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49th Annual Meeting and Exposition of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2007

The promise of new regimens for the treatment of multiple myeloma (MM) has recently been confirmed in a series of controlled studies demonstrating improved activity with acceptable tolerability. The most significant of these studies was VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone), a phase III front-line study in which previously untreated MM patients ineligible for stem cell transplantation (SCT) were randomized to either a standard regimen of melphalan and prednisone or the same regimen plus bortezomib, a proteasome inhibitor.

VISTA

The overall survival at two years in the bortezomib/melphalan/prednisone (VMP) arm was 82% vs. 69% for those on the standard regimen (P=0.0078), which translates into a 40% reduction in the risk of death. The time to progression was 24 months compared to 17 months (P=0.0000001), a 52% improvement. The complete response (CR) rate was seven times higher (35% vs. 5%; P<0.000001). “These results demonstrate that VMP should be considered the new standard of care in this population,” stated Dr. Jesús San Miguel, Chief, Hematology Department, University Hospital of Salamanca, Spain. “The response in the VMP arm was rapid and durable. The 35% CR rate in this population is unprecedented.”

The results of this phase III study conducted by 151 investigators in 22 countries reinforce findings generated in a previous phase I/II trial of the same treatment regimen. In that study, the three-year survival rate was 85% and there was a 32% CR rate. With the addition of near CRs (nCR), the CR rate climbed to 43%. As these response rates approach those observed in patients who have undergone SCT, they represent a major milestone. The addition of bortezomib to the standard regimen was associated with only modest changes in the side-effect profile. The most notable difference was a higher rate of grade 3 or 4 peripheral neuropathy (14% vs. 0%) and fatigue (8% vs. 2%), but grade 3 and 4 cytopenias were comparable, and the discontinuation rates for adverse events was 14% in both arms.

“The good news is that at least we already have three trials [with bortezomib in MM] that show a significant benefit in overall survival. From my point of view, this really changes treatment,” Dr. San Miguel told delegates.

VISTA randomized 682 MM patients who were not considered to be candidates for high-dose chemotherapy and SCT. The median age was near 75 years (only 23 patients were <65 years). The dose of bortezomib was 1.3 mg/m2 twice weekly in weeks 1, 2, 4, and 5 in each of five six-week cycles. This was combined with 9 mg/m2 of melphalan and 60 mg/m2 of prednisone administered on days 1 through 4 of each cycle. Those in the comparator arm received the same regimen of melphalan and prednisone without bortezomib.

It is notable that there was no difference in the median time on therapy in the two arms and that the addition of bortezomib did not significantly alter the dose intensity of melphalan. “The study confirms the added overall benefit of bortezomib over melphalan and prednisone alone,” Dr. San Miguel commented. “The difference was observed very rapidly. By the end of the first year, the survival curves were already diverging.”

Double Stem Cell Transplantation

The recent progress in older patients, who represent the majority of the 2000 new MM patients diagnosed in Canada each year, joins several promising new strategies in younger patients who are candidates for SCT. This includes double autologous SCT, the use of consolidation regimens that include bortezomib and thalidomide, and upfront therapies with either bortezomib or thalidomide. Several groups here at ASH presented results in which better outcomes were achieved with more intensive therapies. The benefit of double autologous SCT has been well documented, but new results from the initial study that tested this strategy demonstrate why some clinicians consider this a standard of care.

In the final analysis of the Bologna 96 study, which randomized 321 MM patients to a single course of stem-cell-supported melphalan at a dose of 200 mg/m2 or the same regimen followed three to six months later by stem-cell-supported melphalan at a dose of 120 mg/m2 plus busulfan 12 mg/m2, the rate of nCR with the additional transplant rose to 47% from 33% (P=0.008). This correlated with significant improvements in relapse-free survival (42 vs. 23 months; P<0.001) and event-free survival (35 vs. 23 months; P=0.001). “Benefits offered by double autologous SCT in terms of extended relapse- and event-free survival were particularly evident among patients who failed to achieve at least a nCR after the first autologous transplant,” reported Dr. Michele Cavo, Seragnoli Institute of Hematology, Bologna, Italy. Emphasizing that attainment of CR is a surrogate marker for key outcomes, including overall survival, Dr. Cavo noted that the final results of Bologna 96, like the earlier results, suggest that double SCT should be considered as a standard in younger MM patients.

Improving Front-line Therapy

Furthermore, a separate non-randomized study by the same group indicated that the front-line therapy prior to the first SCT can be improved. In this study with a median 32-month follow-up, 311 patients received thalidomide 200 mg/m2 and dexamethasone 40 mg/m2 (on day 4 of every month with two added courses on the first and third months) until the second SCT. Thalidomide and dexamethasone were added to the same melphalan regimen evaluated in Bologna 96. In a case-matched comparison with patients in Bologna 96, the addition of thalidomide and dexamethasone was associated with improved relative outcomes. This included about a 60% improvement in relapse-free (P=0.005) and event-free survival (P=0.01).

According to senior author Dr. Elena Zamagni, Seragnoli Institute of Hematology, a study analysis demonstrated that the greatest benefit from double SCT with thalidomide and dexamethasone included in the front-line regimen was observed in those who did not achieve a very good partial response (VGPR) or better in the first SCT, but she did suggest that more aggressive therapy appears to build on the benefits observed in the original study. However, more aggressive therapy may not require more drugs.

In a multicentre study conducted in France, an induction regimen with bortezomib/dexamethasone (B/D) was found to be superior to vincristine/doxorubicin/dexamethasone (VAD) as an induction treatment prior to autologous SCT in front-line therapy for younger MM patients. In this 222-patient study, with two arms of B/D and two arms of VAD, each with or without dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP), B/D was associated with significantly higher CR plus nCR (22% vs. 9%; P=0.0085) and higher VGPR (50% vs. 24%; P=0.0001) after induction. Although the higher CR/nCR rate (38% vs. 28%; P=0.127) fell short of statistical significance after autologous SCT, the advantage for VGPR continued to favour B/D (66% vs. 50%; P=0.021).

Consolidation therapy is another strategy that is being pursued to improve outcomes after autologous SCT in MM patients. In a pilot study with 22 evaluable patients to date, a regimen of bortezomib, thalidomide and dexamethasone was started within six months in patients who had achieved at least a CR or VGPR after autologous SCT. So far, six patients have become negative on polymerase chain reaction (PCR) evaluation, while a measurable anti-tumour effect was observed in eight of 10 PCR-positive patients. According to the senior author of this study, Dr. Marco Ladetto, Hematology Division, University of Turin, Italy, these initial results suggest that “molecular remission is an achievable goal outside of the transplant setting.”

Summary

The options for control of MM are improving. While more aggressive induction and consolidation regimens in younger patients who are SCT candidates appear promising, the VISTA trial results showing survival benefits in an older population, who represent the majority of newly diagnosed patients, is considered the more significant clinical advance. In MM patients who are not candidates for SCT, the basis for naming VMP as a new standard of care is supported by both the survival advantage and the relatively modest increase in risk of adverse events when the addition of bortezomib is compared to melphalan and prednisone alone.