Impact of Daratumumab on Stem Cell Collection, Graft Composition and Engraftment Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Abstract

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as < 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC >1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count >20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Impact of daratumumab-based induction on stem cell collection parameters in Swedish myeloma patients

“…9 The mean number of collected CD34+ x 10 6 /kg was significantly lower (6,7 vs 10, p. <0.0001) and use of plerixafor higher (22 vs 8%, p. <0.0001) in the D-VTd arm. Similar results have been reported by Chhabra et al 13 for the GRIFFIN (D-VRd vs VRD in NDMM with intent to transplant) and MASTER (D-KRd in NDMM) trials as well as in small retrospective series by Manjappa et al 10 and Papaiakovou et al 11 In the present study we were able to show that the addition of daratumumab to induction leads to statistically significant lower stem cell yield (mean 5.14 vs 7.22 x10 6 /kg, p. <0.001), higher mean (1.65 vs 1.42, p. 0.031) and median days of apheresis (2 vs 1, p. 0.018) as well as increased rescue use of plerixafor (37% vs 6%, p. <0.001) in a large, country-wide realworld patient population with NDMM (Figure 1). Daratumumab was the only factor affecting stem cell yield besides age>60 and radiation during induction in multivariate analysis.…”

“…VRD in NDMM with intent to transplant) and MASTER (D-KRd in NDMM) trials as well as in small retrospective series by Manjappa et al . 10 and Papaiakovou et al . 11…”

“…5 As a significant portion of myeloma patients could be subjected to tandem ASCT at first line or second ASCT at first relapse the goal often is to collect at least 4x10 6 CD34+ cells/kg. It has previously been reported [9][10][11] that the addition of daratumumab to induction led to increased use of plerixafor and lower yields of collected CD34+ cells/kg.…”

Daratumumab during Myeloma Induction Therapy Is Associated with Impaired Stem Cell Mobilization and Prolonged Post-Transplant Hematologic Recovery

“…Despite significantly prolonged apheresis, 19% fewer CD34+ cells were collected (p = 0.0139), which is in line with numerous other studies [30][31][32][33][34][35][36]39,41]. However, other reports did not observe significant differences [37,40,49,50]. The GRIFFIN and PERSEUS trials documented lowercollected CD34+ cells in the D-RVd group [6,9].…”

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

“…There are several reports noting that daratumumab administered prior to stem cell collection can decrease the amount of collected stem cells [ 67 ]. About 75% of mobilized CD34+ stem cells also express CD38 at the cell surface, albeit at low densities [ 68 ].…”