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Extending Time to Progression in Refractory Multiple Myeloma with Novel Regimens

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

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

Atlanta, Georgia / December 8-11, 2007

For patients suffering from multiple myeloma (MM) who can tolerate aggressive therapy, high-dose front-line chemotherapy followed by hematopoietic stem cell transplant (SCT) are associated with complete response (CR) rates of 50% or greater. Although these rates of response are several times higher than those achieved without SCT, most MM patients eventually relapse. While the introduction of bortezomib was a major step forward in single-agent treatment of refractory disease, for which previous treatments were only modestly effective, new phase III data demonstrate that outcomes can be further improved with the addition of a second agent.

Combination Therapy in Refractory Multiple Myeloma

“Although MM remains incurable, the availability of new agents with greater efficacy provides the opportunity to improve response rates further via the development of new combination regimens,” reported Dr. Heather J. Sutherland, senior hematologist, Leukemia and Bone Marrow Transplant Program, University of British Columbia, Vancouver. Presenting data on behalf of a multinational group of investigators but providing a Canadian perspective regarding new data on combination therapy in refractory MM, she noted that the doubling of median survival over the past decade (currently five to seven years vs. two to three years in 1998) has been encouraging, but indicated that further advances now seem likely.

In refractory disease, the most significant recent advance has been the completion of DOXIL-MMY-3001, a phase III study that compared bortezomib alone to bortezomib with pegylated liposomal doxorubicin (PLD). As published recently (Orlowski et al. J Clin Oncol 2007;25:3892-901) and updated at the annual ASH meeting, the study demonstrated a notable increase in median time to progression (TTP) and in the proportion of patients alive at 15 months. Toxicity was acceptable.

“The improvement in TTP on the combination vs. bortezomib alone was irrespective of prior therapy or of anthracycline experience,” reported DOXIL-MMY-3001 co-investigator Dr. Joan Bladé, Hospital Clinic Provincial, Barcelona, Spain. Although there was a higher incidence of myelosuppression on the combination, there was no significant difference in peripheral neuropathy or in cardiac events.

Findings with Combination Therapy

The results presented by Dr. Bladé are consistent with the published analysis, which stated that the data “conclusively demonstrate that a pegylated liposomal anthracycline can play a key role in improving the efficacy of combination therapy in the relapsed/refractory setting.”

In the study, 646 patients with relapsed or refractory MM were randomized to receive intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of every 21-day cycle with or without PLD 30 mg/m2 on day 4. In a median follow-up now greater than two years, the TTP was 6.5 months for bortezomib monotherapy and 9.3 months for bortezomib/PLD (P=0.000004). The hazard ratio (HR) for improvement in TTP favouring the combination was 1.82. At 15 months, 76% of the patients who received the combination vs. 65% of those on monotherapy (P=0.03) were still alive. The proportion of patients who experienced a grade 3 or 4 adverse event was higher on the combination (80% vs. 64%; P<0.001), but the rate of treatment discontinuations for adverse events did not differ significantly (30% vs. 24%; P=0.9).

The advantage for the combination was sustained across all major subgroups. For example, when the study population was stratified by prior drug exposure, the HR for improved TTP in patients who had received just one prior regimen (1.71; P=0.036) was comparable to that observed in those who had received two or more (1.91; P<0.001). According to data presented by Dr. Sutherland, the advantage with the combination was also consistent across International Staging System (ISS) disease status at entry and for time since diagnosis. Specifically, the HR was 1.6 (P=0.067), 1.8 (P<0.004), and 2.1 (P<0.0007) for ISS stages 1, 2 and 3, respectively. For disease duration of more than two years, the HR was 1.83 (P<0.0001) vs. 1.75 (P=0.033) for two years or less (Table 1).

The findings not only demonstrate consistent outcome advantages across risk groups, but “the overall safety profile of bortezomib plus PLD was generally comparable between those with higher- and lower-stage disease and between those patients with greater and lesser time since diagnosis,” Dr. Sutherland reported.

Table 1. Combination Therapy


The safety analyses are particularly important because previous exposure to anthracyclines was not an exclusion criterion for entry into this study. While liposomal encapsulation of doxorubicin is specifically designed to improve targeting of this chemotherapy at the tumour site and to reduce systemic risks, cardiotoxicity is among the greatest concerns from prolonged anthracycline exposure. In this study, neither the overall number of cardiac events for bortezomib vs. the combination (10 vs. 12) nor grade 3 or 4 cardiac events (three vs. two) differed significantly. In addition, PLD was not found to compromise delivery of bortezomib. Both the mean number of treatment cycles and mean number of treatment days were the same in the two groups.

