Thalidomide/Dexamethasone (TD) Vs. Bortezomib(Velcade®)/Thalidomide/Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcade® As Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): First Results of a Prospective Phase III PETHEMA/Gem Trial

Abstract

The benefit of ASCT in MM is associated with the degree of tumour decrease with the initial induction chemotherapy. In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcade® in patients 65 years-old or younger with newly diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcade® consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcade® (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. Two-hundred and seventy-five out of the 390 planned patients have been included so far. As of February 15, 2008, 190 patients (median age: 57 yrs., M:96, F:94; IgG:107, IgA:50, light chain:25, others:9) entered the study. 32 (17%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS classification was I in 38%, II in 41%, III in 20% and unknown in 1%. The prognostic factors, including cytogenetics, were similar in the 3 arms. The prognostic factors, including cytogenetics, were similar in the three arms. 173 patients (TD:61, VTD:54 and VBMCP/VBAD/Velcade:58) were already evaluable for response and toxicity to induction therapy. Efficacy and toxicity were assessed on an intention-to-treat basis. The ≥PR rate was 62%, 77% and 70% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (31%) and with VBMCP/VBAD/Velcade® (22%) compared to TD (6%) (p< 0.01). Progressive disease was significantly higher in patients with EMP (31% vs. 12%, p=0.01). This higher PD rate in patients with EMP was similar in the three arms. The incidence of grade 3 and 4 adverse events (AEs) was 38%, 54% and 50% with TD, VTD, and VBMCP/VBAD/Velcade® respectively. The total number of AEs for TD, VTD and VBMCP/VBAD/Velcade® were 37, 36 and 44, respectively. 13% of patients receiving TD developed ≥ grade 3 thrombotic events while 16% of patients in the VTD arm had grade ≥3 peripheral neuropathy. Treatment discontinuation due to toxicity was required in 8 patients (TD: 1; VTD: 5, VBMCP/VBAD: 2). 5 patients died during the induction phase (TD:3, VTD:0, VBMCP/VBAD/Velcade:2). 72 patients were evaluable for response after ASCT. The post-ASCT CR rate were higher with VTD (50%) and with VBMCP/VBAD/Velcade® (39%) compared to the TD arm (26%), although the difference did not reach statistical significance. Our preliminary analysis shows that VTD and VBCMP/VBAD plus Velcade® result in a higher CR rate than TD both before and after ASCT and that the toxicity in the three arms is not significantly different. Longer follow-up is needed to establish whether or not this higher tumour reduction is translated into a significant better long-term outcome. Updated results will be presented at the meeting.

Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

“…Many trials explored consolidation regimens with the rationale to deepen patient response. In the most recently published PETHEMA study, VRd induction, ASCT, and VRd consolidation produced a ≥CR rate of 58% (46% sCR, 12% CR) [75]. These data are consistent with the IFM phase II and phase III studies using VRd consolidation.…”

“…Response deepened over time, as well as MRD negativity. In the PETHEMA study, MRD by NGF with a cut-off sensitivity of 3 × 10 −6 progressively increased from 34.5% post-induction to 53.4 % post-ASCT, to 58% after consolidation [75]. The phase III STAMINA and EMN02/HO95 trials were designed to evaluate the role of consolidation vs. no consolidation in a randomized fashion.…”

Managing multiple myeloma: the emerging role of novel therapies and adapting combination treatment for higher risk settings

“…A study from the IFM group led by Harousseau and colleagues demonstrated that lower dose bortezomib with thalidomide and dexamethasone (vTD) was better tolerated and quite active (as opposed to higher dose bortezomib and dexamethasone alone), although the reduced dose of bortezomib may result in a lower rate of high quality of response. Similarly, Rosiñol and colleagues demonstrated convincingly that, again, the three‐drug combination of VTD was superior to both TD and combination chemotherapy with bortezomib alone (but without IMiD‐based therapy) (Cavo et al , 2008, 2010; Rosiñol et al , 2008, 2009; Harousseau et al , 2009; Moreau et al , 2010). Overall, VTD results in improved responses to induction therapy and improved responses to protocol‐directed treatment, including SCT, and (despite increased peripheral neuropathy) is associated with generally manageable side effects.…”

Multiple myeloma: Role of autologous transplantation

“…VRD has been also associated with improved OS compared with VCD and VD [56]. Induction with VRD has demonstrated high rates of deep responses [16,56,57]; in a phase 3 clinical trial more than one third of transplant-eligible NDMM patients achieved MRD negativity and almost half of the patients with high-risk cytogenetics achieved CR or better [58]. Although lenalidomide-based may be superior to bortezomib-and thalidomide-based regimens [49] and VRD has become the prevalent induction regimen in the United States, VTD or even VCD may be viable options depending on the setting and drug availability [59].…”