This month we will be focusing on data from the recent 12th International Myeloma Workshop (IMW) 2009. This meeting was held on February 26 - March 1, 2009 in Washington, DC. A large amount of information from that meeting was covered for you during our Best of the Day program from the IMW. I would encourage you to view those interviews to gain the perspective of a number of the national thought leaders in multiple myeloma.

“Best of the Day^SM from the 12th International Myeloma Workshop”

Advances and Controversies in Induction Therapy

Induction therapy for transplant eligible newly diagnosed patients with multiple myeloma has undergone significant evolution since the 1990’s when most of us were using the vincristine-doxorubicin-dexamethasone (VAD) regimen prior to ASCT. Thalidomide became available and studies suggested that the thalidomide-dexamethasone (TD) combination was at least as effective, better tolerated, and much more convenient than VAD. Several clinical trials have now documented that lenalidomide plus low-dose (Rd) dexamethasone is more effective than dexamethasone alone and that bortezomib-dexamethasone (VD) is also more effective than dexamethasone alone. Since both of these regimens have also been shown to have efficacy in thalidomide resistant myeloma, both are generally considered to be more effective in front-line therapy than thalidomide-dexamethasone, though for selected patients Thal-Dex may still be a reasonable option. So TD, Rd and VD are all considered reasonable front-line induction doublets for newly diagnosed patients with myeloma.

However, the importance of quality of response with induction therapy and autologous stem cell transplant (ASCT) has become an increasingly discussed topic. Is complete response (CR) before or after ASCT a surrogate for progression-free survival (PFS) or overall survival (OS)? If so, are the CR rates achievable with TD, Rd and VD the best we can do? Should we be using triplets or even 4-drug regimens in order to drive the CR rate pre and post-ASCT to as high a level as possible?

Several presentations and abstracts at the IMW addressed the subject of triplets and 4-drug front-line regimens.

Abstract 451 presented the results of a study performed by the Italian Myeloma Network or GIMEMA. This concerned a phase III trial of bortezomib-thalidomide-dexamethasone (VTD) versus TD pre- and post-melphalan-based double ASCT. Bortezomib-thalidomide-dexamethasone led to significantly higher rates of near complete response (nCR), CR and very good partial response (VGPR) both following induction therapy and post-transplant. After a median follow-up of 20 months, PFS was significantly higher for the patients receiving VTD (P = .04). At 20 months, OS figures were identical at 93%, but follow-up is considered immature.

Abstract 160 from the Spanish Myeloma Group also reported results of another phase III trial comparing induction therapy with TD versus VTD versus vincristine, BCNU, cyclophosphamide, melphalan, prednisone (VBMCP)/vincristine, BCNU, doxorubicin, dexamethasone (VBAD) followed by 2 cycles of bortezomib. Induction was then followed by melphalan based ASCT. The immunofixation negative CR rate was significantly higher for VTD (31%) and VBMCP/VBAD-bortezomib regimen (22%) compared to TD (6%) following induction. Post-ASCT CR rates were also higher for the VTD arm, but not statistically significant. Patients with poor-risk cytogenetics did better with VTD than with TD.

However, there were some concerns raised about the combination of thalidomide with bortezomib because of a surprisingly high rate of cardiac complications seen in a combined PETHEMA-GIMEMA trial (Abstract 154) comparing bortezomib-melphalan-prednisone (VMP) with bortezomib-thalidomide-prednisone (VTP). The authors reported similar efficacy in an older population, but there was a 7% grade 3 or higher cardiac complication rate with the VTP regimen. The authors concluded that thalidomide might not be the best partner for bortezomib.

Another 3-drug regimen had been evaluated initially in relapsed/refractory myeloma and more recently in newly diagnosed myeloma. The combination of bortezomib-lenalidomide and dexamethasone brings together 3 of the most effective, currently available agents for multiple myeloma.

