Abstract
Purpose
Daratumumab-induction regimen has benefitted the multiple myeloma patients with long-lasting effective response. However, studies have showed daratumumab induction therapy reduced CD34+ stem cell yield and increased dependence on plerixafor use during mobilization therapy for subsequent autologous stem cell transplantation (ASCT). Here, we aim to explore the influence of daratumumab-based induction therapy on CD34+ stem cell yield in Indian multiple myeloma patients.
Methods
In this retrospective study, electronic medical records of transplant eligible multiple myeloma patients (n = 91) between December 2015 and February 2023 were considered. Clinical information about induction therapy, mobilization therapy, stem cell collection and transplant status were collected. Data analysis was done using SPSS v.26, with statistical significance at p < 0.05.
Results
Among the 91 patients, 8 received daratumumab induction regimen. The CD34+ stem cell yield among daratumumab and non-daratumumab induction groups did not show significant difference (5.29 ± 1.64 × 106 versus 6.08 ± 3.11 × 106 CD34+ cells/kg; p = 0.101). Patients on daratumumab induction regimen exhibited an increased use of plerixafor when compared to non-daratumumab induction regimen (p < 0.001).
Conclusion
The addition of daratumumab in induction therapy of multiple myeloma did not affect stem cell yield but increased dependence on plerixafor during mobilization therapy.
Keywords: CD34+ stem cell Yield, Daratumumab, Multiple Myeloma, Plerixafor
Introduction
Autologous stem cell transplantation (ASCT) with high-dose chemotherapy plays a significant role in the treatment of transplant-eligible multiple myeloma (MM) patients, leading to improved responses, extended progression-free survival (PFS), and better overall survival (OS) [1]. Daratumumab, a monoclonal antibody targeting CD38 expressed on myeloma cells, is increasingly being adopted for initial MM treatment [2]. The PERSEUS trial, conducted across 14 countries has reported the incorporation of subcutaneous daratumumab (D) along with bortezomib, lenalidomide, and dexamethasone (VRd) therapy and lenalidomide in transplantation-eligible newly diagnosed multiple myeloma patients [3]. However, use of daratumumab has raised concerns for its impact on CD34+ hematopoietic progenitors due to presence of CD38 on up to 75% of mobilized CD34+ hematopoietic progenitors [4]. CASSIOPEIA [2], MASTER and GRIFFIN [5] trials have demonstrated the safety and efficacy of daratumumab combinations without compromising stem cell collection. Al Saleh et al. [6] have suggested a potential delay in neutrophil engraftment in patients administered with daratumumab. Similarly, PERSEUS trial reported occurrence of grade 3 or 4 events such as neutropenia and thrombocytopenia in multiple myeloma patients on D-VRd regimen [3]. Plerixafor mobilizes hematopoietic cells to the peripheral blood to enable adequate stem cell collection [7]. Studies have reported increased use of plerixafor among patients treated with daratumumab induction regimen [8]. In this retrospective-observational study, we investigate the impact of daratumumab on stem cell collection and use of plerixafor as rescue mobilizing agent in Indian NDMM patients.
Materials & Methods
This was a retrospective study in newly diagnosed multiple myeloma (NDMM) patients eligible for transplantation. Data was collected from electronic medical records between December 2015 and February 2023. Clinical information about induction and mobilization therapy, CD34+ cells collection and transplant status were collected. Patients records lacking any one of the required clinical information or change from daratumumab to non-daratumumab induction regimen or vice versa were excluded. Patients were classified by induction regimen into two distinct groups: daratumumab-treated and non-daratumumab-treated. A standardized approach towards stem cell collection and plerixafor utilization was implemented to ensure protocol consistency. Hematopoietic Progenitor Cells – Apheresis (HPC-A) procedure in all NDMM patients was performed using automated cell separator Com.Tec (Fresenius Kabi, Germany). A sufficient stem cell recovery was ensured by a standard washout period of minimum 2 weeks preceding the last induction cycle to the start of the mobilization regimen. Additionally, cases showing peripheral blood CD34+ cells count < 20,000/ mL one day prior of planned apheresis were administered with plerixafor to mobilize stem cells.
Quantitative measures showing normal distribution were summarized using the mean and standard deviation, while qualitative variables were depicted using frequency distributions. Quantitative variables between two groups were compared by Student’s t-test. The analysis of qualitative data was conducted using Chi-square test. The statistical significance was considered at p < 0.05. Analysis of data was performed using SPSS version 26.0 software.
