Autologous Stem Cell Collection after Daratumumab, Bortezomib, Thalidomide, and Dexamethasone versus Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma.

Introduction

In fit newly diagnosed multiple myeloma (NDMM) patients, induction followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is standard-of-care [ 1 , 2 , 3 , 4 , 5 ]. In high-risk subgroups, tandem HDCT/ASCT prolongs progression-free survival [ 6 , 7 , 8 ]. Furthermore, HDCT/ASCT can be performed at relapse or as consolidation after salvage therapy [ 9 , 10 , 11 ]. Hence, a maximum of three HDCT/ASCTs may be performed in a single patient. The prerequisite for this approach is the successful collection of at least three peripheral blood stem cell (PBSC) transplants, each containing a sufficient number of CD34 + PBSCs (usually ≥2.0 × 10 6 /kg body weight [bw]) [ 2 , 12 ]. Application of granulocyte colony-stimulating factor (G-CSF) with or without prior chemotherapy is necessary for PBSC mobilization [ 13 ]. Prior to mobilization, standard-of-care for transplant-eligible patients are triplet therapies comprising a proteasome inhibitor, dexamethasone, and either cyclophosphamide or an immunomodulatory drug (IMiD) [ 3 , 8 , 14 , 15 ]. While some factors such as radiotherapy, higher age, and melphalan are associated with poor PBSC mobilization, data on newer agents are often contradictory [ 16 , 17 , 18 , 19 , 20 ]. Some novel agents such as IMiDs might interfere with PBSC mobilization and collection [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. The addition of an anti-CD38 antibody to an established triplet protocol improves efficacy but might hamper PBSC collection as shown in the phase 3 CASSIOPEIA trial [ 25 ]. However, only data on overall collection results but not on other important surrogate markers such leukapheresis (LP) delay, number of LP sessions, and the use of the chemokine receptor antagonist plerixafor are available so far. Our study evaluates detailed PBSC mobilization and collection metrics in NDMM after induction with daratumumab, bortezomib, thalidomide, and dexamethasone (Dara-VTD) versus bortezomib, cyclophosphamide, and dexamethasone (VCD).

Methods

Patients

For this study, n = 119 consecutive patients with NDMM who underwent PBSC collection at the University Hospital Heidelberg after induction therapy with Dara-VTD or VCD between 2021 and 2022 were included. LP collection metrics were routinely recorded upon LP sessions, such as peripheral blood (PB) CD34 + cell count, PB leukocyte counts, amount of processed blood, PBSC collection result per LP session, G-CSF dosing, plerixafor application, and complete blood count prior to and post LP. Other patient characteristics were extracted from routine medical records. The study is in accordance with the most recent version of the Declaration of Helsinki.

Induction Treatment and PBSC Mobilization/Collection

Patients with NDMM underwent a median of 4 cycles of either VCD (21 days) or Dara-VTD (28 days). The choice of induction therapy was not based on disease characteristics. PBSC mobilization and collection were performed after the fourth induction cycle in 118/119 patients. Response assessment was conducted at least after one and 4 cycles. Mobilization chemotherapy was applied to almost all patients, comprising cyclophosphamide, adriamycin, and dexamethasone (CAD). In case of reduced ejection fraction or a pre-existing cardiac condition (myocardial infarction, coronary heart disease, cardiac bypass surgery, etc.), patients were subjected to cyclophosphamide, 13% of all patients in our cohort. G-CSF was applied on days 9–14. On day 14, the first PB CD34 + cell measurement was conducted. LP was initiated if the PB CD34 + cell count exceeded 10/μL. In case of tolerable safety, the following LPs were conducted until collection of three transplants comprised ≥2.0 × 10 6 CD34 + cells/kg bw. In case of collection failure, reflected by insufficient PB CD34+ cell counts or insufficient collection, preemptive or rescue mobilization with plerixafor was applied [ 26 , 27 ]. In short, PB CD34 + <10/μL after continued G-CSF stimulation until the day after the first planned measurement triggered preemptive plerixafor application. At PB CD34 + 10/µL–20/µL, plerixafor was used per treating physician's discretion. Rescue mobilization was applied if less than 2.0 × 10 6 CD34 + cells/kg bw were collected during first LP (LP1). In case of higher age or suspected inability for relapse transplant, collection goal was reduced to one or two transplants at the attending physician's discretion. In the VCD group, 5/61 patients were subjected to 1–4 additional induction cycles since ASCT had to be postponed due to restrictions caused by the COVID-19 pandemic. Detailed information on induction and mobilization protocols is presented in Table 1 .

