Day Of Apheresis Research Articles

Baseline immune state and T-cell clonal kinetics are associated with durable response to CAR-T therapy in large B-cell lymphoma

AbstractEngineered cellular therapy with CD19-targeting chimeric antigen receptor T cells (CAR-Ts) has revolutionized outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from the day of apheresis (day –28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel by integrating single-cell RNA and T-cell receptor sequencing, flow cytometry, and mass cytometry to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included the presence of B cells and increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B-cell proportion ≥0.5% and ALC/AMC ≥1.2 into a 2-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression-free survival at 1 year in patients meeting 1 or both criteria was 65% vs 31% for patients meeting neither criterion. Our results suggest that patients’ immunologic state at baseline affects the likelihood of response to CAR-T through both modulation of the T-cell apheresis product composition and promoting a more favorable circulating immune compartment before therapy. These baseline immunologic features, measured readily in the clinical setting before CAR-T, can be applied to predict response to therapy.

Analysis of apheresis outcomes in a cohort of Chilean patients treated with autologous stem cell transplantation: A single center real-world experience

Adequate stem cell harvesting is required for autologous hematopoietic transplantation. In deficient mobilizer patients, the collection of stem cells can be challenging because of the impossibility of achieving satisfactory CD34 cell counts with GCSF + - chemotherapy. Plerixafor is a potent and expensive drug that promotes the release of stem cells from the medullary niche to the peripheral blood and allows satisfactory harvests. We performed a retrospective analysis of 370 patients with myeloma and lymphoma harvested at our institution. 99 % of patients achieved satisfactory apheresis using Plerixafor in 45 %. Satisfactory harvests were obtained in patients mobilized with GCSF or plerixafor. In patients who used plerixafor, it was necessary to perform fewer apheresis procedures (P = 0.05). In multivariate analysis, the only factor that predicted the need for plerixafor was the presence of less than 30,000 CD34 / ul on the day of apheresis (OR 0.3. p < 0.001). Since we adopted the plerixafor protocol guided by CD34 counts, the number of patients with harvest failure has decreased. In conclusion, the rational and standardized use of plerixafor favors satisfactory harvest in patients who require autologous transplantation in South-American patients.

EE148 The Institutional Level Impact of Additional Apheresis Days for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation on Costs and Healthcare Resource Utilization

EE148 The Institutional Level Impact of Additional Apheresis Days for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation on Costs and Healthcare Resource Utilization

Single Apheresis Session on the 4th Day of Granulocyte Colony-Stimulating Factor Administration Seems Convenient to Collect Enough Peripheral Blood Stem Cells from Healthy Donors

Background: To minimize adverse events of peripheral blood stem cell (PBSC) collection in healthy donors, it is reasonable to limit the total dose of granulocyte colony-stimulating factor (G-CSF) and/or the number of apheresis days without decreasing of PBSCs yield. Therefore, we have started to collect G-CSF induced PBSCs on day 4 instead of on day 5. So, we retrospectively aimed to investigate the results of this 4-day G-CSF administration. Study Design and Methods: Seventy-six healthy donors who performed on G-CSF induced PBSCs donation consecutively between January 2020 and July 2022 were included in this study. G-CSF (filgrastim) at 2 × 5 µg/kg/day subcutaneously was applied. Apheresis started on day 4. Results: Sixty-nine (90.8%) of 76 donors provided enough PBSCs on day 4 apheresis session. Younger age (p = 0.004), higher PB CD34+ cell count on the 4th day of G-CSF (p < 0.001), and male donor (p = 0.010) were correlated with increased amounts of PBSCs yield. Univariate and multivariate logistic regression analyses to predict very good mobilizers (collected PBSCs ≥8 × 106/kg after the first apheresis) were performed. In multivariate logistic regression analyses, male sex (p = 0.004), PB CD34+ cell count ≥100/µL on the 4th day of G-CSF (p < 0.001), and glomerular filtration rate ≥115 mL/min (p = 0.031) were found to be independent predicting factors to demonstrate very good mobilizer. Conclusion: It seems that starting the apheresis on the 4th day of G-CSF administration is effective and to provide minimal G-CSF exposure in healthy donors.

Cost effective utilization of apheresis for stem cell transplantation in multiple myeloma.

e19528 Background: Salvage autologous stem cell transplantation (ASCT) is an effective and feasible treatment option for patients with relapsed multiple myeloma (MM). It is standard practice to collect stem cells adequate for two transplants for ASCT eligible patients with newly diagnosed MM (NDMM). Stem cell collection is an expensive procedure due to the cost of granulocyte-colony stimulating factor, plerixafor, apheresis, chemotherapy in select cases and finally cryopreservation. However, the rate of utilization of second ASCT is not known. Methods: We conducted a single institution, retrospective study of 511 consecutive patients with NDMM who underwent ASCT to identify the proportion of patients receiving second ASCT. Patients received ASCT as front-line therapy between 1/1/2015-2/13/2019. Demographic and disease characteristics were summarized using median and range for continuous variables, and frequency and percentages were calculated for categorical variables. The cumulative incidence of second ASCT was estimated using the Fine and Gray method, and competing risk regression models were used to estimate the hazard ratios for risk of second ASCT. All statistical tests were two-sided with a type 1 error of &lt; 0.05 indicating statistical significance. All estimates were reported with 95% confidence intervals (95% CI). Results: At a median follow-up of 4.7 years, 25 out of 511 patients received a second ASCT. The cumulative incidence rate at 5 years was 2.6% (95% CI 1.4-4.4%).Age at diagnosis, age at first ASCT and Charlson comorbidity index (CMI) were significantly associated with the risk of second ASCT in univariable analysis (UVA). In multivariable analysis (MVA) age at first ASCT was the only factor that was predictive of a second ASCT. We devised a predictive score for utilization of second ASCT using hazard ratios for each of the three significant factors noted in the UVA. Scoring was done as follows: age &lt; 65 years – 1 point, &gt; 65 years – 7 points; 1 point for CMI 0-1, 2 points for CMI 2 or higher; serum creatinine ≤1.2 – 1 point, &gt; 1.2 – 3 points. Based on the total score, patients are grouped into low ( &lt; = 3), medium (4-6) and high (7+) likelihood categories, with cumulative incidence rates of receiving second ASCT at 4.0% (95% CI: 1.3-9.1%), 3.4% (95% CI 1.4-7.0%) and 0.6% (95% CI 0.1-3.1%) respectively. Patients older than 65 years were 87% less likely to receive a second ASCT compared with those younger than 65 years (HR = 0.13, 95% CI 0.02-0.98). Conclusions: Using this predictive score, goal of stem cell collection for patients with MM could be determined more efficiently. This could avoid extra days of apheresis, chemo mobilization, hospitalizations and need for cryopreservation at least for patients with a low likelihood of second ASCT, translating into cost effective utilization of resources. We plan to validate this score prospectively in a larger group of patients with NDMM undergoing ASCT in the future.

