Strategies for Control of Multiple Myeloma Refined By New and Extended Data Analysis of Major Trials

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.

PRIORITY PRESS - 55th Annual Meeting of the American Society of Hematology (ASH)

New Orleans, Louisiana / December 7-10, 2013

New Orleans - Of data with practice-changing implications for control of multiple myeloma presented at ASH 2013, the most significant involved dosing of front-line therapy in those who are transplant-ineligible. In this group, it was shown that higher cumulative doses of the proteasome inhibitor component of a multidrug regimen provided a relative increase in overall survival (OS). In the context of a second set of phase 3 data showing comparable benefit from different proteasome inhibitor-based regimens, these data should encourage adjustments of the regimen as needed to achieve maximum drug exposure. In a separate series of studies, an unexpected disparity between progression-free survival (PFS) and OS among patients on immunomodulator maintenance therapy suggest that the relative roles of available agents are still in transition as active agents are employed in different combinations and different sequences in order to achieve optimal outcomes.

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

The introduction of the novel proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide greatly expanded front-line therapy options for multiple myeloma. These agents in various combinations are now widely used for induction whether or not stem cell transplant (SCT) is planned. The inclusion of these agents in the treatment of multiple myeloma patients ineligible for SCT due to age or co-morbidities provides evidence of their relatively favourable tolerability profiles. New data presented at ASH correlate greater cumulative doses of bortezomib with survival benefits.

“The data indicate that there should be consideration for maximizing cumulative dose of bortezomib by adjusting dose or schedule as necessary,” reported Dr. Maria-Victoria Mateos, University Hospital of Salamanca, Salamanca, Spain. Characterizing bortezomib as a core therapy for multiple myeloma, Dr. Mateos reported that the most recent data refine strategies for improving the survival advantages that established the combination of bortezomib (V), melphalan (M), and prednisone (P) as a standard in SCT-ineligible multiple myeloma patients.

5-Year VMP Follow-Up: OS Benefit Persists

The analysis of the relationship between bortezomib cumulative dose and outcome was derived from the VISTA study, which was initially published several years ago but a recent median follow-up of 60.1 months associated VMP with a 31% reduction (P<0.001) in the risk of death relative to MP (San Miguel JF et al. J Clin Oncol 2013;31:448-55). In the front-line standard VMP regimen established by VISTA for SCT-ineligible patients, the maximum planned cumulative dose of the four six-week induction cycles, which involved twice-weekly dosing, and the five six-week maintenance cycles, which involved weekly dosing, was 67.6 mg/m2.

Of the 340 patients who received at least one dose of bortezomib, the median cumulative dose was 39 mg/m2. When an analysis was undertaken to compare outcomes in those who received cumulative doses above or below this median, relative benefits differed markedly. This included a 46% improvement (P=0.0002) in the hazard ratio (HR) for survival for those receiving a dose above the median after adjusting for age. In months, the median survival was extended by almost 50% (66.3 vs. 46.2 months).

“To overcome the confounding effects of early deaths due to toxicity or any other reason, a landmark analysis of overall survival (OS) was conducted at 180 days,” reported Dr. Mateos. In this analysis, the relative advantage of a higher cumulative dose was somewhat lower but still statistically significant (HR 0.71; P=0.0356) and clinically meaningful (median survival of 60.4 vs. 50.3 months).

Lessons for Clinical Management

The main reason that patients received a lower cumulative dose was toxicity, which correlated with increased age. Due to the fact that a large proportion of these patients discontinued therapy, one lesson from these data appears to be that a full 12 months of bortezomib is important to maximize benefits, according to Dr. Mateos. She suggested that this should inform clinical practice.

“A less intensive VMP regimen, with limited twice-weekly dosing followed by a less dose-intensive bortezomib schedule, could be used to achieve a similar cumulative bortezomib dose and thus maximize treatment duration and outcomes,” reported Dr. Mateos, citing data showing efficacy from modified VMP regimens that were generated by her own group.

A similar conclusion was derived from a separate updated analysis drawn from the phase 3b UPFRONT study, which is one of the largest community-based studies in multiple myeloma ever conducted. In UPFRONT, patients ineligible for SCT were randomized to VMP, bortezomib plus dexamethasone (VD), or bortezomib, thalidomide, and dexamethasone (VTD). Each was administered over a 21-day cycle. All patients then received maintenance bortezomib over an additional five 35-day cycles.