Statistics

Descriptive statistics were performed using SPSS (v27). Data are depicted as dot plots with absolute numbers and boxplots with whiskers (median, interquartile range, minimum/maximum whiskers) or boxplots with Tukey whiskers without absolute numbers. Proportions of patients were depicted as pie diagrams. For univariate analysis in metric datasets, two-sided unpaired t -tests and Mann-Whitney U tests were performed. For univariate analysis in nonmetric datasets, Fisher's exact test was used. Multivariable logistic regression analysis was performed using SPSS (v27). p values < 0.05 were considered statistically significant.

Results

Patients' Characteristics

In this work, n = 119 patients were included, 70 (59%) of whom were male (Table 2 ). All patients were treated for symptomatic MM according to International Myeloma Working Group criteria [ 28 ]. The median age at diagnosis was 59 years (range 34–71). 68 patients (57%) had IgG and 25 (21%) IgA as monoclonal protein. Bence Jones myeloma was present in 25 patients (21%). 83 patients (70%) exhibited kappa light chain restriction, 1 patient (1%) had nonsecretory MM. 47 (39%) patients exhibited ISS stage 1, 26 (22%) stage 2, and 34 (29%) stage 3. High-risk cytogenetics were found in 43 patients (36%). 58 patients (49%) were treated with Dara-VTD and 61 patients (51%) were treated with VCD. Patients' characteristics were well balanced between the two groups, with a difference in median age at diagnosis (57 years in Dara-VTD vs. 60 years in VCD, p = 0.023). All other baseline patient characteristics were equally distributed among groups. Remission after induction therapy was superior in the Dara-VTD group (very good partial response and nCR 66% vs. 54%, p = 0.011).

PBSC Mobilization Metrics

Mobilization was induced with cyclophosphamide, adriamycin, dexamethasone chemotherapy and G-CSF in 103 patients (87%), with cyclophosphamide and G-CSF in 15 (13%) and with G-CSF only in 1 patient (1%) (Table 3 ). G-CSF was applied at 10 versus 5 μg/kg bw/day in Dara-VTD versus VCD. On day 14 after initiation of mobilization therapy, 76% of the Dara-VTD cohort and 62% of the VCD cohort surpassed the threshold of 10/μL CD34 + cells in the PB and underwent LP (Fig. 1a ). Mean PB CD34 + cell count at LP1 was lower in the Dara-VTD compared to VCD group (65 vs. 106/μL) (Fig. 1b ). Accordingly, CD34 + cell collection at LP1 was lower after Dara-VTD (5.5 vs. 8.3 CD34 + cells ×10 6 /kg) (Fig. 1c ). Patients in the Dara-VTD group required a higher median number of LP sessions (2 vs. 1), and only 31% completed collection after LP1 (vs. 72% in the VCD group) (Fig. 1d, e ).

Utilization of Plerixafor

In patients with impaired mobilization (LP delay ≥1 day or insufficient LP1), the chemokine receptor antagonist plerixafor was applied. Overall, 33% of patients in the Dara-VTD group and 21% of patients in the VCD group received plerixafor (Fig. 2a ). In 9% of patients, plerixafor was applied more than once, resulting in a cumulated dose per 100 patients of 47 versus 36 in the Dara-VTD and the VCD group, respectively (Fig. 2b ). CD34 + cell PB mobilization after plerixafor application was equal in both groups, with a two-fold increase of PBSC (Fig. 2c , p = 0.66). Likewise, CD34 + cell collection results of second LP, after the administration of plerixafor, improved in both groups (Fig. 2d ).