A global assessment of hemostatic function of healthy allogeneic stem cell donors undergoing apheresis by rotational thromboelastometry.

Peripheral blood stem cell (PBSC) collection via apheresis requires the administration of granulocyte colony-stimulating factor (filgrastim) to stem cell donors. Several reports have shown that filgrastim administration and apheresis procedure induce a hypercoagulable state across PBSC collection, which might predispose certain donors to thrombotic complications. We evaluated the hemostatic functions of healthy allogeneic stem cell donors by rotational thromboelastometry (ROTEM). Blood samples from healthy donors (n = 30) were collected at defined time points: before filgrastim (baseline), on the day of apheresis before and after the procedure, and 1 week after apheresis. The results indicated that hemostatic changes are temporary since all parameters in both EXTEM and INTEM assays are restored to their initial values 1 week after the apheresis. We concluded that stem cell apheresis does not induce a hypercoagulable state in healthy donors. This is the first study evaluating the hemostatic functions of stem cell donors by ROTEM.

Outcomes of upfront plerixafor use for mobilization in germ cell tumor patients

High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors (GCTs) from 10% to 52%. Nearly 30% of GCT patients are deemed poor mobilizers after receiving several lines of prior therapy. There is limited data available regarding upfront plerixafor use in GCT patients. We predicted upfront plerixafor use would increase the amount of stem cells collected preventing subsequent mobilizations and improve time to curative therapy. A retrospective, single center, chart review of adult GCT patients who received plerixafor upfront for mobilization at a single center between January 1, 2013 and August 31, 2021 was performed.The primary objective was to evaluate the rate of successful peripheral blood CD34+ cell collections. Secondary objectives consisted of describing the impact of plerixafor use on mobilization and assessing auto-HSCT related outcomes. Sixteen patients received plerixafor upfront after an average of three prior lines of therapy (range: 2-5 lines). Successful collection (≥4 × 106 CD34+ cells/Kg collected within four days) was achieved in 15 (94%) patients in a median of one apheresis day (interquartile range: 1-2 days). All patients proceeded to an initial auto-HSCT and 12 patients (75%) completed both transplants as planned. Survival at 12 months was 50%.The significantly higher amount of CD34+ cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.

Comparative Efficacy of Autologous Hematopoietic Stem Cell Mobilization Regimens in Multiple Myeloma Patients

Aim. To compare the efficacy of mobilization regimens (MR) differing in their composition and intensity, with the purpose of defining the criteria to personalize the choice of MR based on clinical and hematological characteristics of multiple myeloma (MM) patients.&#x0D; Materials &amp; Methods. A retrospective analysis of the autologous hematopoietic stem cell (HSC) mobilization and autograft harvesting results was performed in 177 patients with newly diagnosed MM. The patients were divided into 4 groups. Group 1 included 62 patients with the median age of 53 years who were treated with single injection of cyclophosphamide (CF) dose 3 g/m2 as MR. Group 2 consisted of 71 patients with the median age of 58 years who received vinorelbine 35 mg/m2. Granulocyte colony-stimulating factor (G-CSF) as a monoregimen was administered to group 3 consisting of 33 patients with the median age of 55 years. Group 4 included 11 patients with the median age of 57 years who received G-CSF enhanced by plerixafor administration. G-CSF 10 µg/kg was used as MR. In all chemomobilization cases, daily G-CSF 10 µg/kg started on Day 4 from the administration of the chemotherapy drug prescribed as MR.&#x0D; Results. In the analyzed groups, the median time from MR start to the first leukocyte apheresis session was 11, 8, 5, and 5 days, respectively. On the first leukocyte apheresis day, the median CD34+ cell collection in group 3 was significantly lower than in groups 1, 2, and 4: 2.2 × 106/kg vs. 3.79 × 106/kg, 7.22 × 106/kg, and 3.9 × 106/kg, respectively. The total CD34+ cell collection after two leukocyte apheresis sessions was also the lowest in group 3 compared with groups 1, 2, and 4: 3.22 × 106/kg vs. 5.2 × 106/kg, 4.95 × 106/kg, and 7.5 × 106/kg, respectively. In the analyzed groups, the rate of mobilization with CD34+ cell collection &lt; 2.0 × 106/kg was 6.5 %, 5.6 %, 18.2 %, and 9.1 %. The evaluation of the results in all patients showed a direct correlation of CD34+ cell collection with lenalidomide administered before autologous HSC mobilization. A significant difference in CD34+ cell collection in lenalidomide recipients vs. non-recipients was reported when vinorelbine as MR and G-CSF as monoregimen (р = 0.001 and р = 0.022, respectively) were used. No significant differences were observed either with CF or G-CSF combined with plerixafor treatment.&#x0D; Conclusion. Based on the findings, age of a MM patient, comorbidities, and prior lenalidomide administration can be regarded as key criteria for choosing one of 4 MRs.

