CD38 Antibody Re-treatment in Daratumumab-Refractory Multiple Myeloma After Time on Other Therapies.

Monoclonal antibodies targeting CD38 are important treatment in both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with FDA-approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether or not patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for > 1 year showed greater sensitivity than those with < 1 year, although they still were less sensitivity than those that were daratumumab naïve. CD38 expression on MM cells gradually recovered, although again not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response, but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had < 6 months of clinical benefit, but one patient for who was daratumumab-exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting one year before CD38 antibody re-challenge, but this approach may be best used as a bridge to, or after, CAR-T.