Dr Paul Richardson updated the results of a multi-center study of the lenalidomide-bortezomib-dexamethasone (RVD) regimen in high-risk patients with myeloma (Abstract 224). Thirty-three patients were enrolled in the phase I portion of the study. Seventeen of those received the maximum tolerated dose (MTD). Thirty-five patients were then treated at the MTD doses in the phase II portion of the trial. The deep vein thrombosis (DVT)/pulmonary embolism (PE) rate was 5%. There were no incidences of grade 3 or higher peripheral neuropathy. The overall response rate was 98%, with 71% >VGPR and 36% nCR/CR. Efficacy was independent of ISS stage and cytogenetics. Median time to progression (TTP), PFS and OS have not been reached as yet.

Phase III trials are currently ongoing comparing bortezomib-dexamethasone with or without lenalidomide and lenalidomide-dexamethasone with or without bortezomib. Each of these US cooperative group trials plans to accrue approximately 400 patients.

In abstract 268, Dr Andrej Jakubowiak from the University of Michigan presented the results of a phase I/II trial performed by a team of investigators from the University of Michigan, the Dana-Farber Cancer Institute, Ohio State University, Emory University, the University of Chicago and the Princess Margaret Hospital. They have taken the bortezomib-pegylated liposomal doxorubicin-dexamethasone regimen developed by Dr Robert Orlowski and added lenalidomide. This RVDD regimen is being investigated in a phase I/II trial. Four dose levels are being evaluated and a total of 38 patients have been accrued. Thus far the RVDD regimen appears well tolerated and highly effective in newly diagnosed patients with myeloma.

Dr Shaji Kumar from the Mayo Clinic (Abstract 247) presented the initial results of another multicenter phase I/II trial with a 4 drug combination regimen in newly diagnosed myeloma. This bortezomib-dexamethasone-cyclophosphamide-lenalidomide (VDCR) program adds oral cyclophosphamide to the RVD regimen on days 1 & 8 of the 21 day cycle. The MTD phase II dose level has been established and preliminary response rates in the first 25 patients treated include >PR rate of 100%, >VGPR rate of 68% and a CR/nCR rate of 32% after 4 cycles. This regimen will form 1 arm of the 3 arm randomized EVOLUTION trial. The other 2 arms are RVD and CVD.

Finally the question of maintenance therapy following response to induction and ASCT was discussed by Dr Thierry Facon of the French IFM group. He mentioned that the goals of maintenance should include maximizing response, delaying relapse and increasing the chance of cure. The goals for choosing maintenance therapy should include minimizing toxicity in addition to providing convenient, affordable, oral therapy. Past studies evaluating corticosteroids and interferon as maintenance have failed to demonstrate efficacy. Several trials have evaluated oral thalidomide plus corticosteroids as maintenance therapy and have demonstrated increases in 3-year PFS and OS. However, examination of subgroups within those trials has shown that thalidomide efficacy was primarily in those patients failing to achieve PR following ASCT.

In the MRC IX trial reported by Gareth Morgan (Abstracts 546 & 547) patients were randomized to low-dose maintenance thalidomide or no maintenance after induction with either cyclophosphamide-thalidomide-dexamethasone (CTD) or cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) followed by ASCT. Thalidomide improved PFS in those patients achieving suboptimal responses following ASCT, but did not improve OS. In a companion trial, in older patients randomized to MP versus CTD followed by maintenance thalidomide or not, there was a non-significant improvement in PFS with thalidomide but no effect on OS.

So the efficacy of thalidomide in several trials appears to be primarily as a consolidation therapy in those patients with suboptimal responses rather than as an effective maintenance treatment. In addition, in some trials, patients with deletion 13q did not appear to benefit and patients with deletion 17p actually did worse when give maintenance thalidomide. Also long term thalidomide proved to be difficult for many patients to tolerate, and the discontinuation rate was high.

Ongoing phase III trials in transplant eligible patients are currently examining the potential roles of weekly bortezomib and daily lenalidomide in the maintenance setting. Hopefully both of those agents will prove more effective and better tolerated than thalidomide for long term use as maintenance therapy.

OncoFacts™ Editor:

James Epstein, MD

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