Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM)

Background: CART-BCMA is an autologous T cell product engineered by lentiviral transduction to express a fully human BCMA-specific CAR with CD3ζ and 4-1BB signaling domains and expanded ex vivo using anti-CD3/anti-CD28 beads. We reported early safety and clinical activity of CART-BCMA without lymphodepleting chemotherapy in highly refractory MM patients (pts) (Cohen et al, ASH 2016, #1147). Here we report extended results from this initial cohort, as well as initial safety and efficacy in additional cohorts at 2 dose levels in conjunction with cyclophosphamide (Cy). Methods: Three cohorts are being enrolled: 1) 1-5 x 10⁸ CART cells alone; 2) Cy 1.5 g/m² + 1-5 x 10⁷ CART cells; and 3) Cy 1.5 g/m² + 1-5 x 10⁸ CART cells. CART-BCMA cells are given as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2), with Cy given on day -3. Pts need serum creatinine (Cr) <2.5 mg/dL or Cr clearance ≥30 ml/min; adequate hepatic, cardiac, and pulmonary function; and absolute CD3 count ≥150/µL. BCMA expression on MM cells is assessed but not required for eligibility. CART-BCMA expansion/persistence is assessed by flow cytometry and qPCR. Soluble BCMA levels are measured by ELISA. Responses are assessed by IMWG criteria. Results: As of 7/24/17, 33 pts have consented, with 28 eligible, 21 infused, 4 awaiting infusion, and 3 manufactured but never treated due to rapid progression/clinical deterioration. Of treated patients (n=21), 9 are in Cohort 1, 5 in Cohort 2, and 7 in Cohort 3. Median age is 57 (range 44-73); 71% male; median 4.3 years from diagnosis. Median lines of therapy is 7 (range 3-11); 100% are proteasome inhibitor and IMID-refractory, 67% daratumumab-refractory. 95% had high-risk cytogenetics, 67% del17p or TP53 mutation; 29% extramedullary disease. All expressed BCMA on MM cells and received the minimum target dose of CART-BCMA, with 18 pts (86%) receiving full planned dose, and 3 pts receiving 40% of dose (3^rd infusion held due to fevers). Toxicities in Cohort 1 (n=9) were previously reported, and included cytokine release syndrome (CRS) in 8 pts (3 grade 3/4, with 4 receiving tocilizumab) and neurotoxicity (grade 4 encephalopathy) in 2 pts. In Cohorts 2 and 3 (n=12), CRS has occurred in 9 pts (3 grade 3, 0 grade 4, none requiring tocilizumab), and neurotoxicity in 1 pt (grade 2 confusion/aphasia), with no unexpected/dose-limiting toxicities, and no treatment-related deaths. Regarding efficacy, in Cohort 1 6/9 pts responded (1 sCR, 2 VGPR, 1 PR, 2 MR), with 1 ongoing sCR at 21 months, and other responses lasting 1.5 to 5 months. In Cohort 2, with Cy but 10-fold lower CART dose, 2/5 pts responded (1 PR, 1 MR) but progressed at 4 and 2 months, respectively. In cohort 3, median follow-up is currently 1 month, with 5/6 pts responding (1 CR, 3 PR, 1 MR) and 1 not yet evaluable. All pts had detectable CART-BCMA expansion by qPCR, and 90% were detectable by flow cytometry, with preferential expansion of CD8+ cells, and similar degree of expansion in blood and marrow. Median peak expansion (as measured by copies/µg DNA) is 6160, 14761, and 45268 in Cohorts 1, 2, and 3, respectively, suggesting a benefit with adding Cy, though this was not statistically significant. Achieving PR or better is associated with higher peak CART-BCMA levels and decline in soluble BCMA, but not with baseline soluble BCMA level or intensity of baseline BCMA expression by flow on MM cells. Serial marrow flow cytometry demonstrates that 5/6 pts with ≥PR and detectable residual MM cells have decreased BCMA intensity on MM cells post-infusion compared with baseline. Conclusions: CART-BCMA infusions following Cy lymphodepletion are feasible and have significant clinical activity in highly-refractory MM pts with poor-risk genetics and limited treatment options. Efficacy appears lower at the 10⁷ dose, compared with 10⁸, and remaining pts are now being enrolled in Cohort 3. CRS remains a common but manageable toxicity. Decreased BCMA expression on residual MM cells post-infusion may be an escape mechanism reflecting CART-BCMA-induced immune editing. These data provide further support for exploration of CART-BCMA in relapsed/refractory MM, with updated cohort 3 data to be presented at the meeting.