The aim of the IFM2005-01 phase 3 multicenter study (EudraCT 2005–000537–38, Clinicaltrials.gov NCT00200681) was to compare prospectively efficacy and safety of bortezomib and dexamethasone with vincristine–doxorubicin–dexamethasone (VAD) as induction before autologous stem cell transplantation (ASCT) in patients with previously untreated myeloma less than 66 years of age. The primary end point was post-induction complete response and near-complete response rate. An important issue raised by this study was that of stem cell collection in the bortezomib–dexamethasone arm.1, 2
Patients were centrally randomized (1:1:1:1) to receive VAD induction plus no consolidation (arm A1), VAD plus dexamethasone, cyclophosphamide, etoposide and cis-platinum consolidation (A2), bortezomib–dexamethasone plus no consolidation (B1) or bortezomib–dexamethasone plus dexamethasone, cyclophosphamide, etoposide and cis-platinum consolidation (B2). VAD comprised four 4-week cycles of vincristine 0.4 mg/day and doxorubicin 9 mg/m2/day by continuous infusion, days 1–4, plus dexamethasone 40 mg orally on days 1–4 (all cycles) and 9–12 and 17–20 (cycles 1–2). Bortezomib–dexamethasone comprised four 3-week cycles of bortezomib 1.3 mg/m2 intravenously, days 1, 4, 8 and 11, plus dexamethasone 40 mg on days 1–4 (all cycles) and 9–12 (cycles 1–2). Dexamethasone, cyclophosphamide, etoposide and cis-platinum comprised two 4-week cycles of dexamethasone 40 mg, days 1–4, plus cyclophosphamide 400 mg/m2, etoposide 40 mg/m2 and cis-platinum 15 mg/m2 per day by continuous infusion, on days 1–4. Stem cell mobilization was undertaken with granulocyte-colony-stimulating factor (G-CSF) 10 μg/kg/day from day 15 of the third induction cycle. If stem cell collection was inadequate, a second mobilization was undertaken with cyclophosphamide 3 g/m2 plus G-CSF 5 μg/kg/day after induction cycle 4. The target yield was 5 × 106 CD34+ cells/kg allowing a tandem transplant procedure. Conditioning for the first transplant comprised melphalan 200 mg/m2. Response was evaluated 1–3 months later. A second transplant was not conducted for patients achieving at least very good partial response. Patients achieving less than very good partial response could undergo a second autologous procedure.
A total of 493 patients were enrolled and 482 were randomized; 242 received VAD induction (arm A: 121 A1, 121 A2) and 240 received bortezomib–dexamethasone (arm B: 121 B1, 119 B2). A better response rate was observed in bortezomib–dexamethasone arm. Results for both efficacy and toxicity of induction therapy will be reported in depth elsewhere.3
A total of 441 out of 482 patients were evaluable for stem cell collection, 216 in VAD and 225 in bortezomib–dexamethasone arms, respectively. Overall, 41 randomized patients did not receive G-CSF for stem cell collection due to progressive disease (8 cases), toxic deaths (8), severe adverse events (17), patient's refusal (2), poor performance status (4), diagnosis of lung cancer during treatment (1), diagnosis of amyloidosis during treatment (1). After one mobilization with G-CSF, median yields of 8.50 and 6.80 × 106 CD34+ cells/kg were obtained from patients receiving VAD and bortezomib–dexamethasone, respectively, with a mean of 1.63 and 2.05 aphereses (Table 1). In total, 98 and 97% of patients, respectively, had yields >2 × 106 cells/kg, and 11 and 23%, respectively, had yields <5 × 106 cells/kg. Thirteen and 25% of patients, respectively, underwent a second mobilization with cyclophosphamide+G-CSF. After this second procedure, no patient in arm A and only 1 in arm B had yields < 2 × 106 cells/kg, and 5% of patients in arm A and 6 % of patients in arm B had yields <5 × 106 cells/kg precluding a tandem transplant procedure, if needed.
