Superior Complete Response Rate and Progression-Free Survival after Autologous Transplantation with up-Front Velcade-Thalidomide- Dexamethasone Compared with Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma

Abstract

Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P<0.001), including CR (6% vs 21%, P<0.001), CR+nCR (12% vs 33%, P<0.001) and ≥very good partial response (VGPR) (30% vs 61%, P<0.001). Remarkably, no pt treated on VTD had disease progression, as compared to 4.5% of pts on TD (P=0.002). Serious adverse events were recorded in 13.5% of pts randomized to VTD vs 12.5% of those assigned to TD. Although grade ≥3 peripheral neuropathy (PN) and skin rash (SR) were more frequent with VTD than TD (PN: 9% vs 2.5% of pts, P=0.005) (SR: 7.5% vs 1% of pts, P=0.001), only 4 pts in the VTD arm (2 in each of the two toxicity sub-groups) necessitated early treatment discontinuation. Overall, discontinuation of primary therapy due to treatment-related adverse events was required in 4.5% of pts on VTD vs 5% of those on TD, including a single pt in VTD and 2 pts in TD who died early. Eight additional pts randomized to TD discontinued induction therapy and went off study due to disease progression. Peripheral blood stem-cell (PBSC) harvest and response to first ASCT (secondary study end points) could be assessed in 297 pts (145 randomized to VTD and 152 to TD) for whom data were available at the time of analysis. Pts who achieved the minimum threshold dose of CD34+ cells to safely perform double ASCT (≥4×106/kg) were 91% in the VTD arm vs 87% in TD; median yields were 9.3 and 10.6 (×106 CD34+ cells/Kg), respectively. Pts who actually received the first ASCT were 89% (129/145) in VTD and 80% (121/152) in TD. On an intention-to-treat basis, the rates of high-quality responses in the VTD arm were significantly higher than in TD, including CR (41% vs 20%, P<0.001), CR+nCR (54% vs 29%, P<0.001) and ≥VGPR (75% vs 53%, P<0.001). After a median follow-up of 15 months, progression-free survival (PFS) was significantly superior with VTD as compared to TD (20-month estimate: 93% vs 86%, P=0.04), while the 20-month overall survival rate was 93% for both treatment groups. We conclude that, in comparison with TD, three 21-d cycles of VTD as primary therapy for newly diagnosed MM significantly increased the CR+nCR rates, up to values previously seen with one or two autotransplants preceded by conventional chemotherapy. Importantly, response benefit with up-front VTD vs TD translated into significantly higher CR+nCR rates after ASCT and significantly improved PFS. Effective combinations of novel induction agents, such as VTD, can, thus, have a remarkable impact on both pre and post-ASCT clinical outcome. Updated results, including response to second ASCT and consolidation therapy, will be presented at the meeting.

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

“…This group was also able to demonstrate that bortezomib maintenance was well tolerated and induced additional response. Similar to the report by Cavo et al (2008), bortezomib treatment overcame poor risk caused by renal dysfunction and adverse cytogenetics, together with a beneficial effect on other adverse features associated with poor risk, including t(4;14) and 17p del. Interestingly, additional responses were also achieved with thalidomide maintenance in the conventional arm and improving outcome, pointing to the pivotal role novel therapies provide.…”

“…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.…”

Phase 2 study of two sequential three‐drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma

“…survival (PFS) compared with older induction regimens (Cavo et al, 2008;Harousseau et al, 2008). For patients who are not candidates for HDT-SCT, combinations of new and old drugs offer improved response rates, PFS and overall survival (OS) (Facon et al, 2007;San Miguel et al, 2008).…”

Multiple myeloma: chemotherapy or transplantation in the era of new drugs

“…Both regimens were active as frontline induction, with lower toxicity after PAD2. Results from a GIMEMA trial comparing Bor-Thal-Dex with Thal+ Dex induction and consolidation therapy following double ASCT with Mel 200 mg ⁄ m 2 indicate that Bor-Thal-Dex resulted in a higher ‡ PR rate after induction (33% CR+nCR, 61% ‡ VGPR vs. 12% CR+nCR, 30% ‡ VGPR) and after the first transplantation (54% CR+nCR, 75% ‡ VGPR vs. 29% CR+nCR, 53% ‡ VGPR), which was associated with significantly higher 2-yr PFS (90% vs. 80%; P < 0.001; Table 2) (47). In a phase I ⁄ II study in newly diagnosed patients, the combination Bor-Len-Dex resulted in a PR rate of 98%, including 71% ‡ VGPR and 29% CR+nCR.…”

“…Key studies investigating the use of novel chemotherapies as induction therapy before autologous stem-cell transplantation Dex, dexamethasone; Doxo, doxorubicin; HDT, high-dose therapy; HR, hazard ratio; NA, not available; NS, not significant; OS, overall survival; PLD, pegylated liposomal doxorubicin; PFS, progression-free survival; Thal, thalidomide.Palumbo and Rajkumar have been tested in combination with Dex and other chemotherapeutic agents as induction treatment in newly diagnosed patients(Table 2)(43)(44)(45)(46)(47)(48).…”