Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34+ cell yields as compared with TD (9.75 vs 10.76 × 106 CD34+ cells/kg, P=0.220). For poor mobilizers (<4 × 106 CD34+ cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34+ cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization.
High dose chemotherapy (HDT) with auto-SCT is considered the standard of care for young and fit patients with newly diagnosed multiple myeloma (MM).1 Compared with conventional chemotherapy, newer doublet regimens incorporating either the immunomodulatory drug thalidomide or the first-in-class proteasome inhibitor bortezomib in combination with dexamethasone have increased the rate of high-quality responses before auto-SCT.2, 3 More recently, we and other groups have shown that the triplet combination of bortezomib, thalidomide and dexamethasone (VTD) is superior to two-drug regimens including thalidomide and dexamethasone (TD) or bortezomib and dexamethasone (VD) in terms of enhanced rates of CR and very good PR, a gain translating into prolonged PFS.4, 5, 6 However, the effects of these new drugs on CD34+ hematopoietic stem cells and the niches in which they reside have not been specifically evaluated, particularly in phase 3 clinical studies. Conflicting data, which need to be addressed, exist about the possible interference of some of these drugs, including structurally different agents that belong to the same pharmacological class on PBSC harvest. Although in several studies the total counts of CD34+ stem cells collected after prior exposure to TD or triplet thalidomide-based regimens were lower in comparison with conventional chemotherapy,2, 7 it is likely that this negative effect, if any, is of little clinical relevance and doesn’t impact patients’ ability to receive auto-SCT.2 Unlike thalidomide, lenalidomide is toxic to normal hematopoietic stem cells and suppresses their motility, an effect which, combined with the antiangiogenic properties of the drug, can adversely impair PBSC harvest, particularly after a relatively long treatment duration.8, 9 VD as induction therapy did not negatively affect PBSC mobilization.10 However, when bortezomib at a reduced dose was added to thalidomide and dexamethasone, a significantly lower number of collected CD34+ cells was reported in comparison with VD.5 Similarly, a three-drug combination including CY, thalidomide and dexamethasone was associated with mobilization failure in about 25% of the patients,11 and subjects who received induction therapy with thalidomide, doxorubicin and dexamethasone were reported to have a significantly lower median CD34+ cell yield compared with patients receiving standard chemotherapy.12 Although these results might suggest that triplet induction regimens including one or two of the novel agents thalidomide and bortezomib may be associated with an increased risk for impaired PBSC procurement, conclusive data have not been reported so far. To address this issue, we analyzed the impact of induction treatment with either VTD or TD on PBSC collection, which was a secondary endpoint of the GIMEMA MMY-3006 study.
Materials and methods
The GIMEMA MMY-3006 study (NCT01134484) was a phase 3 open-label, multicentre trial aimed to assess the efficacy and safety of VTD versus TD as induction therapy in preparation for double auto-SCT in newly diagnosed MM. The design, objectives and main results of the study have previously been reported.4, 13 In brief, after three 21-day cycles of VTD or TD induction therapy, all patients were to receive a single dose of CY (ID-CTX) at 4 g/m2, followed by G-CSF 10 μg/kg/day starting from day 2 after ID-CTX until the last day of leukapheresis. Study protocol was designed to perform a double auto-SCT with high-dose melphalan 200 mg/m2 and the target threshold was set at 4 × 106 CD34+ cells/kg. Patients who failed to achieve the threshold dose were allowed to undergo an additional collection of PBSCs either with high-dose G-CSF alone (20 μg/kg) or BM withdrawal. Patients who yielded <4 × 106 CD34+ cells/kg could continue study protocol provided that their CD34+ count was ⩾2 × 106/kg to support a single course of high-dose melphalan. Protocol design and patient flow chart between ID-CTX and auto-SCT are summarized in Figure 1.
Primary study endpoint was the rate of CR and near CR after VTD or TD induction therapy. Safety and toxicity of the triplet and doublet induction regimens, including PBSC collection, was a secondary study endpoint, and was specifically addressed in this sub-analysis. Continuous data were expressed as median with inter quartile range (IQR) and were assessed by Kolmogorov–Smirnov test or Wilcoxon–Mann–Whitney test, as appropriate. Discrete data were expressed as frequencies and percentages and were assessed by the χ2-test or Fisher's exact test, as appropriate. The Kaplan–Meier method was used to estimate time to progression (TTP), PFS and OS, while curves were compared using the log-rank test. A multivariate Cox regression analysis was done to identify independent factors associated with TTP, PFS and OS. Statistical analyses were performed using Stata v.11 (Stata Statistical Software, StataCorp, College Station, TX, USA) and statistical significance was set at P<0.05.