Overall PBSC Collection Outcomes

The PBSC collection outcome is given in Table 4 . Overall PBSC collection was 8.9 × 10 6 CD34 + cells/kg bw in the whole analyzed cohort, with a lower collection result in the Dara-VTD and VCD cohort (8.4 vs. 9.6 × 10 6 CD34 + cells per kg bw, p = 0.02) (Fig. 2e ). Absolute collection failure (overall collection <2 × 10 6 /kg bw CD34 + cells) did not occur; however, the collection target was reached in 79% of patients in the Dara-VTD group and 97% of patients in the VCD group (Fig. 2f ). All patients were subsequently subjected to HDCT/ASCT.

Multivariate Analysis

Multivariable logistic regression analysis regarding the outcome variables' successful collection of three transplants at LP1, PB CD34 + cells at LP 1 (>50/μL vs. <50/μL), use of plerixafor (yes vs. no), and number of LP sessions (>1 vs. 1) was performed (Table 5 ). Induction with VCD significantly correlated with collection success at LP1 (odds ratio [OR] = 4.46, p < 0.01), higher PB CD34 + cells/µL at LP1 (OR = 0.5.79, p < 0.01) as well as lower use of plerixafor (OR = 0.17, p < 0.01) and lower number of LP sessions (OR = 0.19, p < 0.01). Interestingly, mobilization therapy with cyclophosphamide correlated with higher utilization of plerixafor (OR = 11.02, p < 0.01). Furthermore, patients exhibiting high-risk cytogenetics needed an increased number of LP sessions (OR 2.65, p = 0.04).

Discussion

This study reports on PBSC mobilization and collection metrics in patients with NDMM after induction therapy with VCD or Dara-VTD. While data on overall PBSC collection in the CASSIOPEIA trial are available, this study provides more detailed analyses on the impact of different induction regimens on PBSC collection.

The study has various assets: patients' characteristics including cytogenetics (available in 86%) and ISS stadium (91%) are available for a vast majority of patients. Most characteristics are equally distributed among groups, except for higher median age at diagnosis in VCD. Due to the quality of data acquisition, multivariate analysis was feasible, which validated the findings seen in the univariate analysis. Both VCD and Dara-VTD protocols are approved for NDMM by the EMA and are widely used in different countries [ 29 ]. By analyzing additional surrogate markers such as LP sessions, LP delay, and PB CD34 + cell count, a broader picture of mobilization success and mobilization failure is drawn. Since LP duration and blood flow are often based on PB CD34 + cell count, LPs might be terminated earlier after assumed collection success [ 30 ]. This self-limitation hampers the validity of overall collection result as sole endpoint. The quantification of plerixafor doses is important to evaluate cost-effectiveness. In this study, we showed that inferiority of PBSC collection after Dara-VTD versus VCD cannot be fully compensated with plerixafor. However, all patients in our cohort collected at least one sufficient transplant, and all patients were subjected to HDCT/ASCT.

The study has some limitations. First, retrospective analyses may not be ideally suited to fully understand the clinical question presented here. The use of an increased G-CSF dose in the Dara-VTD group (10 vs. 5 μg/kg bw) might influence the collection outcome and might account for a quicker but less sustained stem cell mobilization (as mirrored by lower rates of LP delay). Second, since both daratumumab and thalidomide are part of the Dara-VTD group, the causative agent may not be identified easily. However, a recent analysis reports similar collection results after VTD versus VCD in a small cohort [ 31 ]. While sufficient PBSC collection was feasible in a majority of patients treated with Dara-VTD, increased LP numbers and increased use of plerixafor might have had an impact on quality of life. However, no data are available in this study. Our retrospective analysis is not powered to compare response rates and survival. Long-term analyses on duration of response after HDCT/ASCT with Dara-VTD are needed to further support treatment decisions. While for a majority of patients in the Dara-VTD group PBSC collection goals were met after application of plerixafor, the financial impact should be taken into account [ 32 ].

