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Lenalidomide, bortezomib, dexamethasone with HSCT prolongs PFS in myeloma
The addition of hematopoietic stem cell transplantation to lenalidomide, bortezomib and dexamethasone improved PFS among patients with multiple myeloma, according to results of a randomized controlled phase 3 trial.
“Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma,” Michael Attal, MD, from the Institut Universitaire du Cancer de Toulouse-Oncopole in France, and colleagues wrote.
Standard treatment for multiple myeloma consists of high-dose chemotherapy plus autologous HSCT in adults aged up to 65 years. However, this treatment requires hospitalization and carries a risk for toxicity.
Data have shown a combination of immunomodulatory drugs and proteasome inhibitors plus dexamethasone produced substantial activity in myeloma, but the role and timing of HSCT with the combination had been uncertain.
Therefore, Attal and colleagues evaluated the safety and efficacy of lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium/Takeda) and dexamethasone, also known as RVD therapy, alone or with HSCT in 700 patients with newly diagnosed myeloma aged up to 65 years.
The patients were randomly assigned based on International Staging System stage and cytogenetic risk profile.
All patients received induction therapy with three 21-day cycles of RVD, which consisted of 25 mg daily oral lenalidomide (days 1-14) combined with 1.3 mg/m2 IV bortezomib (days 1, 4, 8 ,11) and 20 mg daily oral dexamethasone (days 1, 2, 4, 5, 8, 9, 11, 12).
After induction, all patients underwent stem-cell mobilization with cyclophosphamide and granulocyte colony–stimulating factor. During consolidation, the RVD–alone group received five cycles with a reduced daily dose of dexamethasone of 10 mg, whereas the HSCT group received 200 mg/m2 melphalan plus autologous transplantation followed by two cycles of RVD with 10 mg dexamethasone.
PFS served as the study’s primary endpoint. Secondary endpoints included response rate, time to disease progression, OS and adverse events.
Median follow-up after randomization was 44 months in the RVD–alone group and 43 months in the RVD plus transplantation group.
The median PFS was longer in patients treated with RVD and transplantation than among patients who received RVD alone (50 months vs. 36 months; adjusted HR for disease progression or mortality = 0.65; 95% CI 0.53-0.8). This benefit remained the same across all subgroups, including those stratified by International Staging System stage and cytogenetic risk.
Complete response rates also were higher in patients who underwent transplantation compared with patients treated with RVD alone (59% vs. 48%; P = .03).
In addition, the percentage of patients without detectable minimal residual disease was higher in those treated with RVD and transplantation than those treated with RVD alone (79% vs. 65%; P < .001).
Patients treated with RVD and transplantation had a higher rate of grade 3 and grade 4 adverse events (92% vs. 47%). Common grade 3 or grade 4 events observed more frequently in the transplantation group included gastrointestinal disorders (28% vs. 7%; P < .001), infections (20% vs. 9%; P < .001), and blood and lymphatic-system disorders (95% vs. 64%; P < .001).
Four-year OS was not significantly different between the groups (81% vs. 82%).
“We found that consolidation therapy with high-dose chemotherapy plus transplantation was associated with longer PFS ... [but] this benefit must be weighed against the increased risk for toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long-term survival,” the researchers wrote. – by Melinda Stevens
Disclosures: Attal reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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With the availability of novel agents for treatment of symptomatic multiple myeloma, the role of upfront autologous stem cell transplant was questioned. In this issue of The New England Journal of Medicine, researchers of the Intergroupe Francophone du Myélome reported the results of a phase 3 randomized study comparing lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Millennium/Takeda) and dexamethasone, or RVD, plus early transplant vs. RVD and delayed transplant. All patients received lenalidomide maintenance. The early transplant approach was associated with deeper responses — more complete responses and more minimal residual disease negativity — and improved PFS. However, there was no OS benefit compared with delayed transplant approach.
The 4-year OS of approximately 80% for all patients was stunning. Longer follow-up will be required to determine if the PFS benefits and the achievement of deeper responses in the transplant arm may result in survival benefits.
Of particular interest is the shorter duration of maintenance in this study. In a recently reported meta-analysis on lenalidomide vs. placebo for maintenance, it took a median follow-up of approximately 7 years to demonstrate OS benefit, and many patients received much longer maintenance. Based on the results from this study, a delayed-transplant approach is feasible. However, upfront transplant remains the standard of care in the era of novel agents considering the deeper responses achieved and the excellent tolerability of autologous stem cell transplant.