Phase I Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma

This study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Genzyme Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. METHODS: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy > 3 weeks, or biological therapy for MM > 2 weeks prior to study treatment. Eight cohorts with different doses and two treatment schedules were planned. In cohorts 1–5, patients received plerixafor at the recommended dose sq on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. To test the hypothesis that higher doses and a different schedule might induce better chemosensitization, in cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Bortezomib was given 60–90 minutes after plerixafor. Patients were assessed after every cycle by modified EBMT/UC criteria. Patients who had a response or stable disease went on to receive a total of 8 cycles with maintenance therapy for patients with at least a minimal response (MR). To examine the in vivo effect of plerixafor and bortezomib on de-adhesion of MM cells and other accessory cells of the bone marrow, peripheral blood samples were obtained from the patients at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. RESULTS: Twenty-five patients were enrolled in this phase I trial from June 2009 to May 2011. Median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). Overall, the combination proved to be well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). One patient came off treatment due to grade 2 painful neuropathy at cycle 5. Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR) and 3 (13%) MR, with an overall response rate (including MR) of 5 (22%) in this relapsed and refractory population. In addition, 15 (65%) patients achieved stable disease (SD), with just 3 (13%) having progressive disease (PD) as their best response. We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3, but less mobilization occurred on the following days. Hematopoietic stem cell mobilization occurred at 4 hours on days 1 and 3, and was less observed with subsequent doses of plerixafor consistent with prior studies. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are encouraging in this relapsed and refractory population. The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo in most of the patients indicates that chemosensitization can potentially be achieved in patients with MM using this approach. Further studies are warranted and a phase 2 trial is underway. This study was supported by R01CA133799-01, and by Genzyme Corporation.

Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Plerixafor in myeloma. Munshi:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy; Celgene: Consultancy. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.