The study enrolled 480 patients, of which 435 (223 randomized to the VTD arm and 212 to the TD arm) received ID-CTX to mobilize PBSCs and formed the basis of the present analysis.
Baseline characteristics of the 435 patients are reported in Table 1. Rates of high-quality responses were significantly higher in the VTD arm, with 32% and 63% of patients achieving at least near CR and very good PR compared with 13% (P<0.001) and 31% (P<0.001) of those randomized to TD, respectively. The two treatment groups were comparable with respect to the time elapsing between the start of induction and the mobilization phase.
The median number of collected CD34+ cells was 9.75 × 106/kg in the VTD arm and 10.76 × 106/kg in the TD arm (P=0.220; Supplementary Table 1). A harvest of >10 × 106 CD34+ cells/kg was yielded in 50% (n=110) and 58% (n=123) of VTD- and TD-treated patients (P=0.228), respectively, and identified the so-called subgroup of excellent mobilizers. Only 13 patients (6%) in the VTD group and 15 patients (7%) in the TD group failed to yield the threshold dose of 4 × 106 CD34+ cells/kg, and were classified as poor mobilizers; 5 patients in each treatment arm yielded <2 × 106 CD34+ cells/kg and were referred to as unsuccessful mobilizers. In both treatment arms, the target threshold was achieved after the first mobilization in 91% of patients (P=0.867). Of these, almost half underwent a single leukapheresis(Supplementary Table 1).
A second mobilization was performed in 31 patients (18 in VTD and 13 in TD, P=0.432), of which 27 were mobilized with G-SCF alone.
ID-CTX was well-tolerated and no treatment-related death was registered. A single patient died suddenly 30 days after CD34+ cell collection, but the death was considered not related to study drugs or mobilization procedure by treating physicians. ID-CTX was received by the majority of the patients (86% in VTD and 82% in TD, P=0.251) as an in-patient procedure, with a median time of hospitalization of 4 days. Hematologic toxicity and transfusion requirements were comparable between the two treatment arms, as was the occurrence of grade 3–4 infective complications (2% in VTD vs 3% in TD) (Supplementary Table 2).
Of the 426 patients who completed mobilization, 218 in the VTD group and 201 in the TD group subsequently proceeded to auto-SCT (Figure 1). One patient in the VTD arm discontinued study protocol due to toxicity. In the TD arm, six patients discontinued due to toxicity (four patients) or disease progression (two patients).
After the first course of high-dose melphalan a median number of 4 × 106 and of 4.5 × 106 CD34+ cells/kg were infused in patients randomized to the VTD and TD arms, respectively (P=0.01). No differences were seen between the two groups regarding hematologic recovery, with the only exception of the median time to platelet engraftment (that is, >20 000/mm3), which was slightly longer in the VTD group (12 vs 11 days, P=0.002). Non-hematologic toxicity was comparable between the two arms.
An univariate analysis of patient-, disease- and response-related variables potentially predictive for a successful PBSC mobilization revealed a significant relationship between the presence at baseline of both ISS stage 1–2 (P=0.004) and Hb>10.5 g/dL (P=0.008) and a CD34+ cell harvest⩾4 × 106/kg (Table 2). Achievement of CR and near CR after induction treatment (P=0.013) was an additional prognosticator for successful PBSC yield. These variables well-predicted for the probability of collecting between 4 and 10 × 106 CD34+ cells/kg or ⩾10 × 106 CD34+ cells/kg, confirming that the subgroups of ‘good’ and ‘excellent’ mobilizers could be pooled together. Conversely, age, platelets, C-reactive protein, cytogenetic abnormalities and BM plasma cell infiltration before harvest did not show any significant relationship on CD34+ cells yield.
When the analysis was performed according to treatment arm randomization, none of the above mentioned variables predicted for successful CD34+ cell harvest in patients randomized to receive VTD. By the opposite, both ISS stage and Hb concentration retained their predictive value for successful PBSC collection in the TD arm of the study.
With a median follow-up of 66 months, Kaplan–Meier analyses showed that 5-year estimates for TTP (17 vs 48%, P<0.0001), PFS (16 vs 46%, P<0.0001) and OS (50 vs 80%, P<0.0001) were significantly shorter for patients yielding <4 × 106 CD34+/kg compared with those with a harvest ⩾4 × 106 CD34+/kg (Figures 2a–c). No statistically significant differences in clinical outcomes were found between good and excellent mobilizers. This finding provided further support to the conclusion that in our analysis patients achieving the threshold dose of 4 × 106 CD34+ cells/kg could be considered as a single prognostic group.
