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Journal of Hematology

Original Article

Volume 13, Number 3, June 2024, pages 79-85

Steady-State Versus Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma: A Single-Center Study to Analyze Efficacy and Safety

Multiple myeloma (MM) is a malignant lymphoproliferative disorder characterized by clonal plasma cell expansion. It represents 1-2% of all cancers and accounts for 17% of the hematological malignancies. It occurs mainly in elderly people. Major complications include the development of lytic bone lesions, hypercalcemia, bone marrow failure and renal impairment. MM is considered to be an incurable disease; however, there has been a significant improvement in patients’ survival, due to the novel drugs that have been introduced recently [1]. The first-line therapy is usually a three- or four-drug combination regimen which includes a proteasome inhibitor, an immunomodulatory drug, steroid and daratumumab as an anti-CD38 monoclonal antibody. After the induction treatment, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) should be considered in approximately half of the patients. Transplant eligibility is determined by the age and comorbidities [2, 3].

Stem cell mobilization procedure usually includes the administration of chemotherapy and granulocyte colony-stimulating factor (G-CSF). The gold standard is intermediate-dose (2 - 4 g/m²) cyclophosphamide, but other regimens, e.g., high-dose etoposide, cytosine-arabinoside or combinations (bortezomib, thalidomide and dexamethasone-cisplatin, adriamycin, cyclophosphamide and etoposide (VTD-PACE), etoposide, dexamethasone, ara-C, and cisplatin (EDAP)), are also applied. Recently, steady-state mobilization method can also be considered. The administration of G-CSF may reduce chemotherapy-associated toxicities and infectious complications. The International Myeloma Working Group (IMWG) recommends collecting at least 4 × 10⁶ CD34⁺ cells/body weight kilogram (bwkg) for each AHSCT, and a double amount is required if a tandem or a second transplantation is planned [4].

Our aim was to compare the efficacy and safety of solo G-CSF versus chemotherapy-based stem cell mobilization in our Hungarian MM patients.

We collected data retrospectively from MM patients who underwent stem cell mobilization procedure in our institute between January 2018 and December 2022. Patients with plasma cell leukemia, solitary plasmacytoma and amyloidosis were excluded from the analysis. The clinical files were reviewed with particular reference to age, sex, clinical stage, previous treatment and response achieved, mobilization strategy, length of hospital stay, infectious complications and the amount of harvested stem cells. The International Staging System (ISS) and revised ISS (R-ISS) stages were determined using the IMWG criteria, if the relevant data were available. The way how fluorescence in situ hybridization (FISH) testing was performed varied, there was no consensus regarding the probes used, but those specific for 17p deletion, translocations (11;14), (4;14) and (14;16) and 1q amplification were generally part of the set. FISH results of unfavorable prognosis included t(4;14), t(14;16) and del(17p).

Response criteria (complete response (CR), very good partial response (VGPR), partial response (PR), no response (NR), and progressive disease (PD)) were also determined via the IMWG criteria.

All patients had undergone central venous catheter insertion before the stem cell mobilization process was initiated. Chemotherapy-based treatment included the administration of intermediate-dose cyclophosphamide (3 - 4 g/m²) or combination regimens (PACE). Filgrastim stimulation at the dose of 10 µg/kg/day was started if the patients’ absolute neutrophil count dropped off below 1,000/µL. Peripheral CD34⁺ cell counts were evaluated by flow cytometry method if leukocyte counts began to increase, and their number exceeded 5,000/µL. In terms of steady-state mobilization, patients received generic G-CSF 10 µg/kg/day subcutaneously for 4 days. On the fifth day, flow cytometry was performed to determine the peripheral stem cell count in the patients’ blood sample. In both groups, patients were administered plerixafor 24 mg/day subcutaneously if leukocyte count exceeded 5,000/µL and peripheral CD34⁺ cell count was in the 5 - 20/µL range. Stem cell harvesting procedure was launched if peripheral CD34⁺ stem cell count exceeded 20/µL. All collections were performed using the MNC program of the Spectra Optia apheresis system. The goal was to harvest at least 4 × 10⁶ stem cells per bwkg for each autologous transplantation.

