple-class refractory status, presence of high-risk cytogenetics, extramedullary disease, bone marrow plasma cell burden, involved free light chain (iFLC) kinetics before collection, and other measures of disease aggressiveness were comparable between cohorts. iFLC levels rose ≥25% and ≥100 mg/L during BT (approximating progressive disease) in comparable proportions (p=0.25) between cohorts: 52% HyperCy, 39% WeeklyCy, and 28% NonCy. All BT instances without subsequent CAR-T were due to manufacturing failures. Among 61 instances of bridging followed by CAR-T, vein-to-vein times were slightly longer (p = 0.03) with HyperCy (45 days) vs WeeklyCy (39 days) and NonCy (46.5 days). Neutrophil recovery timeframes were similar between cohorts, but platelet recovery took longer with HyperCy (64 days) vs WeeklyCy (42 days) and NonCy (12 days). PFS was comparable between cohorts, but median OS was not: 15.3 months with HyperCy versus 30.0 months with WeeklyCy and not reached with NonCy. In our retrospective analysis of BT before CAR-T therapy in MM, HyperCy did not result in superior disease control than WeeklyCy despite a threefold higher dose of Cy. In contrast, HyperCy was associated with longer post-CAR-T platelet recovery and worsened OS despite comparable measurements of disease aggressiveness and tumor burden. Study limitations include our small sample size as well as confounding from gestalt markers of MM aggressiveness that might have led both to poorer outcomes as well as physicians' decisions to prescribe HyperCy. Given the rarity of objective disease responses to chemotherapy in relapsed/refractory MM, our analysis suggests that hyperfractionated Cy regimens do not outperform once-weekly Cy regimens for most patients who require BT before CAR-T therapy.