Peripheral blood stem cells mobilization in patients with relapsed or refractory lymphomas: A single-center experience.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is an established treatment for chemosensitive patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). We present the results of using different salvage chemotherapy plus granulocyte colony stimulating factor (G-CSF) for mobilization of peripheral blood stem cells in R/R lymphoma patients. For salvage chemotherapy, 93 patients received platinum-containing regimens, 4 patients received cytarabine-containing regimens, and 5 patients received other regimens. Patient distributions were HL (n = 35) and NHL (n = 67). In 87.2% of patients, first mobilization trial was successful (>2 × 10 6 CD34+ cells/kg). In 58.8% of patients, first apheresis season >5 × 10 6 CD34+ cells/kg collections was achieved. All 12.7% of patients were poorly mobilized at the first mobilization. There was no statistical difference between the previous chemotherapy numbers and failed mobilization ( P > 0.05). Five patients who were poorly mobilized and 4 patients who were successfully mobilized underwent a previous radiotherapy ( P < 0.05). Thirteen patients who were poorly mobilized in the first mobilization underwent a platinum-containing salvage regimen. At the time of the first mobilization, the average peripheral CD 34 counts in the successfully mobilized group were statistically higher than that in the poorly mobilized group ( P < 0.01). We demonstrated that peripheral CD 34 cell count in the peripheral blood on the first apheresis day was a significant factor for more stem cell mobilization, fewer apheresis sessions, less volume, and earlier neutrophil engraftment for patients with R/R lymphoma and eligible for AHSCT. The history of the previous radiotherapy was a significant factor for poor mobilization.

Trends in hematopoietic stem cell utilization and cost of cryopreservation

Abstract Autologous stem cell transplantation (ASCT) is the standard of care treatment for multiple myeloma. Standard ASCT procedures collect hematopoietic stem cells (HPSC) in excess for multiple transplants due to reports of high mobilization failure and unsuccessful ASCT collections following myeloablative treatments. Cost analysis studies estimate that one year of cryopreservation and one day of HPSC collection would each cost $5000 per patient. Limited data is available on the usage of the second transplant and the storage costs of non-transplanted products. This study evaluates the utilization of cryopreserved HPSC products and calculates the cost of cryopreservation. A retrospective chart review study of a cohort of 240 deceased MM patients, who received ASCT between January 2010 to December 2015. Demographic and clinical data were obtained from the laboratory and electronic medical record. The cohort was categorized into two groups, with 130 patients in Group 1 (≤60 years) and 110 patients in Group 2 (&amp;gt;60 years). Cumulative incidence of a second transplant was computed from the life table using the Kaplan Meier method. The cost of cryopreservation was calculated based on the time HPSC products remained in the freezers before disposal. PBSC was mobilized using Granulocyte Colony Stimulating Factor (GCSF), or GCSF and Mozobil. The average age of patients at first collection is 61 (IQR: 54-66) years and the average age of death is 64 (IQR: 58 -70) years. The average life span of patients after receiving the first transplant is 3 (IQR: 2-5) years. The average number of collection days is 2 (IQR: 1-3). 65 patients had 1-day collections, 105 had 2-day collections and 70 had ≥3-day collections. 175 patients (73%) had &amp;gt;1 day collection. Only 22 patients (9%) received a second transplant and 18 of them (82%) were in Group 1 (≤60). The cumulative incidence of a second transplant by 5 years is 23% for Group 1 and 4% for Group 2. Two-transplant collections required 492 days of apheresis with an overall cost of $2,500,000; however, one-transplant collections would cost $1,400,000 for 279 apheresis days. The median cost of cryopreservation for each patient who did not receive the second transplant is $15,000 (IQR: $8000 - $25,000). Therefore, the estimated cost for all patients in the study is $3,600,000 until the disposal of HPSC products. The incidence of a second transplant is low across all patients and significantly lower in patients greater than 60 years of age. Cryopreserved stem cell products remain under-utilized, leading to substantial financial burden. The duration of HPSC collection and cryopreservation must be re-evaluated for future treatment plans. Institutional policies should be revised based on the utilization trend to lower the operational cost of storage.

Serum Ferritin Levels Prior to Mobilization and Collection May Not Influence Stem Cell Yield

Background Bone marrow transplantation requires collecting an adequate number of hematopoietic stem cells to ensure successful engraftment. Ferritin, a key iron storage protein, is routinely evaluated during pre-collection visits, as low levels often indicate iron deficiency, which may impact stem cell capture. In some practices stem cell collection may be delayed to correct ferritin deficiencies. However, the level at which such intervention is necessary is not well known. Furthermore, delaying stem cell collection can have many implications including risk of infection, psychological stress, increased cost, and logistical challenges. The present study seeks to describe the impact of relative ferritin status on stem cell collection prior to bone marrow transplantation. Methods In a retrospective chart review of 183 patients at our center, 155 patients undergoing autologous transplantation from 2016-2018 and 2022-2023 as well as 28 allogeneic transplant donors between 2016-2023 were included. Patients and donors (n=13) who were missing ferritin levels at pre-collection or stem cell capture data in the electronic medical record (EMR) were excluded from analysis. Patient demographics, ferritin level (FL) at the pre-collection evaluation visit, total stem cell capture (TC), stem cell capture on the first day of apheresis (FC), and the total number of days of apheresis (DOA) were retrieved from the EMR. We classified patients into three groups: FL-1 had a ferritin level less than 50 ng/ml, FL-2 had a level between 50.1-500 ng/ml, and FL-3 had a level greater than 500 ng/ml. The Allogeneic donor cohort had an insufficient number of patients with high ferritin for analysis. A general linear model was used to assess the relationship between TC, DOA, and FC compared to ferritin status while covarying for age, sex, and race. Results In the allogeneic donor population, DOA (p=0.666), TC (p=0.938), and FC (p=0.961) were not statistically significant between groups FL-1 and FL-2. Additionally, there were no statistically significant differences in DOA, TC, or FC when our low ferritin cut off includes levels up to 100 ng/ml. In the autologous transplant population, there were no statistically significant differences between groups FL-1 and FL-2 regarding DOA (p=0.254) or TC (p=0.139), albeit FL-2 had a marginally higher FC (p=0.024). FL-2 had marginally lower FC (p=0.003) and TC (p=0.003) than FL-3, but DOA was not significantly different (p=0.783). Those observations held true when our low ferritin cut off includes levels up to 100 ng/ml. Conclusion Our results suggest that ferritin levels below 50 or 100 ng/ml may not warrant delaying stem cell collection in related allogeneic donors. For autologous transplants, the groups with normal ferritin levels showed slightly better first-day capture; however, the difference was not substantial enough to justify delaying collection because of its lack of effect on days of apheresis and total capture. On the other hand, high ferritin slightly increased the total and first day capture, so high levels should not delay collection either. This retrospective analysis adds valuable data to the relatively under-researched area of ferritin status in stem cell mobilization and offers insight to physicians considering collection delays.