Results
Ninety-one NDMM patients were included in this study having an average age of 56.2 ± 7.6 years. Among 91 NDMM patients, 8 (9%) patients were administered with daratumumab induction regimen. The average age of patients on daratumumab and non-daratumumab induction therapy was 56.1 ± 6.3 years and 56.2 ± 7.8 years respectively and did not show significant difference (p = 0.409). The patients from daratumumab and non-daratumumab groups did not show significant difference when compared for age difference and gender (p > 0.05) (Table 1). Among the 83 patients administered with non-daratumumab induction regimen, 55 (66.6%) were treated with VRD (bortezomib, lenalidomide and dexamethasone), 1 (1.2%) patient was treated with VTd (bortezomib, thalidomide and dexamethasone), 1 (1.2%) patient was treated with VRD and VTd. The use of cyclophosphamide during induction did not differ significantly between patients from daratumumab group (2 patients − 25%) and non-daratumumab group (18 patients − 21.7%) (p = 0.985).
Table 1.
Demographic distribution MM patients administered with Daratumumab and without Daratumumab induction regimen
| Parameters | Daratumumab Treated (n = 8) n (%) |
Non-Daratumumab Treated (n = 83) n (%) |
p value |
|---|---|---|---|
| Age (years) | |||
| < 60 | 5 (62.5%) | 49 (59.0%) | 0.849 |
| ≥ 60 | 3 (37.5%) | 34 (41.0%) | |
| Gender | |||
| Male | 5 (62.5%) | 61 (73.5%) | 0.506 |
| Female | 3 (37.5%) | 22 (26.5%) | |
Frequencies were calculated with n in each group as the denominator. Groups were compared using Chi-square test; p < 0.05 considered statistically significant
An optimal dose of ≥ 4 × 106 CD34+ cells/kg was collected in 8 (100%) daratumumab and 71 (85.5%) non-daratumumab induction regimen patients (p = 0.248). An increase in number of attempts for harvesting the optimal stem cell yield was seen in 2 out of 8 daratumumab (25.0%) and 10 out of 83 non-daratumumab (12.0%) induction regimen patients. The difference was not statistically significant (p = 0.301). A significant increase in use of plerixafor was noted in 6 out of 8 daratumumab treated patients (75.0%) when compared with 13 out of 83 non-daratumumab treated patients (15.7%) (p < 0.001) (Table 2).
Table 2.
Stem cells harvested (CD34+ X106 cells/kg), attempts of harvesting and use of plerixafor in MM patients administered with Daratumumab and without Daratumumab induction regimen
| Parameters | Daratumumab Treated (n = 8) n (%) |
Non-Daratumumab Treated (n = 83) n (%) |
p value |
|---|---|---|---|
| Stem cell harvested (CD34+ X106 cells/kg) | |||
| < 4 × 106 | 0 (0.0%) | 12 (14.5%) | 0.248 |
| ≥ 4 × 106 | 8 (100.0%) | 71 (85.5%) | |
| Attempts of harvesting | |||
| 1 | 6 (75.0%) | 73 (88.0%) | 0.301 |
| > 1 | 2 (25.0%) | 10 (12.0%) | |
| Use of plerixafor | |||
| Yes | 6 (75.0%) | 13 (15.7%) | < 0.001** |
| No | 2 (25.0%) | 70 (84.3%) | |
Frequencies were calculated with n in each group as the denominator. Groups were compared using Chi-square test; p < 0.05 considered statistically significant; ** significant at p < 0.01
Patients on daratumumab yielded an average 5.3 ± 1.6 × 106 CD34+ cells/kg, whereas the average stem cell collection yield obtained in non-daratumumab patients was 6.1 ± 3.1 CD34+ cells/kg and did not show statistically significant difference (p = 0.101) (Table 3). The comparison of day 4 pre-harvest peripheral blood CD34+ count before administration of plerixafor between daratumumab (20.0 ± 20.0 cells/µl) and non-daratumumab (52.5 ± 55.4 cells/µl) induction groups did not show significant difference (p = 0.065). Age and gender did not show significant impact on the stem cell collection (p > 0.05). The factors other than daratumumab affecting the stem cell yield were use of lenalidomide and cyclophosphamide. The use of lenalidomide in patients yielded 6.4 ± 3.2 × 106 CD34+ cells/kg which was significantly higher than those not administered with lenalidomide (5.0 ± 2.3 × 106 CD34+ cells/kg; p = 0.002). The administration of cyclophosphamide reduced the stem cell yield when compared to those not treated with it (5.2 ± 2.4 × 106 versus 6.3 ± 3.2 × 106 CD34+ cells/kg; p = 0.010) (Table 3).
Table 3.
