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Addition of bortezomib to lenalidomide, dexamethasone improves myeloma survival
The addition of bortezomib to lenalidomide and dexamethasone prolonged PFS and OS among patients with newly diagnosed myeloma, according to results of a phase 3 randomized controlled trial.
“Using bortezomib in combination with lenalidomide and dexamethasone in front-line treatment — hitting the disease early and hard — makes a meaningful difference for myeloma patients. Our results represent a potential new standard of care,” Brian G.M. Durie, MD, attending physician at Cedars-Sinai Medical Center, and chairman of the board for the International Myeloma Foundation, said in a press release.
Durie and colleagues evaluated the safety and efficacy of the addition of bortezomib (Velcade, Millenium/Takeda) to lenalidomide (Revlimid, Celgene) and dexamethasone in 525 patients (median age, 63 years) with newly diagnosed myeloma.
The patients were randomly assigned based on International Staging System stage and the intent to transplant. The researchers randomly assigned 264 patients to an initial treatment of 1.3 mg/m2 IV bortezomib (days 1, 4, 8 ,11) combined with 25 mg daily oral lenalidomide (days 1-14) and 20 mg daily oral dexamethasone (days 1, 2, 4, 5, 8, 9, 11, 12), and 261 patients to 25 mg daily oral lenalidomide (days 1-21) plus 40 mg daily oral dexamethasone (days 1, 8, 15, 22). The three-drug combination was given as eight 21-day cycles and the two-drug combination was given as six 28-day cycles.
Upon completion of induction, all patients received 25 mg lenalidomide once a day for 21 days plus 40 mg dexamethasone daily on days 1, 8, 15 and 22 of each 28-day cycle as ongoing maintenance.
PFS from the time of randomization served as the primary endpoint, with analyses based on intention to treat. Of the patients, 52 were deemed ineligible for various reasons and 473 were included in the final analyses.
The median PFS was 43 months in the three-drug group compared with 30 months in the two-drug group (stratified HR = 0.71; 95% CI 0.56–0.9).
Median OS also was significantly improved among patients in the three-drug group compared with patients in the two-drug group (75 months vs. 64 months; HR = 0.7; 95% CI, 0.52–0.95).
Overall response rates — which included partial response or better — were higher in the three-drug group (82%; n = 176 of 216) compared with the two-drug group (72%; n = 153 of 214); 16% of patients (n = 34 of 216) in the three-drug group and 8% of patients (n = 18 of 214) in the two-drug group had a complete response or better.
Grade 3 or higher adverse events occurred in 82% of 241 patients in the three-drug group and in 75% of 226 patients in the two-drug group. A total of 55 patients in the three-drug group and 22 in the two-drug group discontinued induction treatment due to adverse events. No treatment-related deaths were observed in the two-drug group, whereas two were observed in the three-drug group.
This represents a “landmark” in therapy for myeloma, and the three-drug regimen will become more cost-effective as these drugs become generic over time, S. Vincent Rajkumar, MD, faculty member of Mayo Clinic in Rochester, Minnesota, and co-author of the study, said in the release.
“Newer alternatives to [lenalidomide and dexamethasone plus bortezomib] may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over [lenalidomide and dexamethasone plus bortezomib] in randomized trials,” Rajkumar said.
In an accompanying editorial, Heinz Ludwig, MD, director of the Wilhelminen Cancer Research Institute in Austria, and Michel Delforge, MD, hematologist at University Hospital Leuven in Belgium, agree based on the study results that the three-drug regimen presents as an effective first-line treatment for patients. However, the development of other drugs may pose challenges.
“Its role is already challenged by an ongoing phase 3 trial comparing [lenalidomide and dexamethasone plus bortezomib] with carfilzomib [Kyprolis, Amgen]–lenalidomide–dexamethasone. The latter regimen resulted in high response rates of up to 100% after prolonged treatment, including high rates of minimal residual disease negativity both in patients with high-risk smoldering multiple myeloma and in those with active disease,” Ludwig and Delforge wrote.
Despite this, new treatments will need to be developed based on the everchanging myeloma disease.
“This approach might transform the present treatment philosophy from a one-size-fits-all approach to molecular pathology-driven, individualized treatment selection,” they said.
Durie and colleagues concluded: “[These study] results can inform decision-making for front-line therapy using a proteasome inhibitor plus immunomodulatory drugs plus steroid triplet treatment.” – by Melinda Stevens
Disclosure: Durie reports consultant roles with Celgene, Johnson & Johnson, Onyx and Takeda. Rajkumar reports no relevant financial disclosures. Please see the full study for a list of other researchers’ relevant financial disclosures. Ludwig reports multiple financial relationships with Amgen, Bristol-Myers Squibb, Celgene, Cilag, Janssen and Takeda. Delforge reports grants and personal fees from Celgene and Janssen, and personal fees from Amgen, Bristol-Myers Squibb and Takeda.
Perspective
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In the management of newly diagnosed myeloma, there have been two controversies at hand over the past 5 years. The first concerns two vs. three drugs as standard induction therapy, and the second concerns the optimal three-drug combination. This study by Durie and colleagues has answered both questions.
First, not only was there a PFS benefit for the use of three drugs over two for patients with symptomatic myeloma — regardless of age — there was also a survival benefit for the use of a proteasome inhibitor, bortezomib (Velcade, Millennium/Takeda), in combination with an immunomodulatory agent, lenalidomide (Revlimid, Celgene), compared with lenalidomide and low-dose dexamethasone alone. This finding puts to rest the idea that sequential doublets as induction and salvage are just as good as combination therapy at the outset. This study only delivered bortezomib for eight cycles, so the use of eight cycles of a proteasome inhibitor had a significant impact on long-term survival for patients with myeloma.
The second important question relates to the optimal combination as part of induction therapy. There has been controversy over the use of lenalidomide, bortezomib and dexamethasone — or RVD, as used in this study — vs. the use of bortezomib with cyclophosphamide and dexamethasone, or VCD, with opinion driving decisions over data. Given the survival benefit demonstrated in this study, the lack of any phase 3 data supporting the use of VCD, several nonrandomized comparisons demonstrating inferiority for VCD over RVD, and a randomized trial from the Intergroupe Francophone du Myélome demonstrating significant benefit of bortezomib plus thalidomide and dexamethasone (VTD) over VCD, the role of VCD as induction therapy should likely wane.
By not mandating transplant as part of the study, Durie and colleagues clearly established what should be the standard induction therapy for not only transplant-eligible, but also older transplant-ineligible patients. Now that this controversy is sorted out, we can move on to many others in myeloma, given the wealth of new agents that have been approved. This includes determining the optimal proteasome inhibitor in the induction therapy setting — bortezomib, carfilzomib (Kyprolis, Amgen) or ixazomib (Ninlaro, Takeda).
So, while one set of questions has been answered, many more remain.