Predictive Score for Utilization of Second Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Introduction: Salvage autologous stem cell transplantation (ASCT) is an effective and feasible treatment option for patients with relapsed multiple myeloma (MM). It is standard practice to collect stem cells adequate for two transplants for ASCT eligible patients with newly diagnosed multiple myeloma (NDMM). Apheresis is an expensive procedure with the added risk of complications from central venous access such as bleeding, infection and, granulocyte colony stimulating factor administration. However, the rate of utilization of second ASCT is not known. Methods: We conducted a single institution, retrospective study of 511 consecutive patients with NDMM who underwent ASCT to identify factors predictive of receiving second ASCT. Patients received ASCT as front-line therapy between 1/1/2015-2/13/2019. Demographic and disease characteristics were summarized using median and range for continuous variables, and frequency and percentages were calculated for categorical variables. The cumulative incidence of second ASCT was estimated using the Fine and Gray method, and competing risk regression models were used to estimate the hazard ratios for risk of second ASCT. Analyses were performed using Stata version 18 (StataCorp, College Station, TX), and all statistical tests were two-sided with a type 1 error of &amp;lt;0.05 indicating statistical significance. All estimates were reported with 95% confidence intervals (95% CI). Results: At a median follow-up was 4.7 years, 25 out of 511 patients received a second ASCT. The cumulative incidence rate at 5 years was 2.6% (95% CI 1.4-4.4%) (Figure 1).Age at diagnosis, age at first ASCT and Charlson comorbidity index (CMI) were significantly associated with the risk of second ASCT in univariable analysis (UVA). In multivariable analysis (MVA) age at first ASCT was the only factor that was statistically significantly associated with the likelihood of a second ASCT. We devised a predictive score for utilization of second ASCT using hazard ratios for each of the three significant factors noted in the UVA. Scoring was done as follows: age &amp;lt;65 years - 1 point, &amp;gt;65 years - 7 points; 1 point for CMI 0-1, 2 points for CMI 2 or higher; serum creatinine &amp;lt;/=1.2 - 1 point, &amp;gt;1.2 - 3 points. Based on the total score, patients are grouped into low (&amp;lt;=3), medium (4-6) and high (7+) likelihood categories, with cumulative incidence rates of receiving second ASCT at 4.0% (95% CI: 1.3-9.1%), 3.4% (95% CI 1.4-7.0%) and 0.6% (95% CI 0.1-3.1%) respectively. Patients older than 65 years were 87% less likely to receive a second ASCT compared with those younger than 65 years (HR=0.13, 95% CI 0.02-0.98). Conclusion: Using this predictive score, goal of stem cell collection for patients with MM could be determined more efficiently. This could avoid extra days of apheresis, chemo mobilization, hospitalizations and need for stem cell storage at least for patients with a low likelihood of second ASCT, translating into cost effective utilization of resources. We plan to validate this score prospectively in a larger group of patients with NDMM undergoing ASCT in the future.

Efficacy and Safty of Stem Cell Mobilization with Etoposide +Cytarabine Plus G-CSF in Patients with Lymphoma at High-Risk of Mobilizing Failure

Objective：Sufficient peripheral blood stem cell (PBSC) mobilization is important for performing successful autologous stem cell transplantation (ASCT) in patients with lymphoma. However, the optimal mobilization strategy remains a matter of debate in lymphoma.The aim of the study was to explore efficacy and safety of PBSC mobilization using etoposide combined with Cytarabine (EA) plus G-CSF in patients with lymphoma at high-risk of mobilizing failure. Methods：This retrospective study explored efficacy and safety of PBSC mobilization using EA (etoposide 50~100 mg/m2 , qd d1~3; AraC 0.5 g/m2 , q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 81 patients with lymphoma at high-risk of mobilizing failure. As previously reported, patients were defined at high-risk of mobilizing failure if (i) previous collection attempts failed (no special instructions); (ii) previous extensive radiotherapy or a complete course of treatment had affected stem cell activity; or (iii) any of these conditions: advanced disease (2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity &amp;lt;30% at the time of mobilization or age 65 years. Results：The mean total and first apheresis trial CD34+ cells collection was 20.37(range 1.08~138.96) and 18.56(range 0.1~138.96)×10^6 CD34+ cells/kg, respectively. Overall, 79(97.5%) patents harvested adequate mobilization (≥2×10^6 CD34+ cells/kg), while 65(80.2%) patients achieved optimal mobilization(≥5×10^6 CD34+ cells/kg). A single apheresis was sufficient to reached the target yield of adequate apheresis in 67(82.7%) patients on median 15th day (range 11~19). We observed acceptable hematological toxicity and exposure of antibiotic usage in 57 patients with a median of 4 days. No severe infections or mobilization-related mortality were observed. Conclusion：Our resluts suggest that EA plus G-CSF is an effective and safe PBSC mobilization strategy for patients with lymphoma, including those predicted as poor mobilizers. The outcome should be evaluated in a randomized study.