Study variables affecting stem cell yield collection
| Variables | n | CD34+ X106 cells/kg | p value |
|---|---|---|---|
| Daratumumab | |||
| Yes | 83 | 5.3 ± 1.6 | 0.101 |
| No | 8 | 6.1 ± 3.1 | |
| Age (years) | |||
| ≥ 60 | 37 | 5.6 ± 2.7 | 0.419 |
| < 60 | 54 | 6.3 ± 3.2 | |
| Gender | |||
| Female | 25 | 5.9 ± 2.6 | 0.089 |
| Male | 66 | 6.0 ± 3.2 | |
| Induction: | |||
| a. Lenalidomide | |||
| Yes | 66 | 6.4 ± 3.2 | 0.002** |
| No | 25 | 5.0 ± 2.3 | |
| b. Thalidomide | |||
| Yes | 4 | 4.7 ± 0.5 | 0.073 |
| No | 87 | 6.1 ± 3.1 | |
| c. Cyclophosphamide | |||
| Yes | 23 | 5.2 ± 2.4 | 0.010* |
| No | 68 | 6.3 ± 3.2 | |
| d. Pomalidomide | |||
| Yes | 3 | 4.8 ± 0.7 | 0.161 |
| No | 88 | 6.1 ± 3.1 | |
| e. Carfilzomib | |||
| Yes | 4 | 4.6 ± 0.8 | 0.126 |
| No | 87 | 6.1 ± 3.1 | |
Quantitative values represented as mean ± SD. Groups were compared by t-test; p < 0.05 considered statistically significant; * significant at p < 0.05, ** significant at p < 0.01
Discussion
In this study, daratumumab induction regimen in NDMM patients from India did not affect the stem cell yield (5.3 ± 1.6 versus 6.1 ± 3.1 × 106 CD34+ cells/kg; p = 0.101), however the regimen was associated with an increased use of plerixafor (75% versus 25%; p < 0.001). The phase III CASSIOPEIA study reported addition of daratumumab in induction regimen caused lower stem cell yield and increased use of plerixafor. Although, the lower stem cell yield did not show an effect on the feasibility and safety of transplantation [2, 8]. The PERSEUS trial reported administration of subcutaneous daratumumab plus VRd induction and consolidation therapy resulted in a lower CD34+ cell yield compared to VRd alone, although the hematopoietic recovery time post-transplantation was comparable between the two groups [3]. Similar findings have been reported by the MASTER and GRIFFIN trial [5], small retrospective series [9, 10] and real-world patient population studies [11]. In our study, daratumumab induction regimen did not affect the day 4 pre-harvest peripheral blood CD34+ count (20.0 ± 20.0 versus 52.5 ± 55.4 cells/µl; p = 0.065). However, Luan D et al. [12] reported a significant reduction of day 4 pre-harvest peripheral blood CD34+ count in daratumumab treated patients when compared to non-daratumumab treated patients (17.2 vs. 35.4 cells/µL; p = 0.015). The binding of daratumumab to CD38 has been known to trigger apoptosis via complement-dependent cytotoxicity (CDC) [13]. Ma X et al. [14] determined 75% of CD34+ mobilized peripheral progenitor cells co-expressed CD38 with around 10,000 CD38 molecules per cell. Ma X et al. discussed that the way daratumumab treatment modulates CD38 and complement membrane regulatory proteins (cMRP) expression on myeloma cells, it is possible that exposure to daratumumab may lead to attenuation of CD38 expression on CD34+ cells, affecting mobilization kinetics and lineage-specific progenitor cell frequencies or proliferative capacity. Ma X et al. group also reiterated need for further studies to investigate this hypothesis that long-term exposure of CD34+ to daratumumab, especially in addition with other agents may affect the mobilization kinetics and/or proliferative capacity of CD34+ cells [14].
The limitations of this study were small sample size, retrospective nature, limited access to data on key confounder (number of cycles before transplant) and lack of follow-ups. Additionally, the observation of increased plerixafor use in patients treated with daratumumab in the present study, should be validated in larger patient groups to assess its clinical significance.
In conclusion, our study highlights that administration of daratumumab did not affect the stem cell yield but showed dependence on increased use of plerixafor among Indian NDMM patients. Since daratumumab is increasingly being incorporated in front line regimens, the necessity has arisen to develop new management strategies like pre-emptive use of plerixafor to achieve the optimal stem cell yield.
Acknowledgements
The authors appreciate the support and guidance of Dr. Pooja Sharma. Authors also thank Mr Rajiv Sikka and the IT team at Medanta, Dr Ritu Setia and the MRD team for their invaluable support in data collection and record retrieval. Authors thank Gargi Singh, Swesha Chhabra, Saugata Das, Srinivas Pedapolu and Clinical Research Department for their unwavering support.