Patients who were randomized to receive VTD induction therapy had similar TTP (P=0.3282), PFS (P=0.2418) and OS (P=0.8580) curves (Supplementary Figures 1A–C) irrespective of the number of collected CD34+ cells (that is, <4 vs ⩾4 × 106 CD34+/kg). In the group of patients randomized to TD, those who were classified as ‘poor’ and ‘unsuccessful’ mobilizers had a significantly shorter TTP (P<0.0001), PFS (P<0.0001) and OS (P<0.0001) compared with those who were classified as ‘good’ and ‘excellent’ mobilizers (Supplementary Figures 2A–C).
In a multivariate Cox regression analysis, a yield of CD34+ cells ⩾4 × 106/kg was an independent variable significantly related to extended TTP, PFS and OS (Table 3). Additional favorable prognostic variables included randomization to the VTD arm, the absence of del(17q) and/or t(4;14), beta2-microglobulin levels <3.5 mg/dL and the attainment of best CR/near CR (Table 3). When double auto-SCT was entered into the model, no significant relationship was found with clinical outcomes; conversely, the number of collected CD34+ cells retained prognostic value (P=0.001). Similar results were obtained when the number of transplant(s) actually received was replaced by the number of infused CD34+ cells. These data, while confirming that a harvest ⩾4 × 106 CD34+ cells/kg was associated with a higher number of infused CD34+ cells (median 4.4 (IQR 3.4–5.5) vs 2.3 (IQR 1.8–3.7) CD34+ × 106/kg in the subgroups of ‘successful’ and ‘poor’ mobilizers, respectively) and with >70% probability of delivering double auto-SCT, suggest that PBSC yield was per se predictive for an improved outcome.
The optimal number of PBSCs to be collected from a patient who is eligible to receive an auto-SCT still remains a critical issue. The target is dependent from various factors, of which some are related to the patient itself and include age, performance status, comorbidities and the preference to receive HDT upfront or at relapse.8 However, the number of planned auto-SCTs is the most important factor related to the harvest. Two randomized trials performed before the novel agent era prospectively compared a single versus double auto-SCT. In both studies, a survival advantage was reported with tandem auto-SCT, particularly for those patients who failed at least near CR or very good PR after the first auto-SCT.14, 15 This observation has increased the number of tandem auto-SCT offered to patients with a suboptimal response to the first course of HDT. In addition, a second auto-SCT can also be effectively administered as salvage therapy at the time of relapse after the first auto-SCT, especially to patients with a sustained remission between the first and second auto-SCT.16, 17 Therefore, in the current era, it is of primary importance to collect an appropriate number of hematopoietic stem cells and to carefully investigate the possible interference of new drugs with PBSC mobilization. In this sub-analysis of the GIMEMA MMY-3006 study, we analyzed the impact of a three-drug induction therapy including the two novel agents bortezomib and thalidomide versus TD on the ability to collect stem cells. We demonstrated that a short-term induction therapy with VTD did not adversely affect CD34+ cell harvest compared with TD. More than 90% of VTD-treated patients achieved the target value of 4 × 106 CD34+ cells/kg and more than half of patients collected a number of CD34+ cells >10 × 106/kg. Therefore, differently from several prior reports,5, 10 the triplet combination of TD with bortezomib was associated with a high rate of successful stem cell yield.
We hypothesized that the low incidence of collection failure observed in our study could be due, at least in part, to the use of a mobilization strategy including ID-CTX. The capability of CY to produce rebound CD34+ cell spillover into the blood during the recovery phase after chemotherapy-induced cytopenia has long been known.18 It has also been reported that ID-CTX and G-CSF allow for a more rapid stem cell collection and higher number of harvested CD34+ cells compared with G-CSF alone.18, 19 However, concerns on the increased rate of infectious complications following the use of ID-CTX have been raised and some studies have also shown a longer timing to engraftment after HDT and auto-SCT.20 Results from the present analysis do not confirm these data. In our patient cohort, we found a low infective morbidity, and no delayed time to engraftment after the first auto-SCT was observed. Although cross-trial comparisons may be inadequate, we confirmed that ID-CTX resulted in a higher median number of collected CD34+ cells compared with that reported with the use of G-CSF alone after induction therapy using the triplet combination of TD with either bortezomib or doxorubicin.5, 10 Recently, plerixafor has been introduced into the therapeutic armamentarium for PBSC mobilization. In several studies, the addition of plerixafor to G-CSF resulted in a significant increase in the median number of stem cells harvested in comparison with G-CSF alone.21, 22, 23, 24 Based on these and other results, the preemptive administration of plerixafor in patients previously exposed to melphalan or to more than four cycles of lenalidomide has been suggested. Outside these cases, the optimal choice between chemotherapy mobilization, including ID-CTX and G-CSF, and plerixafor combined with G-CSF to maximize PBSC yield cannot be established, due to the lack of data.25 However, adding plerixafor to the mobilization strategy increases the cost of the procedure by >50%.