Dr. Sutherland concluded that overall, results showed that combination treatment with PLD/bortezomib significantly improved TTP and might improve treatment outcomes vs. monotherapy in MM patients with higher-stage disease or protracted disease history.

Promising Results with Immunomodulatory Agents

These results may be just the first step toward incremental but meaningful improvements in MM survival. In the published results, the authors observed that there are already preliminary data suggesting that dexamethasone may increase the activity of the combination of bortezomib/PLD, and they indicated that a large, prospective phase III study is warranted.

Support for this approach has already been provided by initial results from a nine-centre, phase II study in Canada which evaluated a regimen of bortezomib, PLD and dexamethasone administered every 21 days for four cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11 plus PLD 30 mg/m2 day 4 plus pulsed dexamethasone 40 mg days 1-4, 8-11 and 15-18 [cycle 1] and days 1-4 [cycles 2-4]). Although patients had relatively advanced disease at entry (65% with stage III), 26.8% achieved a CR or near CR and 98% had a minimal response or better. Importantly, the regimen was not only well tolerated but also appeared to improve health status from pre-treatment levels.

“Preliminary results indicate that there is a trend towards improvement in quality of life (QOL) outcomes in MM patients being treated with this induction regimen,” reported senior author Dr. Andrew Belch, Cross Cancer Institute, University of Alberta, Edmonton. The significant improvement in self-rated health status using the European QOL Questionnaire (EQ-5D) on treatment relative to baseline is a substantial change from the toxicity commonly observed with other combination regimens, particularly those including an anthracycline.

Clinical studies of immunomodulatory agents, such as lenalidomide and thalidomide, are also demonstrating promise. In a pooled analysis of two randomized studies, the addition of lenalidomide to dexamethasone alone was found to be more effective for overall survival (OS) even though almost half of those in the arm receiving dexamethasone alone crossed over to the combination. “Previous data from the two phase III trials associated the addition of lenalidomide with improvements in objective response rates, including CR rates, and TTP. In this pooled analysis, we show a significant improvement in long-term survival,” reported Dr. Donna Weber, M.D. Anderson Cancer Center, Houston, Texas.

In these two studies, 704 patients with relapsed or refractory MM were randomized to receive dexamethasone in a dose of 40 mg on days 1 to 4, 9 to 12, and 17 to 20 of every four-week cycle or the same regimen of dexamethasone with 25 mg lenalidomide daily for three weeks of each cycle. After four cycles, patients received dexamethasone only on days 1 to 4 of each cycle. While significant improvements were reported previously for median TTP (11.2 vs. 4.7 months; P<0.001), objective response (60.6% vs. 21.9%; P<0.001) and CR (15% vs. 2%; P<0.001), these findings confirmed a survival advantage.

Specifically, the median survival on the combination was 32.4 months vs. 27.3 months (P<0.05) for dexamethasone alone. Although this difference was modest, the authors emphasized that the trial design permitted patients who progressed to cross over to the opposite arm while the study blind was retained. As a result, the advantage for the combination on an intent-to-treat (ITT) analysis was preserved despite the fact that 47% of patients initiated on dexamethasone alone were crossed over to the combination before the study was completed.

Although the authors concluded that the combination of lenalidomide plus dexamethasone is superior to dexamethasone alone in refractory MM, these findings do not challenge the new standard of PLD/bortezomib for refractory MM, because bortezomib has previously been shown superior to dexamethasone (Richardson et al. N Engl J Med 2005; 352:2487-98). In that comparison, which randomized 660 patients, there were highly significant advantages for bortezomib monotherapy vs. dexamethasone monotherapy for both TTP (6.22 vs. 3.49 months; P<0.001) and OS at one year (80% vs. 66%; P=0.003).

Additional combinations are being pursued in refractory MM. This not only includes dexamethasone and lenalidomide but thalidomide, other steroids such as prednisone, as well as bendamustine, an alkylating agent. For example, in new data with thalidomide, which has previously demonstrated activity in refractory MM, longer duration of treatment was a predictor of improved survival. In the analysis of 80 responding patients, those who took thalidomide for at least 10 months had a median event-free survival of 39 months and an OS of 80 months compared to 18 and 32 months, respectively, in those who took thalidomide for a shorter period (P<0.001 for both end points).

“The longer duration of response for a longer duration of treatment independent of disease provides support for the value of maintenance therapy,” reported senior author Dr. Corinna Hahn-Ast, Department of Hematology, University of Bonn, Germany. “Maintenance strategies may offer the opportunity to prolong the survival we are now achieving with shorter regimens.”

