Autologous Peripheral Blood Stem-Cell (PBSC) Collection Is Not Impaired by Bortezomib-Thalidomide-Dexamethasone (VTD) Induction Therapy in Newly Diagnosed Multiple Myeloma (MM)

The novel agents bortezomib, thalidomide and lenalidomide have been successfully incorporated into autologous stem-cell transplantation (ASCT) as up-front therapy for newly diagnosed MM. However, several reports have raised concerns about the impact of novel agent-based induction regimens on PBSC collection. Furthermore, the ability to successfully collect PBSCs following initial therapy with two of these newer drugs needs to be confirmed in large phase III clinical trials.

The GIMEMA Italian Myeloma Network designed a phase III study to compare VTD with thalidomide-dexamethasone (TD) as induction therapy prior to double ASCT. Primary study endpoint was the rate of complete or near complete response to each of these two induction regimens, while their toxicity profile – including the impact on PBSC mobilization and collection - was a secondary study endpoint. To address this latter issue, we performed a post-hoc analysis to compare the effect of the triplet VTD induction regimen versus the doublet TD combination on CD34+ cell collection. After three 21-day cycles of VTD or TD induction therapy, patients received intermediate dose cyclophosphamide (CTX 4 g/m²) followed by G-CSF (10 mcg/Kg/die) to mobilize and collect PBSCs. The target threshold to safely perform double ASCT was 4 × 10⁶ CD34+ cells/Kg.

Patients evaluable for PBSC collection were 435 out of the 474 who received induction therapy. Of these, 223 were initially randomized to VTD and 212 to TD induction therapy. The median number of collected CD34+ cells was 9.7 × 10⁶/Kg in the VTD arm and 10.7 × 10⁶/Kg in the TD arm (p= n.s.). The planned yield of 4 × 10⁶ CD34+ cells/Kg was achieved with a single harvest in more than 90% of patients in both treatment groups (96% in VTD and 92% in TD, p= n.s.). A yield of CD34+ cells >10 × 10⁶ /Kg was reported in 51% and 56% of patients treated with VTD and TD, respectively (p= n.s.). Only 5 patients (2%) in VTD group and 2 patients (1%) in the TD arm failed to collect more than 2 × 10⁶ CD34+ cells/Kg (p= n.s.). The majority of patients (86% in VTD and 82% in TD, p=n.s.) received CTX as an in-patient procedure, the median time of hospitalization being 4 days. Less than 5% of patients developed grade 3–4 infectious complications (2% in the VTD group vs 3% in TD, p=n.s.) which required hospitalization in only 2 patients. Following ASCT, no significant difference was observed between the two treatment arms in terms of hematologic recovery and non hematological toxicity. Kaplan-Meier curves of TTP and PFS were almost superimposable for patients with a CD34+ yield >10 × 10⁶/Kg and in the range between 4 and 10 × 10⁶/Kg (group 1). These curves were very similar also for patients who collected between 2 and 4 × 10⁶/Kg CD34+ cells or <2 × 10⁶/Kg (group 2). These two groups had significantly different clinical outcomes. Indeed, the 40-month estimates of TTP and PFS were 75% for group 1 vs 40% for group 2 and 60% vs 25%, respectively. OS at 40 months for patients with >10 × 10⁶/Kg CD34+ cells was in the 90% range, a value significantly better than what was seen in the remaining subgroups. In a multivariate Cox regression analysis, yields of CD34+ cells >10 × 10⁶/Kg and in the range of 4 to 10 × 10⁶/Kg were independently associated with prolonged PFS (p=0.001 and =0.027, respectively), while CD34+ cells >10 × 10⁶/Kg predicted for extended OS (p=0.002). Absence of t(4;14) and/or del(17q), and ISS stage 1 or 2 were additional favorable prognostic factors for both PFS and OS, while randomization to VTD independently predicted for longer PFS.

Results of the present analysis showed that both TD and VTD shared the advantage of no adverse impact on PBSC collection and the engraftment potential of collected PBSCs. The target for CD34+ cell collection (>4 × 10⁶/Kg) was achieved with a single harvest in more than 90% of patients in both treated groups and a collection failure was reported in 1% to 2% of patients. These favorable results are due to early PBSC collection, which was performed after 3 cycles of TD and VTD, and use of CTX plus G-CSF which allows better stem cell collection and less likelihood of a collection failure. Of particular note, both VTD and TD were associated with a 50% to 59% probability to collect >10 × 10⁶ CD34+ cells/Kg, a variable independently associated with extended PFS and OS.

Off Label Use: bortezomib and thalidomide used as induction therapy for newly diagnosed multiple myeloma patients. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Honoraria.