Both Dara-VTD and VCD are standard-of-care in transplant-eligible patients with NDMM. However, VTD showed superior response parameters compared to VCD [ 33 ]. Furthermore, the addition of daratumumab to VTD led to improved response parameters and survival [ 25 ]. Additionally, other quadruplet therapies are under evaluation in NDMM. In the phase 2 GRIFFIN study, daratumumab-VRD showed remarkable results [ 34 ]. However, Laurent et al. [ 35 ] report on impaired PBSC collection after VRD versus VTD. One could thus speculate that Dara-VRD might lead to even lower PBSC yields compared to Dara-VTD. Further research on PBSC collection after Dara-VRD is needed.

The data on the impact of IMiDs on PBSC collection are contradictory but favor a negative impact. Breitkreutz et al. showed inferior collection results in NDMM patients treated with thalidomide, doxorubicin, and dexamethasone compared with vincristine, doxorubicin, and dexamethasone [ 36 ]. In contrast, Ghobrial et al. did not find significant differences in PBSC collection yield with thalidomide [ 37 ].

Addition of anti-CD38 antibodies to triplet induction therapies might influence PBSC collection results since CD38 is expressed on bone marrow precursor cells [ 38 ]. However, the abundance of CD38 is higher in myeloma cells compared to stem cells [ 39 ]. In line with this observation, the anti-CD38 antibody isatuximab did not induce lysis of stem cells in an in vitro study by Zhu et al. [ 40 ] while exerting efficient killing of MM cells. Clinical data on the influence of CD38 antibodies on PBSC collection are rare [ 41 ]. While overall collection results were reduced after Dara-VTD versus VTD [ 25 ], it was unclear whether application of plerixafor may help overcome this hurdle. Our study provides evidence that plerixafor and higher doses of G-CSF (10 vs. 5 μg/kg bw/day) cannot fully compensate for the impact of daratumumab and thalidomide on PBSC collection metrics.

Furthermore, the increased number of LP sessions as well as the increased utilization of plerixafor in the Dara-VTD group significantly increase the financial impact of stem cell collection in these patients. Cost-effectiveness of Dara-VTD should be further discussed, as both direct and indirect costs are increased when compared to VCD.

In order to validate our findings, additional studies, e.g., comparing VCD and daratumumab-VCD may be helpful. Furthermore, data on stem cell collection after isatuximab-based quadruplet induction within the GMMG-HD7 study (isatuximab-RVd vs. RVd) may help to understand the impact of anti-CD38 mAb therapy on stem cell yield. In summary, PBSC collection after daratumumab-VTD is impaired when compared to PBSC collection after VCD induction.

Statement of Ethics

The retrospective study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty, Heidelberg University.

Conflict of Interest Statement

The first authors and all coauthors confirm that there are no potential conflicts of interest to disclose, except the following. Joseph Kauer: Honoraria: AstraZeneca. Sandra Sauer: travel grants or honoraria for presentations for Celgene, BMS, Janssen, Takeda, and Amgen. Katharina Kriegsmann: research funding and honoraria from Sanofi. A.S. received travel grants from Hexal and Jazz Pharmaceuticals, research grant from Therakos/Mallinckrodt, consultant by Janssen-Cilag and BMS, and is co-founder of TolerogenixX Ltd. A.S. is a part-time employee of TolerogenixX Ltd.

Author Contributions

Conceptualization: Sandra Sauer, Katharina Kriegsmann, and Joseph Kauer; methodology: Anita Schmitt; formal analysis, visualization, and writing − original draft preparation: Joseph Kauer and Katharina Kriegsmann; investigation: Joseph Kauer and Cathleen Nientiedt; resources, project administration, and supervision: Sandra Sauer and Katharina Kriegsmann; data curation: Cathleen Nientiedt, Joseph Kauer, and Anita Schmitt; writing − review and editing: Sandra Sauer, Marc-Steffen Raab, and Carsten Müller-Tidow; funding acquisition: not applicable. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Acknowledgments

The authors thank Renate Alexi, Erika Exenberger-Schiebel, Edgar Rieck-Wahl, and Andreas Smeykal for valuable help in data acquisition.

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Associated Data

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.