Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma
Authors: Ghobrial Irene M. , Laubach Jacob P. , Shain Kenneth H. , Baz Rachid , Boswell Erica N , Henrick Patrick M , Azab Abdel Kareem , Hanlon Courtney , Chuma Stacey , Leblebjian Houry , Noonan Kimberly , MacNabb Megan H. , Warren Diane , Armand Philippe , Paba-Prada Claudia E. , Munshi Nikhil C. , Schlossman Robert L , Anderson Kenneth C. , Richardson Paul G. 
Published: October 2019

Abstract
INTRODUCTION: 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). The phase I portion of this study was to determine the maximum tolerated dose (MTD). The phase II portion was designed to assess the toxicity profile and the proportion of overall confirmed response (CR + PR). This was based on preclinical studies demonstrating that plerixafor (Mozobil, Sanofi 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. Phase I included eight cohorts with different doses and two treatment schedules. In cohorts 1–5, patients received plerixafor at the recommended dose subcutaneously (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. 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. For the phase II portion patients received plerixafor at the MTD, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. Patients who had a response or stable disease went on to receive a total of 8 cycles followed by maintenance therapy. Peripheral blood samples were obtained from the patients in the phase I portion of trial 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 the phase I portion of trial and 23 patients in the phase II study. In the phase I study, the 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. 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%). In the phase II portion, twenty-three patients have been treated to date. The median age was 70 (56-83), the median lines of prior therapy were 3 (1-5). The median number of cycles on therapy was 7 (1-12). Grade 4 toxicities include lymphopenia (9%), thrombocytopenia (17%) and pneumonia (4%). Grade 3 toxicities included anemia (9%), thrombocytopenia (17%), neutropenia (4%), lymphopenia (13%), hyperglycemia (9%), hypophosphatemia (9%), elevated ALT, AST and Lipase (4%). In the phase I study, 23 patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR) and 3 (13%) MR. In addition, 15 (65%) patients achieved stable disease (SD). For the phase II study, the response rate of PR or better was 13/23 (43%) including 4 (17%) VGPR and 6 (26%) PR in this relapsed/refractory population. In addition, 7 (39%) patients had stable disease (SD), and 3 (13%) had progressive disease (PD). 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.
CONCLUSIONS: The combination of plerixafor and bortezomib was very active in this study, with minimal neuropathy or other toxicities seen to date, and the regimen was generally well tolerated. The responses observed are encouraging, with 43% PR or better in this relapsed and refractory population, including patients with significant exposure to prior bortezomib therapy.

Disclosures
Ghobrial: Sanofi: Research Funding; 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; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other. Off Label Use: Plerixafor is not FDA approved for relapsed myeloma. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Schlossman:Millennium: Consultancy. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.