Rationale for and Design of Papilio-1: A Phase 1/2, Multicenter, Open-Label Study to Evaluate the Feasibility, Safety, and Efficacy of Point-of-Care-Manufactured Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells (GLPG5301) in Relapsed/Refractory Multiple Myeloma

Background and Significance Despite improvements in treatment, patients with multiple myeloma (MM) ultimately relapse or become refractory to available regimens. Triple-refractory (refractory to CD38 monoclonal antibodies [mAbs], 1 proteasome inhibitor [PI] and 1 immunomodulatory drug [IMiD]) or penta-refractory (refractory to CD38 mAbs, 2 PIs and 2 IMiDs) patients have a poor prognosis and are in urgent need of novel treatment options. Chimeric antigen receptor (CAR) T-cell therapies have been used to target B-cell maturation antigen (BCMA) and have shown good clinical activity in patients with relapsed/refractory MM (RRMM). Faster manufacturing procedures may improve clinical outcomes by lowering discontinuation rates and reducing the need for bridging therapy. GLPG5301, a BCMA-directed CAR T-cell therapy, is produced using a novel decentralized and automated point-of-care manufacturing model. This allows administration of a fresh product within 7 days of apheresis. The objective of Papilio-1 is to evaluate the feasibility, safety and efficacy of GLPG5301, manufactured at the point-of-care, in adult patients with RRMM. Study Design and Methods Papilio-1 (CTIS: 2022-500782-27-00) is a Phase 1/2, multicenter, open-label study of GLPG5301 in patients with RRMM after ≥2 prior lines of therapy. Key eligibility criteria are presented ( Table). The study will be conducted in centers across Europe. The Phase 1 primary objective is to evaluate the safety of GLPG5301 and determine the recommended Phase 2 dose (RP2D). The Phase 1 primary endpoint is incidence of serious adverse events, including dose-limiting toxicities (DLTs), until 14 days post-infusion. The Phase 2 primary objective is to evaluate GLPG5301 efficacy. The Phase 2 primary endpoint is best objective response until 2 years post-infusion. Secondary endpoints include: type, frequency and severity of adverse events; duration of response; progression-free survival (PFS); overall survival (OS); minimal residual disease; soluble BCMA levels; time to response; time to progression; GLPG5301 levels in blood and bone marrow; serum levels of chemokines and cytokines; and number of successfully manufactured GLPG5301 products. Exploratory assessments include additional GLPG5301 pharmacokinetics (PK) and pharmacodynamics (PD). Patients will undergo leukapheresis of mononuclear cells for point-of-care manufacturing of GLPG5301 after screening ( Figure). Prior to infusion of GLPG5301, patients will receive fludarabine/cyclophosphamide lymphodepleting chemotherapy, followed by a resting period of at least 2 days. GLPG5301 will be administered as a fresh product, followed by in-hospital monitoring for 7 days. Safety, efficacy, PK and PD will be assessed until end of treatment (100 days post-infusion), and monthly until study completion (2 years). Patients will be enrolled in a long-term follow-up for up to 15 years. In Phase 1, dose escalation will be based on the occurrence of DLTs occurring within 14 days of infusion, according to predefined criteria. Three dose levels (DLs) will be assessed (DL1, DL2 and DL3). Six patients will receive the lowest dose level (DL1) and be evaluated for DLTs and efficacy. The appropriate dose for the following cohort will be then determined by the Safety Review Committee. This will be repeated until RP2D is determined. Approximately 30 patients will be treated with the RP2D in Phase 2. Safety and efficacy data will be analyzed using descriptive statistics. Response status will be summarized as best response (number, percentage, 95% confidence interval) and graphically displayed using swimmer plots by dose. Other binary endpoints will be described using a similar method. PFS and OS will be assessed using the Kaplan‒Meier method and calculated from the median survival time. Summary In Papilio-1, the feasibility, safety and efficacy of GLPG5301, a point-of-care-manufactured BCMA-directed CAR T-cell therapy, will be evaluated in adult patients with RRMM.

Cellular Dynamics Following CAR T Cell Therapy Are Associated with Response, Resistance and Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma

Introduction The introduction of B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). While long-term follow-up of CD19 CAR T cells demonstrated a connection between CAR T cell expansion and persistence with outcome, very little is known about persistence and effects on bystander cells of BCMA-targeting CAR T cells. Methods We analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. Pts were grouped based on their remission evaluated 100 days after infusion into responders (partial response or better, n=16) or non-responders (progressive disease, n=11). Peripheral blood (pb) was drawn at day of leukapheresis, at day of infusion/after lymphodepletion (LD, d0) and at several time points following Ide-cel infusion (d7, d14, d30 and d100). In order to reflect a comprehensive picture of the longitudinal dynamics of CAR and non-CAR T cells, we subjected pb mononuclear cells to advanced flow cytometry. Additionally, we assessed the impact of cellular dynamics on the occurrence of cytokine release syndrome (CRS), tocilizumab application and the incidence of cytopenia. Results The median number of infused CAR T cells was 430x10 6 (range: 248.8 - 489.1x10 6) with one exception (25.7x10 6). There was no correlation between the median number of infused cells and in vivo expansion of CAR T cells after infusion as well as response or the development of CRS or cytopenia. Significant differences between responders and non-responders were already detected on day of leukapheresis: While non-responders showed similar numbers of CD4+ and CD8+ T cells, responders had significantly higher CD8+ T cell counts as compared to CD4+ T cells (p&amp;lt;0.05, Figure 1). Additionally, significantly reduced percentages of effector memory CD8+ T cells were detected in responders as compared to non-responders. The latter group showed significantly increased numbers of CD3+CD8+ T cells at the day of infusion indicating a less effective LD in non-responders. Following CAR T cell infusion, peak expansion occurred two weeks after infusion and was significantly higher in responders as compared to non-responders (p&amp;lt;0.001, Figure 2). CD3+ CAR T cell compartment predominantly comprised of CD8+ T cells regardless of response (median: 85%). Analysis of the distribution of CAR and non-CAR T cells after infusion revealed that the majority of CD4+ T cells in responders and non-responders were untransfected. Similar results were detected for CD8+ T cells in non-responders. However, in responders CD8+ CAR T cells approximated CD8+ non-CAR T cells with no significant differences on d7 and d14. With regard to T cell differentiation, almost the entire CD4+ T cells exhibited either a central memory or effector memory phenotype after CAR T cell infusion. Shortly after CAR T cell infusion, effector memory CD8+ T cells outbalanced all other CD8+ T cell subtypes. Most pts had no detectable CAR T cells 100 days after infusion, regardless of remission. Overall, 22 pts (81%) developed CRS shortly after CAR T cell infusion and 7 of these (32%) required tocilizumab treatment. Whereas percentages of CD3+ CAR T cells were significantly elevated in both CRS positive groups (p&amp;lt;0.05) shortly after infusion, absolute numbers were significantly increased only in CRS positive pts without tocilizumab. Analysis of blood counts following CAR T cell infusion revealed that cytopenias persisted longer in CRS pts treated with tocilizumab, which was also reflected by significantly increased numbers of days below thresholds for all cell lines (anemia, thrombocytopenia and leukopenia, p&amp;lt;0.01). Even though the occurrence of CRS and especially the treatment with tocilizumab affected blood cell composition, it did not correlate to response. Conclusion We demonstrate that BCMA-targeting CAR T cells only transiently persist in pb after infusion. Still, initial CAR T cell expansion, predominantly caused by effector memory CD8+ CAR T cells, was linked to response and CRS in RRMM pts. A correlation between CRS and tocilizumab administration with prolonged cytopenias following CAR T cell infusion was also observed. Our data provide first evidence that responders and non-responders can early be distinguished by differential cellular composition in CAR and non-CAR T cell compartments with distinct features already present at day of apheresis.

Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL)

Introduction: Obesity causes low-grade inflammation and immune escape, where T-cells lose their ability to infiltrate tumors. However, such T-cell exhaustion, characterized by increased expression of inhibitory checkpoint receptors, has led to better responses to immune checkpoint blockade therapy in patients with higher body mass index (BMI) (Wang Nature Medicine 2019). Previous studies have shown no significant association of obesity with safety or efficacy of Chimeric Antigen Receptor T-cell (CAR T) therapy in hematologic malignancies (Faruqi Blood Advances 2022). However, data on the impact of BMI on outcomes in LBCL and CAR T expansion kinetics is limited. We conducted a single-site study to investigate the effect of obesity on efficacy and safety outcomes, healthcare utilization, and CAR T expansion in patients with relapsed/refractory LBCL treated with Axicabtagene Ciloleucel(axi-cel). Methods: 189 patients with relapsed/refractory LBCL who were consecutively treated with axi-cel from 12/2017 to 5/2022 were included in the study. BMI was calculated on the day of apheresis. Patients were then divided into three BMI categories based on CDC guidelines: underweight/normal (≤24.99kg/m 2), overweight (&amp;gt;25kg/m 2 and ≤29.99kg/m 2), and obese (&amp;gt;30kg/m 2). Response was assessed using the Lugano 2014 criteria, and toxicities via the CTCAE version 5.0 and ASTCT grading. CAR T expansion was measured by real-time flow cytometry with anti-idiotype-FMC63 conjugated to Dylight 650. Areas under the curve (AUCs) were calculated for CAR T expansion in the 28 days following infusion using the linear trapezoidal method on raw values, and results were transformed using a base-10 logarithm. Continuous outcomes were compared using a Kruskal-Wallis test, categorical outcomes using Chi-square tests, and time-to-event outcomes using the Kaplan-Meier estimator and the log-rank test. Statistical significance was determined at p &amp;lt; 0.05. All analyses were conducted in R 4.3.0. Results: Out of 189 patients, 46% (n=87) were in the underweight/normal group, 29% (n=56) in the overweight, and 24% (n=46) were obese. Baseline demographics and clinical characteristics between groups were similar except for gender ( p=0.009). Complete response (CR) and overall response (ORR) including partial response (PR) and CR were compared among these cohorts. Neither complete response nor overall response was found to be significantly different amongst the BMI categories for their best response within 12 months of CAR T infusion ( p=0.9886 and 0.802, respectively). Median progression-free survival (PFS) was 14.6 months (IQR 4.93, 44.81) for the underweight/normal weight cohort, 14.89 months (IQR 5.82, 40.07) for the overweight cohort, and 28.37 months (IQR 3.88, NA) for obese; but was not statistically significant ( p=0.8004) [Figure 1]. Median overall survival (OS) was 44.81 months (IQR 18.18, NA) for the underweight/normal weight cohort and 40.07 months (IQR 23.18, NA) for the overweight category. This was not achieved for the obese category, and no statistical difference was found ( p=0.3478). When cytokine release syndrome (CRS) or immune cell-associated neurologic toxicity syndrome (ICANS) events were compared among these groups, there was no significant difference in either overall incidence or when graded as severe (›3), based on BMI category. Similarly, no significant differences were found in healthcare utilization variables, including length of hospital stay, ICU admissions, tocilizumab, anakinra or steroid use. Differences in day 7 and day 14 CAR T expansion were not statistically significant ( p=0.754 and 0.355, respectively). For AUC calculations, there was no statistically significant difference amongst the BMI categories (CD4: p=0.8284, CD8: p=0.8695, CD4 + CD8: p=0.8820) [Figure 2]. Conclusion: Contrary to the effect of obesity on response to therapies like checkpoint inhibitors we demonstrate that BMI does not significantly impact patients treated with CAR T. Weight has been central to chemotherapy dosing for lymphoma, but despite weight-based dosing for axi-cel, correlative studies on CAR T expansion kinetics did not indicate any significant difference. These findings suggest that obesity may not substantially influence the outcomes or dosing considerations of CAR T therapy, supporting the use of CAR T therapy as an effective treatment option for lymphoma patients, regardless of their BMI.

