Сопоставление мобилизации стволовых клеток с химиотерапией и цитокином (G-CSF) и цитокином в одиночку у пациентов миеломы (MOCCCA): случайная стадия II, открытая маркировка, испытание ненарушения.

Introduction

A rapidly growing number of novel emerging treatment options have recently been reported for relapsed/refractory myeloma patients, including CAR-T-cell therapies and bispecific antibodies. In first line treatment, a bortezomib and lenalidomide-based induction regimen eventually combined with anti-CD38 treatment followed by high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) remains standard of care in newly diagnosed and fit myeloma patients [ 1 – 8 ]. Despite several decades of experience with HDCT/ASCT in myeloma patients, and despite its frequent use, the optimal strategy for CD34+ mobilization preceding ASCT remains a matter of debate. Cyclophosphamide combined with granulocyte colony-stimulating factor (G-CSF) or G-CSF alone is most frequently used for peripheral stem cell mobilization [ 9 , 10 ]. In Switzerland, the preferred mobilization treatment before ASCT is non-myelosuppressive chemotherapy with a single-dose of vinorelbine, a vinca alkaloid, combined with G-CSF, which provides reliable, safe and highly predictable collection of sufficient peripheral stem cells in a single-day procedure [ 11 – 14 ]. Vinorelbine is neurotoxic and can aggravate pre-existing neuropathy [ 15 , 16 ]; therefore, in patients with pre-existing neuropathy gemcitabine, an antimetabolite, together with G-CSF is alternatively used and has been reported to be safe while somewhat less efficient for stem cell mobilization [ 13 , 17 ]. However, up to 20% of patients are poorly mobilizing after both chemotherapy and G-CSF or with G-CSF alone. In such patients, the CXCR4 antagonist plerixafor is administered as additional rescue treatment usually enabling sufficient CD34+ mobilization [ 18 – 21 ].

Previous reports suggest that the use of G-CSF alone—as compared to chemotherapy plus G-CSF—is a reasonable mobilization strategy, even though stem cell yields are commonly lower [ 22 – 25 ]. However, it is currently unknown whether cytostatic chemotherapy is necessary at all for similarly reliable mobilization as with combined chemotherapy and G-CSF. This randomized, monocentric, non-blinded, phase II study aimed to demonstrate that the mobilization with G-CSF alone is non-inferior compared to a standard combined mobilization strategy with vinorelbine/gemcitabine and G-CSF. To our knowledge, it is the first randomized comparison between a non-myeloablative mobilization strategy and G-CSF only.

Methods

Study design

This was a randomized, monocentric, non-blinded, phase II trial recruiting from September 2018 to December 2022 at the University Hospital of Bern, Switzerland. The study had approval by the local Ethics Committee of Bern, Switzerland, with the decision number 2018-00615.

Patients

Patients with multiple myeloma or amyloidosis had to be older than 18 years and considered clinically fit for subsequent consolidation with high-dose melphalan-based chemotherapy with autologous stem cell support. Eligible were patients after standard first-line induction treatment for multiple myeloma or second-line induction treatment in refractory multiple myeloma. Pregnancy had to be excluded in female patients. The data was collected by the study investigator in the RED Cap Software. All patients gave written informed consent.

Randomization

In total, 136 patients were planned to be randomized 1:1 to either chemotherapy plus G-CSF (CG) or G-CSF only (G), using RED Cap software as randomization tool. Remission status at registration, preexisting peripheral neuropathy, and prior lenalidomide treatment were applied as parameters for a randomized stratification.

Procedures

In the experimental arm (G) patients received G-CSF (filgrastim, weight adapted) twice daily from day 1 until the morning dose of the last day of stem cell collection. In the standard arm, (CG) patients received either a single dose of vinorelbine 35 mg/m 2 intravenously over 10 min, or, in case of preexisting peripheral neuropathy, a single dose of gemcitabine 1250 mg/m 2 intravenously over 30 min. on day 1, whereas G-CSF was applied twice daily from day 4 until the morning dose of the last day of stem cell collection.

In both groups, G-CSF was given at 60 Mio I.U. s.c./d (split in two daily doses of 30 Mio) for patients ≤69 kg body weight, at 78 Mio I.U. s.c./d (48 Mio I.U. in the morning and 30 Mio I.U. in the evening) for patients between 70 and 89 kg body weight, and at 96 Mio I.U. s.c./d (in two daily doses of 48 Mio I.U.) for patients ≥90 kg body weight.

