Timing of Daratumumab Administered Pre-Mobilization in Multiple Myeloma Impacts Pre-Harvest Peripheral Blood CD34+ Cell Counts and Plerixafor Use
Authors: Luan Danny , Christos Paul J , Ancharski Michael , Guarneri Danielle , Pearse Roger , Rossi Adriana C , Shore Tsiporah B. , Mayer Sebastian , Phillips Adrienne A. , Hsu Jingmei , Vasovic Ljiljana V. , Hsu Yen-Michael S. , van Besien Koen , Niesvizky Ruben , Rosenbaum Cara A. 
Published: November 2020

Background: Daratumumab (DARA) is a monoclonal antibody which targets CD38 on plasma cells and B cell progenitors. DARA has been effectively combined with other therapies in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), while DARA-based induction regimens in transplant-eligible patients (pts) are increasingly being used in clinical practice. Given that hematopoietic stem cells also express CD38, DARA may potentially affect stem cell mobilization and hematopoietic reconstitution following autologous stem cell transplant (ASCT). Although no clinically significant impact of DARA on stem cell mobilization or hematopoietic recovery was described in large phase 3 trials of triplet induction regimens +/- DARA in newly diagnosed MM, stem cell yields were lower and plerixafor more commonly used in the DARA-containing arms [Moreau et al, Lancet 2019; Voorhees et al, Blood 2020]. Significantly longer time to neutrophil (PMN) engraftment was also reported in pts receiving DARA-based induction who underwent upfront ASCT [Al Saleh et al, Am J Hematol 2020]. In this study, we examine the impact of timing of DARA administration pre-mobilization on day 4 pre-harvest peripheral blood CD34 cell count, stem cell apheresis yield, and post-ASCT engraftment.
Methods: Between 1/1/2016 and 12/31/2019, newly diagnosed and RRMM pts receiving DARA-based induction regimens with ≥1 dose of DARA administered within 1 month prior to stem cell mobilization were identified retrospectively and compared to matched controls receiving similar induction regimens without DARA. Granulocyte colony-stimulating factor (G-CSF) was administered per institutional standards and plerixafor added based on day 4 pre-harvest peripheral blood CD34 counts. PMN and platelet engraftment post-ASCT was defined as the first of 3 consecutive days with sustained PMN count &gt;500 x 106/L and independence from platelet transfusion in the preceding 7 days with a count &gt;20 x 109/L, respectively. Pre-harvest peripheral blood CD34 counts and stem cell apheresis yields were obtained from the Cellular Therapy Laboratory at NewYork-Presbyterian Hospital. The study was approved by the Weill Cornell Medicine IRB.
Results: We identified 16 pts who received DARA-based induction with ≥1 dose of DARA administered within 1 month of apheresis (DARA group) and 16 non-DARA-containing regimen-matched controls (non-DARA group). Demographics of the DARA and non-DARA groups were well matched (Table 1). DARA pts received their last dose of DARA a mean of 17.3 days prior to the first day of apheresis, with 8 pts receiving their last dose within 2 weeks and the remaining 8 pts between 2 weeks and 1 month prior. Overall, mobilization outcomes were inferior in the DARA group (Table 2). DARA pts had significantly lower day 4 pre-harvest peripheral blood CD34 counts compared to non-DARA pts (17.2 vs 35.4 cells/µL; P=0.0146). Institutional algorithm required plerixafor to be given for day 4 CD34 count ≤40 cells/µL. Fifteen of the 16 DARA pts received plerixafor vs. 11 non-DARA pts (P=0.07). Additionally, DARA pts required significantly more apheresis days (2.4 vs 1.6 days; P=0.0279). Differences in stem cell yield were not significant (8 vs 10 x106cells/kg; P=0.1391). Hematopoietic recovery post-ASCT was not affected by DARA administered in the month preceding mobilization.
Conclusions: In summary, we report lower day 4 pre-harvest peripheral blood CD34 count, increased requirement for plerixafor, and longer apheresis duration in newly diagnosed and RRMM pts receiving DARA within 1 month ofstem cell mobilization. These limitations are largely overcome by plerixafor usage which, combined with G-CSF, resulted in successful stem cell collection in all patients. Limitations in our study include small sample sizes, retrospective control selection, and fewer pts in the DARA group achieving ≥VGPR prior to mobilization. Nevertheless, our findings are consistent with inferior mobilization outcomes reported in the DARA-containing arms of phase 3 trials of triplet induction +/- DARA and highlight the nearly universal requirement for plerixafor usage when DARA is administered within a month prior to apheresis. Prospective study of day 4 pre-harvest peripheral blood CD34 counts and other predictors of stem cell yield should be incorporated into future clinical trials of CD38 monoclonal antibody-based induction regimens for transplant-eligible MM pts.

Disclosures
Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Niesvizky:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Rosenbaum:Amgen: Research Funding; GlaxoSmithKline: Research Funding; Akcea: Honoraria; Celgene: Honoraria; Janssen: Research Funding.