These data make studies combining thalidomide with the current standard of bortezomib/PLD attractive, particularly because this combination has already demonstrated activity in previously untreated patients. However, one reason to pursue novel therapies is the hope that some combinations will yield synergistic rather than solely additive benefits. In experimental work being conducted in collaboration between the Institute of Biology in Nantes, France, and Harvard Medical School, Boston, Massachusetts, the rationale for combining bortezomib and doxorubicin was reinforced by findings that these agents have different but compatible effects on the myeloid cell leukemia-1 (Mcl-1) protein, which provides an anti-apoptotic signal. According to senior investigator Dr. Steven Le Gouill, Department of Hematology, Hôtel-Dieu, Centre hospitalier universitaire de Nantes, bortezomib cleaves Mcl-1 to increase apoptosis, but lack of Mcl-1 confers tumour cells with resistance to bortezomib. Doxorubicin, which works independently of the Mcl-1 pathway, inhibits the resistance mechanism while preserving its own anti-tumour activity.

The compatible mechanisms may in part explain the recent report of a high degree of activity associated with bortezomib, doxorubicin and dexamethasone (BDD) as an induction salvage regimen in refractory MM. When followed by thalidomide and dexamethasone, BDD produced a 92% objective response rate in 29 heavily pretreated refractory MM patients, according to Dr. Sung Sook Lee, Asan Medical Center, Seoul, South Korea. The OS at one year was 59%, which exceeded response rates in historical controls. Although hematological toxicity was substantial, patients tolerated a median of five cycles.

“The median dose intensity was 1.44 mg/m2/week for bortezomib and 5.25 mg/m2 for doxorubicin, which corresponds to 83.2% and 87.7%, respectively, of the planned dose intensities,” Dr. Lee reported.

One strategy to improve tolerability of treatment is to employ markers of response so that therapy is only intensified when needed. The feasibility of this approach was given preliminary support in another substudy of the bortezomib/PLD phase III study. In this substudy, response to treatment after cycle 1 and 2 was evaluated in relationship to change in the serum free-light chain (sFLC) levels, which is frequently altered by MM.

“Among patients who achieved normalization of sFLC after cycle 1, the TTP was 345 days vs. 225 days (P=0.0005) in those who did not,” stated Dr. Robert Orlowski, Division of Hematology/Oncology, University of North Carolina, Chapel Hill. A difference of similar magnitude and significance was also observed for TTP when patients with normal and abnormal sFLC were compared after cycle 2. The early normalization of sFLC was also associated with increased rates of objective response.

Prospective studies are needed to determine whether this or other markers of response can be valuable for adjusting treatments to improve rates of response, but with an increasing number of agents demonstrating activity in MM, some method of individualizing treatment is attractive. One approach that might be relevant to combinations that include dexamethasone is dose adjustment of the steroid. While low-dose dexamethasone (40 mg on days 1, 8, 15 and 22) was found to be as active as high-dose dexamethasone (40 mg on days 1 to 4, 9 to 12, and 17 to 20) in a combination regimen with lenalidomide that was evaluated in newly diagnosed MM (Rajkumar et al. ASH 2007, Abstract 74), a similar finding was generated by a study conducted in refractory disease. In this analysis of 233 patients, 177 remained on a standard 40-mg dose of dexamethasone while 46 patients received dose reductions.

“Patients in the dose reduction group have significantly longer TTP (59.9 vs. 24.1 weeks; P=0.003), median OS (121.9 vs. 109.7 weeks; P=0.19) and median progression-free survival (59.9 vs. 24.1 weeks; P=0.001) compared to those on standard-dose dexamethasone,” noted Dr. Jésus San Miguel, Hospital Universitario de Salamanca, Spain. Although many of the relative improvements in toxicity favouring adjusted-dose dexamethasone did not reach statistical significance, the more important result may be that dose adjustment did increase efficacy, an advantage that might have accrued from better lenalidomide dose intensity, although this hypothesis has not yet been explored.

Summary

Meaningful improvements in outcome have been recently achieved in the treatment of refractory MM. While a newly completed phase III study indicates that bortezomib/PLD should be considered a new standard for this disease, other active therapies demonstrating promise may prove valuable as additions or alternatives to this regimen. Although combination therapies appear to increase toxicity relative to single-agent regimens, the substantial improvements in TTP and the significant improvements in survival indicate that more aggressive regimens are warranted. New studies testing the addition of active agents, such as lenalidomide, thalidomide and bendamustine, to the current standard regimen are anticipated.

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