The planned day for stem cell collection was day +5 in G patients, and day +8 in CG patients. The number of circulating peripheral CD34+ stem and progenitor cells was first assessed at the planned collection day and if applicable all subsequent days until stem cell apheresis. Apheresis procedure was initiated when at least 20.0 × 10 6 /l circulating CD34+ cells were present in the peripheral blood. At a CD34+ count of between 10.0 and 20.0 × 10 6 /l, stem cell collection was postponed to the following day and filgrastim was continued until collection. When the CD34+ count was below 10 × 10 6 /l, plerixafor was given for additional stimulation and the apheresis procedure was scheduled for the subsequent day.

CD34+ assessment in the peripheral blood and of stem cell harvests was performed by flow cytometry on a CANTO (BD Biosciences, Switzerland) flow cytometer according to ISHAGE guidelines.

Hematological engraftment was assessed daily and was defined as the first day of neutrophils rising above 0.5 × 10 9 /l and platelets rising above 20.0 × 10 9 /l for three days after HDCT in the absence of platelet transfusion.

The presence of del(17p), t(4;14) and t(14;16) were considered high risk cytogenetics.

Outcomes

The primary objective was to demonstrate non-inferiority of mobilization with G-CSF alone compared to combined chemotherapy and G-CSF. Mobilization was considered successful if the total number of collected CD34+ cells in a single day procedure was exceeding 5.0 × 10 6 /kg body weight in the absence of additional use of plerixafor. This collection goal enables two ASCTs (or an additional CD34+ boost in the eventual case of engraftment failure). We assumed a success rate of 85%. The non-inferiority margin was 0.15 suggesting that G-CSF only was considered non-inferior to chemotherapy and G-CSF, if its success rate was no more than 15% worse than with CG.

The secondary objectives were to assess the need of additional use of plerixafor, pain and quality of life associated with the mobilization procedure in patients treated with chemotherapy and G-CSF as compared to cytokine stimulation alone. Additional secondary objectives were the assessment of differences in hematologic engraftment after ASCT and the comparison of adverse events between both treatment arms.

Toxicities and adverse events (AE) were assessed according to the CTCAE 5.0 during the study period (Supplementary Table S 1 ). Quality of life and pain levels were assessed using the EORTC Q30 questionnaire filled at the first and the last day of the mobilization treatment [ 26 , 27 ] (Supplementary Table S 2 ). For pain assessment there was an additional numeric rating scale [ 28 ] (Supplementary Fig. S 1 ).

Statistical analyses

Sample size was calculated beforehand using the PASS11 software (NCSS Statistical Software, Kaysville, UT, United States). We set the alpha level to 0.05, the success rate to 0.85 and the non-inferiority margin to −15%. The sample size calculation revealed a minimal sample size of 136 patients (68 patients per arm) to achieve 80% power. For the primary endpoint, a non-inferiority margin of −15% was applied. In an intention-to-treat analysis, we calculated 95% confidence intervals for the difference in proportions between the two groups and applied a two-tailed chi-square test. Other categorical variables were presented as numbers and percentages. Statistical differences in these variables between the groups were assessed using either a chi-square test or, in cases where the patient count in one field of a 2 × 2 table was below 5, a Fisher’s exact test. For numerical variables, we presented the median and interquartile range. Differences between groups in numerical variables were examined using a Wilcoxon-Signed-Rank test. All analyses were done with R version 4.3.1 using the “stat” and “tableone” packages.

Results

Between September 2018 and October 2022, we included 136 patients with multiple myeloma and amyloidosis at the University Hospital of Bern. In the CG arm, all patients received the stem cell mobilization treatment as planned: 33 (49%) patients received gemcitabine as mobilization chemotherapy, and 35 (51%) patients had vinorelbine. Two patients in the G arm did not receive the mobilization treatment, one patient due to an intermittent acute neurologic event (stroke) and one patient withdrew consent.

Patients and disease characteristics are summarized in Table 1 . There were no statistically significant differences between both treatment groups. The median age in the cohort was 62.0 years (median IQR 55.8–67.0), 61.5 years (median IQR 56.8–66.3) in the CG arm and 63.0 years (median IQR 54.8–68.3) in the G arm. High-risk cytogenetics were observed in 15 (22%) patients in the CG group and in 11 (16%) patients in the G group. The most frequently used induction regimen was bortezomib, lenalidomide and dexamethasone (VRD) in both groups. 60 (88%) patients in the CG arm and 62 (91%) patients received ≤4 lenalidomide containing cycles (Table 2 ).

