Reports

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PRIORITY PRESS - 53rd Annual Meeting & Exposition of the American Society of Hematology

San Diego, California / December 10-13, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The introduction of the proteasome inhibitor bortezomib and the immunomodulating agents thalidomide and lenalidomide for treatment of multiple myeloma (MM) has generated marked improvements in outcome. In new results of the phase III VISTA trial, which established the combination of bortezomib, melphalan and prednisone (VMP) as a standard for the treatment of elderly patients with MM, an overall survival (OS) benefit was still observed over melphalan and prednisone (MP) 5 years after randomization. New phase III data with the combination of lenalidomide, melphalan and prednisone (RMP) followed by lenalidomide maintenance also shows sustained superiority over MP alone. Rates of survival, including disease-free survival, are unprecedented in patients who are not candidates for stem-cell transplant.

According to Dr. Jesús F. San Miguel, Hospital Clínico Universitario, Salamanca, Spain, patients initially randomized to MP do not catch up even by introducing a novel agent, like bortezomib, in a second-line therapy. “This is important data because it tells us to use bortezomib up front. Do not reserve it for the patients who relapse.”

The initial results of VISTA, a trial randomizing 682 previously untreated MM patients ineligible for high-dose therapy, were published more than 3 years ago and associated VMP with a 39% (HR 0.61; P<0.001) improvement in OS relative to MP (San Miguel et al. N Engl J Med 2008;359:906-17). With follow-up now out to 60.1 months and only 5% of patients lost to follow-up, the survival curves remain widely separated with a 13.3 month-increase in median OS advantage for VMP over MP (56.4 vs. 43.1 months; P=0.0004).

“The OS benefit with VMP was seen across patient subgroups, including those aged =75 years, those with an International Staging System of III and those with renal impairment,” reported Dr. San Miguel, who noted that the VMP 13-month advantage translated into a 31% reduction in death (P=0.0004) and compares favourably with a 6-month increase in OS that was recently derived from a meta-analysis of trials comparing thalidomide with MP to MP alone.

VMP Early Use: Evaluating Long-term Outcomes

The analysis of this long-term follow-up evaluated whether early use of VMP produces a more resistant disease when relapse occurs. However, the relative OS benefit remained similar in those who relapsed and went on to second-line therapy. Even though there was no restriction on the use of novel treatments, including second-line bortezomib, the OS HR for VMP relative to MP was 0.745 (P=0.0162). An exploratory analysis of secondary cancer risk showed no signal for increased risk. Rather, relative to an expected cancer rate of 1.9% in this population, the rates of cancer were 1.6% for VMP and 1.3% for MP, which did not differ statistically.

No study has previously demonstrated a survival advantage for 1 regimen over another in MM patients ineligible for high-dose therapy >3 years of follow-up, making the VISTA results a milestone in this malignancy, but other strategies with novel agents are being pursued.

Maintenance Therapy Update

A phase III study evaluated RMP followed by lenalidomide maintenance (RMP-R), RMP alone and MP alone in 459 patients =65 years with newly diagnosed MM. Patients were randomized to RMP or MP induction regimens. Then the RMP-R group went on to maintenance lenalidomide 10 mg from days 1 to 21 of a 28-day cycle after 9 cycles of induction therapy, while the other 2 groups received placebo.

While an OS advantage has not yet been demonstrated, RMP-R did show superior progression-free survival (PFS) over no maintenance. The median PFS was 31 months for RMP-R, 14 months for RMP and 13 months for MP, producing a 60% relative advantage for maintenance relative to the other 2 arms (HR 0.395; P<0.001). “The advantage of the maintenance therapy was independent of essentially all variables, including the quality of the response at induction and prognosis,” reported Dr. Antonio Palumbo, University of Turin, Italy. “One of the important lessons from this study was that the level of response continued to improve, with best response not achieved in some patients until all 9 cycles of induction had been administered,” he observed. However, the advantage for PFS in the maintenance arm was the most important finding. So far, the 30% improvement in OS (HR 0.70; P=0.133) has not reached significance.

Safety was acceptable and 13% of those receiving RMP vs. 4% of those receiving MP discontinued therapy due to toxicity during induction. The most common adverse events were hematologic with grade 3/4 neutropenia occurring in 39% of the RMP group. Febrile neutropenia occurred in =1% of all 3 arms. During maintenance, there was no evidence of cumulative toxicities with only 5% discontinuing for adverse events.

“Even in a group of relatively frail, elderly patients, both the induction and the maintenance were associated with an acceptable rate of toxicity,” Dr. Palumbo told delegates. “I think we are moving to continuous therapy in this population,” he concluded. Although quality-of-life analyses are not complete and there has been no OS advantage, the low rate of adverse events suggests that the doubling of the PFS with a maintenance regimen is clinically significant.

The advantage of maintenance therapy was also supported by new data from the maintenance phase of a study presented by the Spanish Myeloma Group, in which VMP was found to provide efficacy rates comparable to bortezomib, thalidomide and prednisone (VTP) for induction (Mateos et al. Lancet Oncology 2010;11:934-41). In the maintenance portion, all 260 patients received bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) q3 months with either thalidomide 50 mg daily (VT) or prednisone 50 mg every-other-day (VP). The maintenance could be continued for up the 3 years.

“Both maintenance regimens substantially increased the complete response (CR) rate, which climbed from 24% after induction to 42% at the most recent follow-up,” reported Dr. Maria-Victoria Mateos, Hospital Clínico Universitario, Salamanca. Although the response rates, including the CR rates, were consistently higher on VT vs. VP, the differences in PFS or OS did not reach statistical significance (both P=0.1) except in those with high-risk cytogenetics. In this subgroup, there was a significant advantage for VT. Both therapies were characterized as well tolerated although the relative rates of specific adverse events differed.

As did Dr. Palumbo, Dr. Mateos concluded that maintenance therapy does appear to be the next step in extending clinical benefits from novel therapies in previously untreated elderly MM patients. She also noted that response rates climbed progressively over the induction regimen and then continued to climb with maintenance, underlining the importance of continuous treatment to deepen the quality of the response which, in turn, is associated with greater duration of response.

In MM, the question of whether to start with a proteasome inhibitor or an immunomodulator remains. Here at ASH, a retrospective study seeking to determine whether survival differed according to which agent was used first, analyzed a series of 208 patients treated over a 6.5-year period. Results indicated no significant differences between those who received either bortezomib or thalidomide first, but non-concurrently. According to Dr. Amila M. Patel, Moffitt Cancer Center, Tampa, Florida, in patients with baseline renal insufficiency at diagnosis, the median OS was 53.9 months in those who received bortezomib first and 24.1 months in those who received lenalidomide first (P=0.01). Dr. Patel claimed this is the first study to compare the impact of sequence of novel agents in MM. She concluded that although there was no clear benefit from starting with one therapy over another, “a bortezomib-based therapy should be considered first-line” in those with poor renal function, she concluded.

Summary

The introduction of novel therapies in MM patients who are not eligible for transplant has yielded major improvements in outcome. The persistent advantage of VMP over MP, the previous standard in this disease, after 60.1 months of follow-up has been one of the major recent successes in the treatment of hematologic malignancies. In MM patients first diagnosed after age 65, which is the most common period of onset, the evidence that maintenance therapy can extend the benefits of the induction regimens makes this disease increasingly controllable even if it cannot yet be cured. ?