Three Bortezomib-Based Therapies Compared

“All three bortezomib-based regimens demonstrated substantial activity with objective response rates of up to 80%, but no treatment demonstrated superiority to another in regard to major endpoints, such as progression-free survival (PFS) or OS. The main difference between the arms was relative tolerability,” reported Dr. Ruben Niesvizky, Myeloma Center, Weill Cornell Medical Center, New York City.

In particular, VTD was associated with higher toxicity rates than the other two arms. In contrast, given similar rates of response, the relative tolerability of VD was notable. Although VMP has emerged as a standard regimen on the basis of VISTA, Dr. Niesvizky characterized VD as an attractive alternative when co-morbidities or age make treatment-related toxicities a particular concern. In all groups, bortezomib as single-agent maintenance was well tolerated even among those who experienced toxicities on VTD.

“Bortezomib maintenance produced limited additional toxicity compared to the induction regardless of the initial regimen,” Dr. Niesvizky confirmed. In evaluating the significance of these data for selecting therapy, Dr. Niesvizky cited the VISTA data provided by Dr. Mateos. Specifically, he concurred that the optimal therapy appears to be one that permits patients to achieve the maximum cumulative dose.

“Patients should be monitored carefully for treatment-related toxicities with appropriate dose reductions to prolong therapy and maximize quality of life and survival outcomes,” he suggested.

Doublet Phase 3 Lenalidomide Trial

No new data were presented at ASH regarding the relative role of lenalidomide and thalidomide in combination with bortezomib, but a phase 3 study did compare lenalidomide (R) and D (RD) to MP plus thalidomide (MPT) in SCT-ineligible multiple myeloma patients. In this study, called FIRST, 1,623 patients were randomized to one of three arms: 1) RD for 28-day cycles until disease progression; 2) RD in 18 28-day cycles; or 3) MPT in 12 42-day cycles. After a median 37 months of follow-up, a preplanned interim analysis associated prolonged RD treatment with a 28% improvement in the primary endpoint of PFS (HR 0.72; P=0.00006) relative to MPT. 

Calling the safety profile of RD “manageable,” the senior author of the study, Dr. Thierry Facon, Hospital Claude Huriez, Lille, France, concluded that RD should be considered superior to MPT.

However, the role of lenalidomide in relation to bortezomib has not been fully explored beyond small studies testing these agents in combination. By testing RD as continuous therapy, the FIRST study is notable for diverging from the more common practice of dividing extended therapy into its induction and maintenance components. Interpretation of these results is complicated by long-term follow-up data from a separate phase 3 trial that was unable to correlate improvements in OS with those previously documented for PFS.

IFM 2005-02 Trial: PFS and OS Do Not Correlate

In this follow-up analysis from the IFM 2005-02 trial, which randomized multiple myeloma patients to lenalidomide maintenance or placebo after SCT, the median PFS advantage of lenalidomide after an average 67 months of follow-up remains highly significant (46 vs. 24 months; P<0.001), but no advantage for OS has emerged (81 vs. 82 months; P=0.8). This surprising result appears to be explained by a relative disadvantage imposed by lenalidomide during the time from progression after first-line therapy to the progression after second-line therapy or last follow-up. In this period, the median PFS was only 10 months for lenalidomide versus 18 months for placebo (P<0.0001).

“The poor outcome after progression for patients in the lenalidomide maintenance group is the best hypothesis for the lack of an OS benefit,” reported the lead author of this study, Dr. Michael Attal, Purpan Hospital, Centre Hospitalier Universitaire (CHU), Toulouse, France. Asked to speculate about how this should be interpreted by clinicians now offering lenalidomide maintenance in this setting, Dr. Attal declined, saying only, “all I can say is that these are the data.”


Outcomes in multiple myeloma have improved in an era that witnessed the introduction of the proteasome inhibitor bortezomib and immunomodulators, such as lenalidomide. These therapies demonstrate high degrees of activity and are relatively well tolerated, making them appropriate for induction even when patients are ineligible for transplant. Phase 3 trials have now established VMP as a treatment standard in both groups of patients, but ongoing efforts to define the optimal sequence of induction and maintenance treatments make further refinements in protocol likely.  


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