Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Preliminary Results of a Phase 1/2 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Relapsed or Refractory Myeloma

Abstract BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma are enrolling on a standard 3+3 dose escalation design. Patients receive a 2-week run-in of single-agent oral HCQ (at escalating doses), followed by addition of standard dose bortezomib (on days 1, 4, 8, and 11 of 21-day cycles). Dose-limiting toxicity (DLT) is defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. Response is assessed on day 1 of each cycle according to International Working Group criteria. We use electron microscopy (EM) to characterize changes in autophagic vesicles (AVs) in serial samples of peripheral blood mononuclear cells (PBMCs) and CD138-selected bone marrow plasma cells (BMPCs) RESULTS: Ten patients have enrolled in the first 3 dose levels (see table). The median age is 63.5 (range 43–68), and 5 (50%) are male. The median number of prior lines of therapy is 4 (range 1–8). Seven patients had received prior Bz. No DLTs have been observed. Adverse events have generally been those expected with Bz: thrombocytopenia (30%, grade 3: 20%), anemia (70%, grade 3: 30%), and fatigue (70%, all grade 1/2), as well as neutropenia (20%, grade 3:10%). Grade 2 treatment-emergent peripheral neuropathy occurred in 1 patient (grade 1 in 3 patients). No patients developed retinal toxicity. Four patients had pulmonary infections: 1 viral influenza, 1 H. influenzae, and 2 lobar pneumonias; all resolved with appropriate antibiotics and did not preclude continued therapy. One patient died from complications of C. difficile colitis that occurred at the end of the 4th cycle, after antibiotic therapy for an upper respiratory infection. One patient had a minor response after previously progressing on single-agent Bz. EM analysis of PBMCs and BMPCs show no significant changes in AVs thus far with the lowest dose of HCQ. Enrollment is ongoing at higher doses of HCQ (escalating from 400 to 1200 mg daily). CONCLUSION: At the lowest dose levels tested, combined Bz and HCQ is tolerable, without evidence of synergistic toxicity. EM is a feasible pharmacodynamic assay for patient tumor and normal cells. Further dose escalation will determine whether combined autophagy and proteasome inhibition is achievable and safe with these agents. Updated clinical and correlative results will be presented. Dose Cohort Prior response to Velcade Best response on study Weeks on study Reason for discontinuation HCQ 200 mg qod PD Progression 11 Progression + Bz 1.0 mg/m2 SD Stable disease 32+ - - Stable disease 18 Lack of response ___________ _________ ___________ ________ __________________ HCQ 200 mg qod SD→PD Stable disease 14 Lack of response + Bz 1.3 mg/m2 PR→PD Minor response 14 Adverse event (unrelated) - Stable disease 21+ - ___________ _________ ___________ ________ __________________ HCQ 200 mg qd - Stable disease 9+ - + Bz 1.3 mg/m2 SD→PD Stable disease 8+ - PR→PD Progression 3 Progression PR→PD Not evaluable 4+ -