Categorical variables were given as their frequencies and percentages, while continuous variables with medians and ranges. The Kolmogorov-Smirnov test was used for evaluation of data normality. Discrete variables were compared using a Chi-square test, while analysis of variance (ANOVA) was used for the measurement of associations between patient characteristics and outcomes. Pearson’s correlation and t-test were used to assess whether the difference in the means of two variables reaches statistical significance. Binary logistic regression and multivariable logistic regression was used to determine which factors were significant in determining outcomes. The level of statistical significance was considered at P < 0.05. Post-hoc power analysis was used to assess statistical power. Statistical analyses were performed using SPSS26.0 (IBM Corp., Armonk, NY, USA).

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research project was approved by the Regional Ethical Committee of the University of Debrecen (permission number: DEKK/RKEB/IKEB 6548-2023). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

In that 5 years’ period, 210 patients underwent stem cell mobilization procedure. Their demographics were generally balanced. A moderate male predominance was observed (51.1%), while the average age was 61 years (range 32 - 75). One-hundred and six patients received chemotherapy-based protocols for stem cell mobilization, while 104 patients were administered G-CSF alone. The most commonly used chemotherapeutic mobilization protocol was cyclophosphamide monotherapy (84.9%) in patients also receiving MM-specific, PACE-based combination therapies (15.1%). There was no difference in the epidemiological, disease-related or treatment parameters between the two groups with different mobilization strategies. Patients’ main clinical features and induction therapies as well as their results are presented in Table 1.

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Table 1. Patient Characteristics and Comparison of Different Stem Cell Mobilization Approaches

In the solo G-CSF group, there was a significantly higher need for plerixafor administration (45% vs. 13%, P < 0.001), unsuccessful stem cell mobilization was more frequent (11% vs. 3%, P = 0.024) and the mean amount of collected stem cells was significantly lower (6.9 vs. 9.8 × 10⁶/bwkg, P < 0.001) than in the chemotherapy group. On the other hand, infections were less frequent (4% vs. 27%, P < 0.001) and the number of days spent in hospital was significantly lower (6 vs. 14 days, P < 0.001). There was no significant difference between the median days of apheresis (Table 1). Multivariable analysis identified chemotherapy + G-CSF stem cell collection protocol as a sole and independent risk factor for infectious complications (P = 0.001), while the solo G-CSF protocol (P < 0.001) and daratumumab exposure (P = 0.003) predicted requirement for subsequent plerixafor therapy (Table 2). No independent prognostic factor for mobilization failure was found.

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Table 2. Univariate and Multivariable Logistic Regression Analyses of Disease Parameters, Associated With Infectious Complications, Plerixafor Use and Mobilization Failure

We also investigated the impact of induction treatment to stem cell mobilization. Most patients received bortezomib-based triplets: VTD, bortezomib, lenalidomide and dexamethasone (VRD) or bortezomib, cyclophosphamide and dexamethasone (VCD). The amount of harvested stem cells was significantly lower in those patients who received lenalidomide-containing regimens than in those who were given lenalidomide-free induction therapy (6.6 vs. 9.3 × 10⁶/bwkg, P < 0.001). Besides, plerixafor was more frequently used in the lenalidomide group (40.8% vs. 23%, P = 0.007). Also, there was a marked, but not significant difference in the ratio of unsuccessful mobilization attempts (11.3% vs. 4.3%, P = 0.056) (Fig. 1). However, lenalidomide exposure alone does not predispose to either plerixafor use or mobilization failure (Table 2). Eighteen patients were exposed to daratumumab before stem cell collection, which is only a relatively small portion of the whole population. Nevertheless, our preliminary data showed that daratumumab did not influence the efficacy of the stem cell harvesting procedure; however, the need for plerixafor administration was higher (77.8% vs. 24.5%, P < 0.001) (Fig. 1 and Table 2).

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Figure 1. The effect of LEN, Dara and mobilization strategy on the amount of bone marrow stem cells collected (a-c), the number of days of apheresis (d-f) and the length of hospital stay (g-i). LEN: lenalidomide; Dara: daratumumab; G-CSF: granulocyte colony-stimulating factor.

The incorporation of novel drugs to the induction treatment may question the necessity of autologous stem cell transplantation even in young and fit MM patients. However, recent studies have reported that AHSCT significantly improves progression-free survival in patients who undergo the treatment compared to those who do not [5]. Therefore, international guidelines still recommend the administration of high-dose melphalan followed by autologous stem cell transplantation in the eligible population [6].