Author Contributions
Conceptualization: Aseem Kumar Tiwari, Nitin Sood, Geet Aggarwal; Methodology: Aseem Kumar Tiwari, Nitin Sood, Geet Aggarwal, Durga Chougule; Formal analysis and investigation: Durga Chougule, Padam Singh, Manish Kumar Singh; Writing - original draft preparation: Durga Chougule, Geet Aggarwal; Writing - review and editing: Aseem Kumar Tiwari, Nitin Sood, Geet Aggarwal, Durga Chougule, Padam Singh, Manish Kumar Singh; Resources: Aseem Kumar Tiwari, Nitin Sood, Padam Singh, Manish Kumar Singh; Supervision: Aseem Kumar Tiwari, Nitin Sood.
Declarations
Ethics Approval
The study was approved by Medanta Institutional Ethics Committee [1625/2023 (Academic)]
Source(s) of Support
The project was supported by CREATE Grant from Pfizer Limited (India) provided to Medanta Institute of Education and Research, Gurugram.
Conflicting Interest
Authors declare no conflict of interests.
Presentation at a Meeting
No.
Footnotes
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References
- 1.Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H et al (2017) Multiple myeloma: ESMO Clinical Practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl4):iv52–iv61 [DOI] [PubMed] [Google Scholar]
- 2.Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L et al (2019) Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet 394(10192):29–38 [DOI] [PubMed] [Google Scholar]
- 3.Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M et al (2024) Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for multiple myeloma. N Engl J Med 390(4):301–313 [DOI] [PubMed] [Google Scholar]
- 4.Snoeck HW, Lardon F, Lenjou M, Nys G, Van Bockstaele DR, Peetermans ME (1993) Differential regulation of the expression of CD38 and human leukocyte antigen-DR on CD34 + hematopoietic progenitor cells by interleukin-4 and interferon-gamma. Exp Hematol 21(11):1480–1486 [PubMed] [Google Scholar]
- 5.Chhabra S, Callander N, Watts NL, Costa LJ, Thapa B, Kaufman JL et al (2023) Stem Cell Mobilization Yields with Daratumumab- and Lenalidomide-Containing Quadruplet Induction Therapy in Newly Diagnosed Multiple Myeloma: Findings from the MASTER and GRIFFIN Trials. Transplant Cell Ther 29(3):174.e1–174.e10 [DOI] [PubMed]
- 6.Al Saleh AS, Sidiqi MH, Gertz MA, Muchtar E, Lacy MQ, Warsame RM et al (2020) Delayed neutrophil engraftment in patients receiving Daratumumab as part of their first induction regimen for multiple myeloma. Am J Hematol 95(1):E8–E10 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Spoerl S, Peter R, Wäscher D, Götze K, Verbeek M, Peschel C et al (2017) Patients’ outcome after rescue plerixafor administration for autologous stem cell mobilization: a single-center retrospective analysis. Transfusion 57(1):115–121 [DOI] [PubMed] [Google Scholar]
- 8.Hulin C, Offner F, Moreau P, Roussel M, Belhadj K, Benboubker L et al (2021) Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib/thalidomide/dexamethasone in the phase 3 CASSIOPEIA study. Haematologica 106(8):2257–2260 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Manjappa SM, Fox R, Reese J, Firoozamand A, Schmikla H, Nall S et al (2020) Impact of daratumumab on stem cell collection, graft composition and engraftment among multiple myeloma patients undergoing autologous stem cell transplant. Blood 136(suppl1):35–37 [Google Scholar]
- 10.Eleutherakis Papaiakovou E, Terpos E, Kanellias N, Migkou M, Gavriatopoulou M, Ntanasis-Stathopoulos I et al (2023) Impact of daratumumab on stem cell mobilization and collection, engraftment and early post-transplant complications among multiple myeloma patients undergoing autologous stem cell transplantation. Leuk Lymphoma 64(13):2140–2147 [DOI] [PubMed] [Google Scholar]
- 11.Lemonakis K, Tatting L, Lisak M, Carlson K, Crafoord J, Blimark CH et al (2023) Impact of daratumumab-based induction on stem cell collection parameters in Swedish myeloma patients. Haematologica 108(2):610–614 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Luan D, Christos PJ, Ancharski M, Guarneri D, Pearse R, Rossi AC et al (2020) Timing of daratumumab administered pre-mobilization in multiple myeloma impacts pre-harvest peripheral blood CD34 + cell counts and plerixafor use. Blood 136(suppl1):15–16 [Google Scholar]
- 13.Piedra-Quintero ZL, Wilson Z, Nava P, Guerau-de-Arellano M (2020) CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol 11:597959 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ma X, Wong SW, Zhou P, Chaulagain CP, Doshi P, Klein AK et al (2018) Daratumumab binds to mobilized CD34 + cells of myeloma patients in vitro without cytotoxicity or impaired progenitor cell growth. Exp Hematol Oncol 7:27 [DOI] [PMC free article] [PubMed] [Google Scholar]