Seven-Day Vein-to-Vein Point-of-Care Manufactured CD19 CAR T Cells (GLPG5201) in Relapsed/Refractory CLL/SLL Including Richter's Transformation: Results from the Phase 1 Euplagia-1 Trial

Background Despite treatment advances, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) remain incurable. Patients (pts) with concurrent Richter's transformation (RT) have poor prognoses with limited treatment options. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have shown activity in pts with CLL/SLL or RT, yet data are limited and no therapies are approved. Due to limited treatment options and short survival of pts with RT, rapid treatment delivery is essential. A novel decentralized and automated point-of-care (PoC) manufacturing model was developed to administer fresh, autologous CAR-T treatments within 7 days of apheresis. An update on the Phase (Ph) 1 Euplagia-1 trial of PoC manufactured GLPG5201 is presented. Methods Euplagia-1 (CTIS: 2022-501686-47-00) is a Ph1/2 study of PoC-manufactured GLPG5201 in pts with R/R CLL or SLL, including pts with RT. Pts with CD19+ R/R CLL/SLL with ≥2 prior therapy lines are eligible. Pts with RT are eligible regardless of prior therapy. GLPG5201, an anti-CD19/41BB CAR-T therapy, is administered as a fresh product following fludarabine/cyclophosphamide lymphodepleting chemotherapy. Upon screening, pts receive daily ibrutinib until leukapheresis. The primary objectives are safety and determining a recommended Ph2 dose (Ph1), and objective response rate (ORR; Ph2). Secondary objectives include additional efficacy measures, pharmacokinetics and feasibility of PoC manufacturing. Results As of April 26, 2023, 12 pts were enrolled in Ph1 at dose level (DL) 1 (35×10 6 CAR+ T cells, n=6) or DL2 (100×10 6 CAR+ T cells, n=6) at a single institution. All pts were diagnosed with R/R CLL, 7/12 with concurrent RT. Median age was 66 years (range 58-71); 8/12 pts were male. Median prior lines of therapy were 4 (range 2-10); 10/12 pts received a BTK inhibitor, 9/12 pts venetoclax, and 1 pt an allogeneic stem-cell transplant. Five of 7 pts with RT relapsed after, or were refractory to, R-CHOP. Six of 12 pts had a TP53 mutation, 1 pt had a 17p deletion; 11 pts had an unmutated IGHV status and 2 had a complex karyotype reported. GLPG5201 was manufactured for all pts and administered as a fresh infusion. Median vein-to-vein time was 7 days (range 7-14). Due to lower manufactured CAR+ T cell yield, 3 pts received DL1 instead of the intended DL2. A preserved early memory phenotype for CD4+ and CD8+ CAR T cells was observed in the final product, compared with apheresis starting material ( Figure). Most treatment emergent adverse events (TEAEs) were Grade 1-2; most Grade ≥3 events were hematological ( Table). Six (50%) pts had Grade 1-2 cytokine release syndrome (CRS), with no CRS Grade ≥3. No neurotoxicity was reported. A dose limiting toxicity occurred in 1 pt (Grade 4 neutropenia, DL2), which was manageable and within expectations in this pt population. No unexpected GLPG5201-related toxicities were observed; no deaths occurred while pts were on study. Eleven pts responded to treatment (best ORR 92%). Complete response (CR) was observed for 9 pts (CR rate [CRR] 75%). ORR and CRR were 83% and 67% at DL1, and 100% and 83% at DL2, respectively. All but 1 pt with RT responded (ORR 86%); CR was achieved by 5/7 pts with RT (CRR 71%). One pt with RT was refractory with CD19-negative disease. At the time of analysis, 9/11 (82%) pts had ongoing responses; duration was up to 9 months post-infusion (median follow-up 3.2 months; range 1-9). Two pts progressed after an initial response, 1 pt with CD19-negative disease. Robust CAR T-cell expansion was observed in all pts by qPCR, with a median maximum expansion of 4.4×10 5 copies/µg DNA (C max). Median T max was 14 days (range 9-20 days). Median AUC 0-28d was 5.3×10 6 copies/µg DNA × days. GLPG5201 could be detected in peripheral blood up to 9 months post-infusion. Conclusion Data from 12 pts enrolled in the Ph1 Euplagia-1 study demonstrate that PoC CAR-T manufacturing with a short vein-to-vein time is feasible. GLPG5201 is administered as a fresh product; median vein-to-vein time is 7 days. There are no unexpected safety findings, and no CRS Grade ≥3 or any ICANS are reported. Efficacy data are encouraging, with a 92% best ORR and 75% CRR; 6/7 pts with RT responded. With this novel PoC manufacturing model, an early phenotype of less differentiated CAR T cells is preserved in the final product. GLPG5201 demonstrates rapid in vivo expansion and durable persistence post-infusion . Euplagia-1 is ongoing, and updated data will be presented.

Comparison of two apheresis systems for granulocyte collection without hydroxyethyl starch.

Granulocyte transfusion (GTX) is a treatment option for severe infections in patients with neutropenia. In previous studies, hydroxyethyl starch (HES) was used to enhance red blood cell sedimentation for granulocyte collection (GC). However, there are safety concerns about HES, and HES is not readily available in some countries. Therefore, we compared the granulocyte counts and GC efficiency achieved by two apheresis systems without HES. All consecutive GC procedures performed between July 2011 and March 2018 at our hospital were analysed. COBE Spectra was used until 5 February 2016, and Spectra Optia was used afterwards. HES was not used. Twenty-six GC procedures were performed, including 18 performed using COBE Spectra and 8 using Spectra Optia. When Spectra Optia was used, >1 × 1010 neutrophils were collected from seven of the eight (88%) procedures. Although there was no significant difference in the granulocyte yield between COBE Spectra-based and Spectra Optia-based GC procedures, the collection efficiency of Spectra Optia was significantly higher than that of COBE Spectra (p = 0.021). Furthermore, the granulocyte yields of Spectra Optia-based GC tended to be more strongly correlated with the peripheral blood neutrophil count on the day of apheresis than those of COBE Spectra-based GC. Our results suggest that Spectra Optia achieves greater GC efficiency than COBE Spectra, even without HES. GTX may be a therapeutic option for severe neutropenia, even in places where HES is not available.

