A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib plus Dexamethasone in Relapsed Multiple Myeloma.

Purpose: Ulocuplumab (BMS- 936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12. Experimental design: This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Len-Dex, Arm A), or bortezomib and dexamethasone (Bor-Dex, Arm B), in patients with relapsed/refractory MM. Results: Forty-six patients were evaluated (median age, 60 years; range, 53-67). The median number of prior therapies was 3, (range, 1-11), with 70% of subjects having received ≥ 3. This trial had a dose-escalation and a dose-expansion part. Using a 3-plus-3 design on both arms of the trial, ulocuplumab9s dose was escalated to a maximum of 10 mg/kg without reaching maximum tolerated dose (MTD).The most common treatment-related adverse events were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with Len-Dex showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiDs). Conclusion: This study showed that blockade of the CXCR4-CXCL12 axis by ulocuplumab is safe with acceptable adverse events and leads to a high response rate in combinationwith lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4-inhibitors a promising class of anti-myeloma drugs that should be further explored in clinical trials.