An important, not yet reported, finding of our analysis was that a yield of CD34+ cells >4 × 106/kg was an independent prognosticator for extended PFS, TTP and OS in the whole patient population. We found that in the TD arm of the study, the subgroup of ‘poor’ mobilizers (for example, collecting <4 × 106 CD34+ cells/kg) had a significantly shorter PFS, TTP and OS compared with the successful mobilizer subgroup. This difference was not seen in the VTD arm of the study, suggesting that the triplet VTD regimen as induction and consolidation therapy was able to overcome the negative impact on prognosis of a poor PBSC yield. Therefore, for the first time, we demonstrated that the outcome of MM patients was influenced not only by well-recognized disease- and treatment response-related factors, but also by a new biological variable, such as the number of harvested CD34+ cells. In this context, we hypothesized that a successful PBSC mobilization might reflect a more permissive BM milieu, an hypothesis further supported by the correlation between CD34+ cell yields and achievement of best CR/near CR (43% for patients with <4 × 106 CD34+ cells/kg vs 70% for patients with ⩾4 × 106 CD34+ cells/kg, P=0.003). To further verify this hypothesis, we evaluated whether the positive impact on prognosis of a successful PBSC mobilization was related to the number of auto-SCT(s) performed or to the number of infused CD34+ cells. Although this relationship was confirmed, as logically expected, the outcome of good mobilizers was not influenced by the number of infused CD34+ cells (data not shown), supporting the hypothesis that a successful PBSC mobilization is a surrogate marker for a better outcome. These findings were also strengthened by the multivariate analyses, in which the more powerful model was the one including the number of harvested CD34+ cells as compared with that of infused CD34+ cells or to the number of transplant(s) received.
One limitation of the present study is that it was not designed to evaluate the BM microenvironment, and therefore no biological data on stromal cells are available. The lack of prognostic relevance of collected CD34+ cells in the VTD arm of the study may be a limitation of the efficiency of this new biomarker in a population of patients receiving this triplet induction therapy. However, the finding that bortezomib combined with thalidomide and dexamethasone is able to overcome the negative prognostic effect of a poor mobilization is an important notion, which might help clinicians to select the optimal treatment among the many so far available for newly diagnosed MM patients.
In conclusion, a short-term induction therapy containing two novel drugs such as bortezomib and thalidomide does not impair stem cell harvest in MM patients. The number of collected CD34+ cells has emerged as a novel and independent variable predictive for favorable outcome after auto-SCT.
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This study was funded and sponsored by the Seràgnoli Institute of Hematology at the University of Bologna, Bologna, Italy. The study was partly supported by Janssen providing bortezomib free of charge, by the University of Bologna through a grant to MC (Ricerca Fondamentale Orientata), and by BolognaAIL. FED is a Cancer Research UK Senior Clinical Fellow.
MC was the principal investigator and takes primary responsibility for the paper; AB, GP and MC designed the research and wrote the paper; AB, GP and APe performed the analysis; FP, FN, FB, SR, LC, SV, AML, MB and APa were the subinvestigators of the study and recruited the patients; PT, BAZ, EZ and KM provided patients and collected the data; MRM and SR performed cell laboratory work and collected the data; FED and GJM provided important intellectual inputs.
AB has received honoraria from Celgene, MC has received honoraria and served on speakers’ bureaux for Janssen-Cilag, Millennium Pharmaceuticals, Celgene and Novartis and has been a consultant for Janssen-Cilag and Millennium Pharmaceuticals. FP has received honoraria from Janssen-Cilag, Celgene, Schering-Plough and Roche; AP has served on an advisory committee for Celgene, Janssen-Cilag, Amgen, Bristol-Myers Squibb, Millenium and Onyx and has received honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Onyx and Amgen; MB has received honoraria from Novartis and Bristol-Myers Squibb. The remaining authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
About this article
Results from a multicenter, noninterventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor
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