Post-CAR-T Checkpoint Inhibition Can Result in Durable Responses in a Minority of Patients with Multiple Myeloma (MM) or Non-Hodgkin's Lymphoma (NHL): Results of a Phase 2 Study of Nivolumab after CAR-T Failure

Background While checkpoint inhibition may theoretically improve T-cell effector function following CAR-T failure, a prospective trial of pembrolizumab following CAR-T in non-Hodgkin lymphoma (NHL) showed an ORR of only 25% (Chong Blood 2022). Nivolumab (nivo) has not been studied prospectively in this setting, and the efficacy of post-CAR-T checkpoint inhibition in multiple myeloma (MM) has not been characterized. Methods We conducted a single-center phase 2 trial (NCT04205409) of nivo 480mg IV every 4 weeks for MM or NHL pts with relapse following any CAR-T product as last line of therapy. The primary endpoint was overall response rate (ORR). Secondary endpoints included AEs, immune-related AEs (irAEs), and CRS/ICANS. Other endpoints included PFS, CAR-T expansion following first nivo dose, and PD-L1/PD-1 IHC expression on tumor biopsies. Results We enrolled 20 pts (11 MM, 9 NHL) as shown in Table 1. Prior to nivo, the best response to CAR-T had been CR in 64% of MM pts and 44% of NHL pts, while 1 MM pt and 1 NHL pt had had PD as best response. Median time from infusion to post-CAR-T relapse was 537 days (range 30-1100) in MM and 134 days (range 28-434) in NHL. Median time between CAR-T infusion & C1D1 nivo was 624 days (range 59-1211) in MM and 149 days (range 34-506) in NHL. The ORR was 15% overall: 18% (2/11) for MM and 11% (1/9) for NHL. In all 3 responders (Table 2), clinical benefit was evident following a single nivo dose. Both MM patients achieved VGPR by light chains within 4 weeks, with one also showing rapid resolution of an 8.6-cm plasmacytoma. For these two patients, median duration of response is 15 months (Table 2). The responding NHL patient [who had had a pre-enrollment Deauville Score (DS) 5 response at Day +60 following axi-cel] – achieved a complete response (DS3) one month following nivo initiation. Conversely, in all non-responders, PD was evident within one month of nivo as well. Two irAEs (one Gr2 pneumonitis, one Gr2 rash) occurred in non-responders, both of which resolved with brief courses of prednisone. CRS or ICANS did not occur following nivo initiation. There were 3 deaths within 100 days, all unrelated to treatment and all in non-responders: PD (n = 2) and hypotensive cardiac arrest without myocarditis (n = 1). The results of ongoing analyses with CAR T-cell expansion and PD-1 staining will be presented at the meeting. Conclusions To our knowledge, this is the first prospective evaluation of nivo following CAR-T failure. While our study's 18% ORR in MM was numerically higher than the 4% figure previously described with nivo monotherapy in R/R MM (Lesokhin JCO 2016), responses to PD-1 blockade following CAR-T failure in NHL were rare. irAEs were relatively uncommon and manageable with steroids, while CRS and ICANS did not occur. The durable responses achieved by a subset of MM patients is of interest, and further correlative analyses are ongoing to better understand the mechanism of response.