Bortezomib in Combination with Cyclophosphamide and G-CSF for Hematopoietic Stem Cell Mobilization in Patients with Multiple Myeloma
Authors: Bagal Bhausaheb , Gokarn Anant , Bonda Avinash , Chavan Swapnil , Punatar Sachin , Nayak Lingaraj , Kannan Sadhana , Mathew Libin J , Patkar Nikhil , Tembhare Prashant , Poojary Minal , Ojha Shashank , Subramanian Papagudi Ganesan , Gujral Sumeet , Saikia Tapan , Khattry Navin 
Published: October 2019

Abstract
Background: Proteasome inhibitors (PI) have become integral part of front-line treatment of multiple myeloma. Murine model experiments have shown mobilization of hematopoietic stem cells from bone marrow to peripheral blood after PI administration via down regulation of very late antigen 4 (VLA-4) which mediate adherence of hematopoietic stem cells to the bone marrow microenvironment via interaction with vascular cell adhesion molecule (VCAM-1). Human studies with bortezomib in combination with G-CSF for mobilization have yielded encouraging results with no additional toxicity and no malignant plasma cell mobilization was observed. Cyclophosphamide based chemo-mobilization offers advantage in term of higher stem cell yield and is able to overcome adverse impact of prior lenalidomide therapy on stem cell harvest. In the current study we added bortezomib to cyclophosphamide-GCSF (B-Cy-GCSF) chemo-mobilization regimen to study the effect of bortezomib on stem cell harvest and compared this with our earlier protocol of only cyclophosphamide-GCSF (Cy-GCSF) mobilization.
Methods: Patients of multiple myeloma aged between 18 to 70 years were eligible for the study in the period between March 2016- June 2018. Patients after induction therapy achieving at least partial response and having no more than grade 1 peripheral neuropathy were enrolled. Patients received bortezomib at a dose of 1.3 mg/m2 on day 1, 4, 8 and 11 and cyclophosphamide (Cy) was administered at a dose of 1 g/m2 on day 8 and 9 followed by G-CSF 10µg/kg in two divided doses from day 11 onwards till target stem cell collection of at least 5 X 106/Kg. The peripheral blood CD34 (PB CD34) counts were monitored from day 14 and harvest was initiated when it reached above 20 cells/µL. The peak PB CD34 count achieved, the number of days of harvest required, the CD34 dose yield and the engraftment kinetics were recorded and compared with earlier patients who had undergone Cy-GCSF chemo-mobilization. These patients had received Cy 1 g/m2 on d1 and d2, G-CSF 10 mcg/kg from d4 onwards and PBCD34 monitored from d7 onwards.
Result: A total of 37 patients were enrolled between March 2016 and June 2018. Median age of study cohort was 46 years (range 27-63) and 27 (73 %) were males. Median lines of therapy received were 1 (range 1 to 2) and 8 (21.6 %) had received lenalidomide prior to stem cell harvest. The median peak peripheral blood CD34 cell counts 71.3 cells /µL (range 27.5 -306). Median CD34 cells collected were 9.21 X 106 /Kg (range 4.95-17.1). Target CD34 cell collection was achieved after a median of one day harvest (range 1-2). Median time to neutrophil and platelet engraftment was 11.5 and 13.5 days respectively. These results were compared with 88 patients who had undergone Cy-GCSF chemo-mobilization earlier at our center from May 2008 till February 2016 as seen in Table1 . In Cy- G-CSF cohort, median number of harvest required for target CD34 was 2 (range 1-4) and median CD34 cell yield was 8.2 X 106/Kg (0.4-24.2).
Target CD34 cells yield of 5 X 106/Kg was achieved with single apheresis in 58.6% of patients after B-Cy-GCSF mobilization as compared to 44.3% in Cy-G-CSF group, although this was not statistically significant (p=0.1). While 3(3.4 %) had failed chemo-mobilization after Cy-GCSF, none of patients in bortezomib group had mobilization failure.
Conclusion: Patients undergoing B-Cy-GCSF mobilization have higher stem cell yield and required less days of harvest. This strategy should be explored in a larger cohort of patients.

Disclosures
No relevant conflicts of interest to declare.