94 (69%) of all patients had successful stem cell mobilization with total collected CD34+ cells >5.0 × 10 6 CD34+ cells/kg in a single day apheresis procedure without additional plerixafor, 53 (78%) patients in the CG arm and 41 (60%) in the G arm ( p = 0.04) (Table 3 ). The difference between both arms equals 18% (95% CI: 1%, 34%) in favor of the CG therapy; thus, the non-inferiority margin (15%) was not maintained. Therefore, our data suggest that G-CSF monotherapy must be considered inferior to CG therapy regarding CD34+ cell collection.

In both groups, stem cell collection was started at the planned apheresis day in 48 (71%) patients in each group (Fig. 1 ). A single day apheresis procedure was observed in 64 (94%) patients in the CG group and 61 (89%) patients in the G group. The median number of totally collected CD34+ cells was different in both groups, with 9.99 × 10 6 /kg b.w. (median IQR 7.40–13.88) in CG patients and 7.42 × 10 6 /kg b.w. (median IQR 5.61–10.56) in patients with G alone ( p < 0.001) (Table 3 , Fig. 2 ). In 62 (91%) patients in the CG arm, the mobilization goal ( ≥ 5.0 × 10 6 /kg b.w. CD34+ cells) was achieved, compared to 56 (82%) patients in the G arm ( p = 0.26). There was a single patient with mobilization failure (CD34+ collected <2.0 × 10 6 /kg b.w.) in the G arm (who nevertheless proceeded to HDCT and ASCT with successful engraftment) (Table 3 ). More patients in the G arm needed additional plerixafor with 18 (26%) patients versus 9 (13%) patients in the CG arm, respectively ( p = 0.06) (Table 3 ).

In total, 130 (96%) patients underwent high dose chemotherapy with melphalan and subsequent ASCT. 66 (97%) patients had ASCT in the CG arm, with two patients withdrawing consent. In the G arm, three patients withdrew consent (one of them before mobilization treatment started) and one patient had a stroke event before mobilization treatment, thus, 64 (94%) patients ultimately received ASCT.

The median time until neutrophil engraftment (neutrophil count > 0.5 × 10 9 /l) after ASCT was 11 (median IQR 10–15) days in CG patients compared to 12 (median IQR 11–17) days in G patients ( p = 0.31), and the median time until platelet engraftment (platelet count ≥ 20 × 10 9 /l) was 12 days in both groups ( p = 0.17) (Table 4 ). There was one single (1%) patient with an engraftment syndrome after HDCT and ASCT in G arm.

There were no significant differences in the two groups for duration of hospitalization for HDCT and ASCT with a median of 20 days (median IQR, 18–23) in the CG group and 21 days (median IQR, 18–22) in the G group ( p = 0.92). Most patients, 37 (54%) in the CG arm and 44 (65%) in the G arm, had at least one febrile episode during hospitalization for HDCT and ASCT ( p = 0.22) (Table 4 ).

Adverse events from start of mobilization treatment until ASCT are summarized in the Supplementary Table 3 and indicate no significant difference between both arms.

Between both arms, there were no significant differences regarding the pain assessment reported on the first and on the last day of the mobilization treatment. The median pain level in the G arm was 3/10 at both time points ( p = 0.31), whereas in the CG arm the median pain level was 3/10 on the first day of mobilization treatment and 4/10 on the collection day ( p = 0.19) (Fig. 3 ). There was no difference in the quality of life assessment (EORTC Q30 questionnaire) under treatment between the two arms on the first and the last day of the mobilization procedure (Supplementary Table 4 ).

Discussion

For fit myeloma patients being planned for HDCT/ASCT, chemotherapy such as with cyclophosphamide together with G-CSF or a strategy with G-CSF alone are commonly used for peripheral stem cell mobilization [ 9 , 10 , 29 ]. In Switzerland, the standard of care is a non-myeloablative chemotherapy regimen such as vinorelbine plus G-CSF or gemcitabine plus G-CSF providing low risk of fever in neutropenia, ambulatory cost-efficient management of the mobilization treatment and a reliable apheresis planning [ 11 , 13 , 15 , 17 ]. Whether non-myeloablative chemotherapy is, in fact, needed for successful mobilization remains unclear, as a direct prospective comparison to a sole cytokine mobilization regimen has so far not been performed. In this prospective randomized phase-II study, we directly compared the mobilization potential of cytokine stimulation with G-CSF alone versus combined chemotherapy with vinorelbine and G-CSF (or in case of relevant neuropathy with gemcitabine and G-CSF) applying a non-inferiority design.