Prior Daratumumab Exposure and It's Correlation to Parameters Related to Apheresis Prior to Hematopoietic Stem Cell Transplantation in Multiple Myeloma

A number of recent studies have brought to light the potential detrimental effect the biologic monoclonal antibody daratumumab, directed towards CD38, may have on the collection of stem cell collection for hematopoietic stem cell transplantation (HSCT). In our evaluation of this claim, we retrospectively reviewed multiple myeloma patients who underwent autologous HSCT at a major tertiary transplant center between 2017 and 2022. A total of 240 patients were identified which included 62 patients who received daratumumab prior to stem cell collection and 178 patients who had no prior daratumumab exposure. Basic demographic data was collected as well as radiation, chemotherapy, and smoking history. No significant differences were identified between the groups based on demographics, smoking, or radiation exposure. Parameters related to peripheral stem cell collection were identified and recorded. We found that in patients exposed to daratumumab prior to apheresis, the mean number of days of apheresis required to reach the target collection goal was statistically increased compared to control (1.42 days ± 0.07 vs 1.26 ± 0.03; p&amp;lt;0.05). Furthermore, medications used to increase peripheral stem cell collection yield were also increased. It was demonstrated that the mean number of doses of plerixafor and G-CSF analogs were increased in the daratumumab group vs the control (1.08 ± 0.12 vs 0.6 ± 0.05; p&amp;lt;0.001 and 5.98 ± 0.31 vs 5.17 ± 0.06; p &amp;lt;0.001 respectively). Total number of stem cells collected both as an absolute number and controlled for the number of days of apheresis were lower in the daratumumab group compared to the control (5.31x10^6 ± 0.31 vs 6.68x10^6 ± 0.20; p&amp;lt;0.05 and 4.16x10^6 ± 0.32 vs 5.84x10^6 ± 0.21; p &amp;lt; 0.001 respectively). These results suggest that pre-apheresis exposure to daratumumab has a detrimental effect on peripheral stem cell collection. These results have a significant implications for both long term patient care and healthcare system resource utilization. The clinical outcome implications of daratumumab are currently not well known and further study is needed to determine if alterations in stem cell collection protocols would result in improved stem cell collection yields for patients with pre-collection daratumumab exposure. All data is expressed as mean ± SEM

Impact of Daratumumab on Hematopoietic Stem Cell Mobilization with G-CSF and on-Demand Plerixafor in Newly-Diagnosed Multiple Myeloma Patients

Introduction Autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients with newly diagnosed (ND) multiple myeloma (MM); therefore, an adequate hematopoietic stem cell (HSC) collection is crucial to allow patients to proceed to ASCT and ensure optimal hematologic recovery. A more frequent use of plerixafor (PLX) and lower HSC yields have been reported in patients treated with daratumumab, a backbone of induction therapy for NDMM patients. Chemotherapy-free mobilization with G-CSF and on-demand PLX is an effective mobilization strategy lacking chemotherapy-related toxicities. Here we present the results of a multicenter, retroprospective and prospective, observational study, aiming to compare the impact of daratumumab on HSC mobilization with G-CSF + on-demand PLX in patients with NDMM treated with bortezomib-thalidomide-dexamethasone (VTd) or VTd plus daratumumab (D-VTd). Methods NDMM patients undergoing a first HSC mobilization attempt with G-CSF (10 mcg/kg/day) were enrolled and observed up to 30 days after ASCT. According to its label, on-demand PLX was administered in patients with &amp;lt;20 CD34 + cells/µL after ≥ 4 days of G-CSF or in case &amp;lt;1×10 6 CD34 + cells/kg were collected on the first day of apheresis. The primary endpoint of the study was the rate of poor mobilizing patients (≤2x10 6 CD34 + cells/Kg collected or need for PLX to reach an adequate HSC harvest). Key secondary endpoints included: the rate of suboptimal (2 to 4 CD34 + cells/kg) and optimal (≥4 CD34 + cells/Kg) collection; the median number of apheresis required to obtain ≥2x10 6 CD34 + cells/Kg; the impact of daratumumab on HSC engraftment. Results A total of 190 NDMM patients (median age, 62 years) were enrolled in 2 Italian centres (IRCSS Istituto Clinico Humanitas and Città della Salute e della Scienza di Torino) and analyzed; of these, 70% (133/190) were treated with VTd and 30% (57/190) with D-VTd. The median number of induction cycles was 4 in both groups. Best response after the induction phase was at least very good partial response (VGPR) in 87/133 (65%) and 41/57 (72%) of patients treated with VTd or D-VTd, respectively (p=0.4). The median time from the end of induction to G-SCF administration was 24 days in the VTd group and 29 days in the D-VTd group (p=0.5). The rate of poor mobilizing patients was 31% (41/133) in the VTd group and 54% (31/57) in the D-VTd group (p=0.002), mainly due to a higher rate of PLX use in the D-VTd as compared to the VTd group (53% vs. 28%; p=0.001), while the rate of patients who failed HSC mobilization (≤2x10 6 CD34 + cells/kg collected) was similar in the two groups (2% vs. 3%; p=1). Despite a numerically higher median number of CD34 + cells collected in the VTd group (7.9) as compared to the D-VTd group (7.1; p=0.009), no difference in the rate of patients who collected 2-4 (5% vs. 5%; p=1) and ≥4 CD34 + cells/Kg (95% vs. 95%; p=1) was observed in the VTd and D-VTd groups, respectively. A higher median number of CD34 +/µL on the first day of count was observed in the VTd as compared to the D-VTd group (24.5 vs. 19, p=&amp;lt;0.001). Among patients who had &amp;lt;20 CD34 +/µL [32% (43/133) vs. 51% (29/57)] on the first day of count, a similar increase in the CD34 +/µL (48.5 vs. 55) was observed in the two groups after PLX administration. The median number of apheresis session needed to complete the harvestwas 1 fo the VTd group and 2 in the D-VTd group (p=0.1). Neutrophil and platelet recovery were achieved in 100% of patients with a median time to neutrophil recovery of 15 and 13 days in the VTd and D-VTd groups, respectively (p=&amp;lt;0.001) and a median time to platelet recovery of 16 and 14 days in the VTd and D-VTd groups, respectively (p=0.001). Conclusion G-CSF plus on-demand PLX for HSC mobilization demonstrated to be an effective strategy in NDMM patients treated with VTd with or without daratumumab, resulting in very low rates of mobilization failures irrespective of the use of daratumumab during induction. Despite a higher rate of patients requiring PLX for HSC collection and lower CD34 + yields, the incorporation of daratumumab as part of the induction treatment did not negatively impact the possibility to achieve an optimal HSC collection. Our results, along with the lack of chemotherapy-associated toxicity, support the use of a chemotherapy-free HSC mobilization with G-CSF and on-demand plerixafor also in patients receiving daratumumab upfront.