Comparison of Various Stem Cell Mobilization Regimens for Multiple Myeloma - a 15-Year Retrospective Institutional Analysis from India
Authors: Mirgh Sumeet , Bagal Bhausaheb , Punatar Sachin , Gokarn Anant , Jindal Nishant , Chichra Akanksha , Nayak Lingaraj , Reddy Laxma , Hiregoudar Sumathi , Poojary Minal , Saha Suryatapa , Ojha Shashank , Parab Sarika , Tembhare Prashant , Patkar Nikhil , Chatterjee Gaurav , Rajpal Sweta , Mathew Libin Jacob , Subramanian Papagudi Ganesan , Menon Hari , Khattry Navin 
Published: December 2023

Introduction
For multiple myeloma (MM), Cyclophosphamide (Cy) based chemo-mobilization offers advantage in term of higher stem cell yield and can overcome adverse impact of prior lenalidomide therapy on stem cell harvest. However, considering need for hospital stay and risk of febrile neutropenia, steady state mobilization with G-CSF and pre-emptive plerixafor (PEF) is becoming increasingly popular. Until few years back, cost of PEF was prohibitive thereby limiting its use and prompting a search for alternative cheaper drugs. Mouse models have shown that Proteasome Inhibitors aid in hematopoietic stem-cell (HSC) mobilization by down-regulating very-late antigen-4 (VLA-4) on bone marrow stromal cells which interacts with vascular cell adhesion molecule (VCAM-1) on HSC. We previously reported that bortezomib (Bort) in combination with Cy-G-CSF showed a trend towards higher CD34 yield and reduced need for apheresis sessions, without additional toxicity. There is limited data comparing mobilization regimens, especially from low-middle income countries where HSC collection may not be done after 4-6 cycles of first-line therapy. We hereby report our 15-year experience of various mobilization regimens for MM.
Methods
All patients with MM who underwent HSC mobilization from September 2007 - December 2022 were included in this analysis. Various mobilization regimens [Group 1 - G-CSF + Bort (August 2018 - December 2022); Group 2 - G-CSF + plerixafor (August 2018 - December 2022); Group 3 - Bort-Cy-GCSF (April 2016 - July 2018); Group 4 - Cy + G-CSF (September 2007 - March 2016)] were used as per respective time-periods (Table 1). Our aim was to collect CD34 cell dose of 5million/kg to suffice for 2 transplants. G-CSF (5 mcg/kg subcutaneously BD) was given on days 1-5 (Groups 1 and 2). Bort (1.3mg/m 2 iv / sc) (Group 1) or PEF (Group 2) were given on day 4 twelve hours prior to planned apheresis on day 5. Apheresis was done on day 5, and additionally on day 6, if first harvest was inadequate for 2 transplants. In group 3, Bort (1.3mg/m 2 iv) was given on days-1,4,8,11, with Cy (1gm/m 2 iv) on days 8 and 9, followed by G-CSF from day 11 onwards. Cy (1gm/m 2 iv) was given on day 1 and 2 (Group 4), followed by G-CSF from day 4 onwards. Stem cell harvest was done in groups 3 and 4 once peripheral blood CD34 (PB CD34) was &gt;20/µL. In groups 3 and 4, if PB CD34 was &lt;20/µL for 2 subsequent days, PEF was used according to physician's discretion, if available. Similarly in Group 1, if PB CD34 was between 10-20/µl on day 4, PEF was used according to physician's discretion. PEF was used in any group after the first harvest if the cell dose was deemed inadequate, at physician's discretion. Primary objective was to determine proportion of patients with CD34 + dose ≥5x10 6/kg in first apheresis in various groups. Secondary objectives were to determine total median CD34 + dose (x10 6/kg) collected, median CD34 + (x10 6/kg) in first apheresis, and frequency of mobilization failure. Mobilization failure was defined as total collected CD34 + dose of &lt;2x10 6/kg or abandoned harvest attempt anticipating a poor collection.Analysis was done as per planned regimen (intention to treat analysis).
Results
Total 205 patients were analyzed. Median age was 48 years (27-65 years) and 143 (70%) were males (Table 1). Median day of first collection in groups 3 and 4 was day10 from the first dose of cyclophosphamide. Percentage of patients who collected ≥5x10 6 CD34 + cells/kg in first apheresis were 26%, 53%, 69% and 63%, respectively in Groups 1-4 (p=0.0001) (Table 1). CD34+ cell-dose in first apheresis and total dose collected are shown in Table 1. In comparison to groups 1 and 2, both chemo-mobilization groups (group 3 and 4) had a significantly higher total cell dose (Figure 1). In comparison to group 1, both Cy chemo-mobilization groups had a significantly higher cell dose in first harvest, but there was no significant difference between group 2 and group 4 (p=0.23) (Figure 1). PEF was required additionally in 47%, 22%, and 7% of patients in groups 1, 3 and 4 respectively (P&lt;0.00001). Amongst transplanted patients, there was no difference in neutrophil or platelet engraftment and the frequency of engraftment syndrome in various groups.
Conclusion
Cy-based chemo-mobilization regimens have advantage of higher total stem cell yield, while they are equivalent to G-CSF + Plerixafor for harvest in single apheresis. Addition of Bortezomib to Cyclophosphamide may help to increase stem cell yield.