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

Plerixafor (Mozobil^®), a potent CXCR4 inhibitor, is approved in combination with G-CSF to mobilize hematopoietic stem cells (HSCs) for autologous transplantation in multiple myeloma (MM) and non Hodgkin's lymphoma (NHL). Another area of investigation consists of exploring whether disruption of the CXCR4 pathway by plerixafor could potentiate the effect of chemotherapy in active disease. This study aimed to establish the maximum tolerated dose (MTD) of plerixafor in combination with bortezomib in patients who have active relapse/refractory MM. This was informed by preclinical studies showing that plerixafor induces de-adhesion of MM cells with sensitization to combination therapy with bortezomib in pre-clinical animal models.

Eligibility criteria include: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) measurable disease, 3) not receiving chemotherapy> 3weeks, or biological/novel therapy for MM > 2 weeks. Patients with active disease received plerixafor at the recommended dose sc on days 1–6 of every cycle. Dose levels include 0.16, 0.24, 0.32, 0.40, and 0.48 mg/kg. Bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Dose levels include 1.0 and 1.3 mg/m2. Bortezomib was given 60–90 minutes after plerixafor. Patients were assessed after every cycle. Patients who had response or stable disease went on to receive a total of 8 cycles without planned maintenance therapy. 4 dose levels were initially planned at a maximum of 0.24 mg/kg plerixafor. The protocol was then modified to include 3 higher doses of plerixafor, to further evaluate the hypothesis that higher doses may induce better chemosensitization. To examine the in vivo effect of plerixafor and bortezomib on de-adhesion of MM cells and other accessory cells of bone marrow, blood samples were obtained from patients at 0, 2, 4 and 24 hours post-plerixafor injection on days 1 and 3, and time points 0, 2, and 4 hours on days 6, 10 and 13 of cycle 1 and examined for the presence of plasma cells or CD34+ cells using flow cytometry.

Thirteen patients have been treated to date, three in each cohort with cohort 5 currently enrolling. The median age is 60, the median lines of prior therapy is 2. All of the patients received prior bortezomib. Three patients were assessed by light chain, two patients had extramedullary disease. The median number of cycles on therapy was 5 (1-8). None of the patients came off study due to toxicity. To date, there have been no dose-limiting toxicities. Overall, the combination is very well tolerated. Grade 3 possibly related toxicities include lymphopenia (30%), hypophosphatemia (15%), anemia (8%), and hyponatremia (8%). No grade 2 or higher neuropathy has been noted in these patients. Twelve patients are evaluable for response, including 1 (8%) complete remission (CR) and 1 (8%) minimal response (MR), with an overall response rate including MR of 2 (16%) in this relapsed/refractory population. In addition, 8 (66%) patients had stable disease (SD), and 2 (18%) had progressive disease (PD). We also examined the number of plasma cells, CD34+ HSCs, and other accessory bone marrow cells (including endothelial progenitor cells and plasmacytoid dendritic cells) in the peripheral blood. Analysis of these samples is ongoing, but preliminary data indicate de-adhesion of plasma cells.

: The combination of plerixafor and bortezomib is very well tolerated with minimal neuropathy or other toxicities. The responses observed are encouraging in this relapsed/refractory population. The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo indicates that these cells can be separated from their protective stromal environment which may make them more sensitive to chemotherapy. This study was supported by R01CA133799-01, and by Genzyme.

Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.