First, our study failed to demonstrate non-inferiority of G-CSF only with regards to peripheral CD34+ mobilization compared with combined non-myeloablative chemotherapy and G-CSF stimulation. In fact, the chemotherapy and G-CSF combination allowed to collect at least 5.0 × 10 6 CD34+ cells/kg b.w. in the absence of plerixafor (as was the definition for a successful autologous CD34+ harvest in this study) in a single day procedure in 78% of all patients, whereas only 60% of patients reached this goal with G-CSF alone. Nevertheless, all but six patients (two in the CG arm and four in the G arm; all for unrelated reasons with patient wish in five cases, and a neurologic event before mobilization in one patient) ultimately proceeded to ASCT.

Our findings support previous data, comparing G-CSF and chemotherapy (cyclophosphamide) to G-CSF alone, indicating that collected stem cell yields are commonly higher in patients who received chemotherapy in addition to G-CSF, as the median number of collected CD34+ cells was 9.99 × 10 6 /kg b.w. in the chemotherapy group compared to 7.42 × 10 6 /kg b.w in patients with a sole cytokine mobilization ( p < 0.001) [ 22 , 23 , 25 ]. With a G-CSF only mobilization regimen, >20% of patients are known to be poor CD34+ mobilizers [ 30 ]. In our population, 26% of patients in the G-CSF group received at least one dose of plerixafor. Even though the difference between our arms was not significant, plerixafor was given twice as often in the G-CSF only arm to achieve sufficient stem cell yields. Notably, with the option of salvage plerixafor and several collection days, all patients except one achieved a total number of collected CD34+ cells above 2.0 × 10 6 /kg b.w.

There were no significant differences in quality of life from start to end of mobilization treatment in both groups. The duration of hospitalization, number of febrile episodes and time to hematologic engraftment after HDCT showed no significant difference between the chemotherapy/G-CSF and the G-CSF only group.

Our data suggests no significant difference in adverse events during mobilization between the CG and the G arm. However, the report of patients with infections during or related to mobilization treatment with vinorelbine/gemcitabine is with 4 (6%) very low compared to the expected infection rate with an myeloablative mobilization treatment with cyclophosphamide which has been demonstrated to be 10–25% [ 22 , 31 , 32 ].

Our study suggests that G-CSF only is less effective than the chemotherapy/G-CSF combination with regards to CD34+ mobilization. This advocates that chemotherapy/G-CSF mobilization with vinorelbine/G-CSF for patients without pre-existing polyneuropathy or with gemcitabine/G-CSF for patients with pre-existing polyneuropathy should remain standard of care. However, the data also supports previous findings suggesting that—in cases where chemotherapy is preferred to be avoided for whatever reason—successful stem cell mobilization is also possible with G-CSF alone with the salvage option of additional plerixafor. However, we were not able to identify a clear subset of patients who would benefit from G-CSF only.

Even if the mobilization chemotherapy regimens with gemcitabine or vinorelbine are considered non-myeloablative and are usually well tolerated, cytotoxic agents may harbour the risk of fever in neutropenia, anaemia, gastrointestinal toxicities, and other complications. The selection of such regimens should consider these potential side effects.

Our study provides the first randomized comparison between a non-myeloablative mobilization strategy and G-CSF only, and these results may contribute to further define the most appropriate mobilization strategy for an individual myeloma patient.

Supplementary information

Supplementary tables and figures

Author contributions

TP was responsible for conceptualisation, methodology, formal analysis, funding acquisition, validation, supervision, writing the original draft; BJ was responsible for conceptualisation, funding acquisition, formal analysis, investigation, writing the original draft; LT was responsible for formal analysis, investigation, writing the original draft; HN was responsible for methodology, software; CV was responsible for project administration, data curation; UB edited and critical reviewed the manuscript. TP, BJ, GR, MS, MD, AW, SS, MH provided patients to the study. All authors contributed to writing the manuscript and approved the final version.

Funding

This trial was supported by a grant of the EMPIRIS foundation Zurich Switzerland. Open access funding provided by University of Bern.

Data availability

The datasets generated during and analysed during the study are available from the corresponding author on reasonable request.

Competing interests

MD received financial support for attending haematology meetings from Kite Gilead/Novartis and serves as an advisory board member for Novartis. There are no financial disclosures from any of the other authors.

Ethics approval and consent to participate

We confirm that all methods were performed in accordance with the relevant guidelines and regulations. The study had approval by the local Ethics Committee of Bern, Switzerland, with the decision number 2018-00615. Written informed consent was obtained from all participants.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Barbara Jeker, Laura Thalmann.

Supplementary information

The online version contains supplementary material available at 10.1038/s41409-024-02468-z.

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Associated Data

Supplementary Materials

Supplementary tables and figures

Data Availability Statement

The datasets generated during and analysed during the study are available from the corresponding author on reasonable request.