Of the evaluable population, 200 (82.6%) and 207 (86.2%) patients who had received VAD and bortezomib–dexamethasone induction, respectively, underwent a first ASCT. Thus, despite adequate stem cell collection, high-dose melphalan and ASCT were not performed in 34 patients, due to progressive disease (15 cases), patient's refusal (3), renal function impairment (2), severe infections (6), poor performance status (4), respiratory failure (2), precluding high-dose therapy or toxic deaths after stem cell mobilization (2). A median number of 3.77 and 3.16 × 106 CD34+ cells/kg were infused in patients enrolled in arm A and arm B, respectively, during the first ASCT procedure (Table 2). There was no difference regarding duration of hospitalization, duration of neutropenia or thrombocytopenia, transfusion requirements, duration of G-CSF administration or antibiotic uses in the 2 arms of the trial. Two toxic deaths were observed in arm A (1%) versus 1 in arm B (0.5%). A better response rate following the ASCT was observed in bortezomib–dexamethasone arm, and results for outcome and for the need of a second ASCT will be reported in depth elsewhere.3
The IFM2005-01 trial showed the superiority of bortezomib–dexamethasone over VAD before ASCT. Other recent studies also indicate that this combination is highly effective4, 5, 6 and could be considered as the backbone of induction regimens before high-dose therapy.7, 8, 9
We here report that a single mobilization with G-CSF was adequate and allowed the harvest of a sufficient number of CD34+ cells for a single transplant in 97% and for a tandem transplant in 77% of the patients treated upfront with bortezomib–dexamethasone. Thus, less than one-fourth of the patients of the bortezomib–dexamethasone arm required subsequent potentially toxic chemomobilization with cyclophosphamide plus G-CSF to reach the target yield of 5 × 106 CD34+ cells/kg. In comparison with VAD, the median number of CD34+ cells harvested in the bortezomib–dexamethasone arm was significantly lower without impairing the ability of performing ASCT. An identical number of patients in both arms of the study (98 and 97%, respectively) had yields >2 × 106 CD34+ cells/kg high enough to perform a single ACST, but a higher number of patients in the bortezomib–dexamethasone arm required a second mobilization using cyclophosphamide plus G-CSF to reach the target of 5 × 106 CD34+ cells/kg. This is not surprising as doxorubicin infused with the VAD regimen induces some degree of cytopenia improving stem cell harvest after G-SCF priming. The course of the first ASCT was very similar across the two arms of the study, despite a lower median number of CD34+ cells infused in the bortezomib–dexamethasone arm. Hematologic recovery was identical as well as transfusion requirements and duration of hospitalization.
This study, the largest one reporting on stem cell collection after bortezomib–dexamethasone as induction prior to ASCT, provides important informations for the management of myeloma patients treated with high-dose therapy in the era of novel agents.
Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia 2009; 23: 1904–1912.
Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 2009; 114: 1729–1735.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib-dexamethasone is superior to vincristine-doxorubicin-dexamethasone as induction prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: results of the IFM2005-01 phase 3 trial. J Clin Oncol 2010, in press.
Harousseau J-L, Attal M, Leleu X, Troncy J, Pégourié B, Stoppa AM et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91: 1498–1505.
Jagannath S, Durie BG, Wolf JL, Camacho ES, Irwin D, Lutzky J et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005; 129: 776–783.
Rosiñol L, Oriol A, Mateos MV, Sureda A, Garcia-Sanchez P, Gutierrez N et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J Clin Oncol 2007; 25: 4452–4458.
Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N et al. Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 2008; 141: 512–516.
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. A phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: superior clinical outcomes with VTD compared to TD. Blood 2009; 114: 351a.
Richardson P, Lonial S, Jakubowiak A, Jagannath S, Raje NS, Avigan DE et al. High response rates and encouraging time-to-event data with lenalidomide, bortezomib, and dexamethasone in newly diagnosed multiple myeloma: final results of a phase I/II study. Blood 2009; 114: 1218a.
The authors declare no conflict of interest.
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Moreau, P., Hulin, C., Marit, G. et al. Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005–01 trial. Leukemia 24, 1233–1235 (2010). https://doi.org/10.1038/leu.2010.82
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