A Phase II Trial of Chloroquine in Combination with Bortezomib and Cyclophosphamide in Patients with Relapsed and Refractory Multiple Myeloma

Background: preclinical data suggest that autophagy can serve as an adaptive mechanism facilitating tumor cell survival and resistance to therapy-induced apoptosis. Subsequently, inhibitors of autophagy are thought to enhance the efficacy of therapeutic strategies designed to induce tumor cell apoptosis. Based upon our preclinical results, we hypothesized that the addition of chloroquine, an autophagy inhibitor, to the combination of a proteasome inhibitor, and cyclophosphamide might result in a synergistic effect.

Patients and Methods: We designed a phase II trial of bortezomib, cyclophosphamide and chloroquine in patients with refractory myeloma (defined by > 25% increase in M-protein) who progressed on a combination of bortezomib and cyclophosphamide. Treatment consisted of 42 day cycles repeated until disease progression with bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11, 22, 25, 29 and 32; cyclophosphamide 50 mg orally twice a day; and chloroquine at 500 mg orally daily on days 1-14 and 22-35. The primary endpoint was to estimate clinical benefit (CR+VGPR+PR+SD) after 2 cycles.

Results: Between October 2011 and April 2013, 11 patients including 7 men and 4 women were enrolled and treated. The median age was 62 years (range 53-80). All patients were ISS stage II and III. Prior therapies for most patients included transplant, bortezomib, cyclophosphamide and lenalidomide. One patient withdrew after C1D1 and two patients progressed prior to completion of cycle 1. Of the 8 evaluable patients who completed at least 2 cycles, 3/8 achieved a partial response, 1/8 showed stable disease and 4/8 progressed with a clinical benefit rate of 4/10 (40%). Among the 3 patients who achieved a partial response, median duration of response was 4 months (250, 131 and 117 days respectively). The most common non-hematological adverse events (AEs) observed in >25% of patients (any Gr/Gr >3) and felt to be at least possibly related to the study drug were: fatigue (91%/18%); constipation (72%); myalgia, nausea (64% each); cough (55%), diarrhea, neuropathy (45% each); congestion (36%/9%); anorexia and dyspnea (27% each). The most commonly observed hematological AEs were neutropenia (45%/36%) and thrombocytopenia (55%/45%). Data from LC3 and beclin1 assays used to measure correlations of clinical response with in vitro autophagy inhibition will be presented.

Conclusions: this study suggests that the addition of chloroquine to bortezomib and cyclophosphamide is effective in overcoming proteasome inhibitor resistance in a significant fraction of heavily pretreated patients, with an acceptable toxicity profile.