The method of stem cell mobilization depends on several factors, such as disease activity, the number of transplantations planned and the presence of risk factors that may predict poor mobilization potential [7]. Chemotherapy-based regimens include the administration of intermediate-dose cyclophosphamide, etoposide, cytarabine or combination therapies (e.g., PACE). This strategy can be recommended for heavily pretreated patients with active disease, as more potent mobilizing effects can be achieved. The beneficial effect of chemotherapy on the underlying disease during stem cell collection for patients with MM is a matter of debate [8]. Steady-state mobilization is accompanied with lower toxicities as only G-CSF is administered. Plerixafor, a selective and reversible CXCR4 inhibitor, can be added to the therapy if the primary mobilization seems to be ineffective [9]. However, several studies reported the superiority of chemotherapy-based mobilizations in terms of the harvested stem cell amounts and the number of successful attempts [10]. Formerly, intermediate-dose cyclophosphamide treatment followed by G-CSF was our first choice when we indicated stem cell mobilization in our MM patients. However, coronavirus disease 2019 (COVID-19) pandemic forced us to change our strategy, as the avoidance of therapies associated with possible infectious complications and long-term hospital stays were crucial. Therefore, we began to prefer steady-state mobilization from 2020. Our goal was to compare the efficacy and cost-effectivity of the two mobilization strategies in a retrospective way.

Half of our patient population received chemotherapy-based treatment, while the other half was administered G-CSF alone. In the chemotherapy group, the harvesting procedure was more effective considering the number of collected stem cells and the ratio of unsuccessful attempts. Our results indicate that chemotherapy produced a significantly higher harvest of the amount of stem cells than solo G-CSF. Both approaches provided a conveniently sufficient amount of product to store. Also, with both approaches, we were able to collect multiple times the minimum number of stem cells required for AHSCT by the IMWG guidelines [4]. Not surprisingly, hospitalization was significantly longer, and infectious complications were more frequent with chemomobilization. However, only 13% of the patients required plerixafor administration, while this ratio was 45% in the G-CSF group. These results are in line with what reported in previous studies [11, 12]. On the other hand, financing issues can be also taken into account. An Italian study has recently reported on 50 patients who underwent stem cell mobilization, and found that chemo-free strategy was associated with lower costs [13]. On the other hand, a Chinese group found no significant difference between the efficiency of steady-state and chemotherapy-based mobilization approaches, while the more frequent plerixafor use resulted in a high financial burden when no chemotherapy was administered [14].

We also investigated the impact of induction therapies administered before the stem cell harvesting procedures. Lenalidomide is known to have a negative effect on stem cell mobilization, and our results are also in accordance with this finding. Daratumumab administration has been recently approved in the first-line therapy of transplant-eligible patients [15]. Results from pivotal studies confirmed that patients who received daratumumab-containing triplets are more likely to require plerixafor support upon the stem cell collection [15, 16]. Our preliminary data also showed that previous daratumumab treatment did not influence the success rate of stem cell harvesting procedure; however, the need for plerixafor administration was significantly higher and the amount of collected stem cells was significantly lower than in those patients who were daratumumab-naive.

The main limitation of this work is the patients included in the study were recruited from only one hematological center. Moreover, daratumumab is still not widely available in the first-line therapy of MM; therefore, a relatively low number of patients could receive it as part of the induction treatment. We think that adding data of other centers as well as including more patients treated with daratumumab may make our results more remarkable.

Our study is the first that highlights the negative impact of daratumumab pretreatment on the efficacy of stem cell collection. Our results support that chemotherapy-based mobilization strategies are still cost-effective, despite the higher rate of infectious complications and longer hospital stays. The results presented here also suggest that the reduced potential for mobilization expected both with lenalidomide and daratumumab pretreatment and with solo G-CSF can be overcome by the administration of plerixafor. This recognition may motivate caretakers to choose a chemotherapy-free strategy with a lower risk of infections for the frail population, thereby bringing personalized medicine closer to MM patients.

Acknowledgments

None to declare.

Financial Disclosure

There was no specific funding source to be mentioned.

Conflict of Interest

None of the authors had any conflict of interest.

Informed Consent

No informed consent was required for retrospective data collection.

Author Contributions

Conceptualization, formal analysis, data curation, visualization, and writing original draft preparation: NOA, KF and LV; treatment of the patients, investigation and resources: NOA, KF, LIP, GK, AI and LV; supervision: LV; writing review and editing: NOA, KF, LIP and LV. All authors have read and agreed to the published version of the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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Journal of Hematology is published by Elmer Press Inc.