In the French phase III IFM 2009 trial reported in The New England Journal of Medicine by Michel Attal, MD, of the Institut Universitaire du Cancer de Toulouse-Oncopole, and colleagues, consolidation treatment with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) was associated with poorer progression-free survival vs high-dose chemotherapy and autologous hematopoietic transplant in patients aged ≤ 65 years with multiple myeloma.1 However, no difference was observed in overall survival at 4 years.
In the open-label trial, 700 patients from 69 sites in France, Belgium (6 total patients), and Switzerland (1 patient) were randomized between November 2010 and November 2012 to receive induction therapy with 3 cycles of RVD and then consolidation therapy with either 5 additional cycles of RVD (n = 350) or high-dose melphalan plus hematopoietic transplant followed by 2 additional cycles of RVD (n = 350). Induction consisted of lenalidomide at 25 mg on days 1 to 14; bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11; and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.
After induction, all patients underwent hematopoietic mobilization with cyclophosphamide and granulocyte colony-stimulating factor. Consolidation RVD included a reduced dexamethasone dose of 10 mg; melphalan was given at 200 mg/m2. Both groups received lenalidomide maintenance for up to 1 year, at 10 mg/d for the first 3 months with a possible dose increase to 15 mg thereafter. The primary endpoint was progression-free survival in the intent-to-treat population.
For the RVD vs transplant groups, the median age was 59 vs 60 years; 59% vs 61% were male; 60% vs 64% had immunoglobulin G and 20% vs 21% had immunoglobulin A myeloma; 33% vs 34% had International Staging System stage I disease, 49% in both had stage II disease, and 19% vs 17% had stage III disease; and among 256 vs 259 evaluable patients, 17% vs 18% had high-risk cytogenetic abnormalities (t[4;14] translocation, t[14;16] translocation, or 17p deletion).
Progression-Free and Overall Survival
In the RVD group, 331 patients (95%) entered the consolidation phase and 321 (92%) entered the maintenance phase. In the transplant group, 323 patients (92%) underwent transplantation, 315 patients (90%) began RVD after transplantation, and 311 patients (89%) entered the maintenance phase. The median duration of follow-up was 44 months in the RVD group and 43 months in the transplant group.
[The progression-free survival] benefit must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation….— Michel Attal, MD, and colleagues
Median progression-free survival was 50 months in the transplant group vs 36 months in the RVD group (adjusted hazard ratio [HR] = 0.65, P < .001). The benefit of transplant was observed across all patient subgroups, including according to the stratification factors of disease stage and cytogenetic risk. The rate of complete or very good partial response was 47% vs 45% after induction (P = .87), 78% vs 69% after consolidation (P = .03), and 85% vs 76% after maintenance (P = .009), respectively. Overall, complete response rates were 59% vs 48% (P = .03), and 79% vs 65% of patients had no minimal residual disease detected (P < .001). Progression-free survival was longer among patients with no detected minimal residual disease (adjusted HR = 0.30, P < .001).
Overall survival at 4 years was 81% vs 82% (adjusted HR = 1.16, P = .87). Median survival was not reached in either group. Overall survival was longer among patients with no detectable minimal residual disease (adjusted HR = 0.34, P < .001). Disease progression occurred in 207 patients in the RVD group; second-line therapy was received by 172 symptomatic patients, with subsequent salvage transplantation in 136 patients (79%). Disease progression occurred in 149 patients in the transplant group; second-line therapy was received by 123 symptomatic patients, with subsequent second transplantation in 21 patients (17%).
Grade 3 or 4 adverse events occurred in 97% of the transplant group vs 83% of the RVD group; those events that were significantly more common in the transplant group were blood and lymphatic system disorders (95% vs 64%, P < .001, including neutropenia in 92% vs 47% and febrile neutropenia in 15% vs 3%), gastrointestinal disorders (28% vs 7%, P < .001), and infections (20% vs 9%, P < .001). Grade 3 or 4 thromboembolic events occurred in 5.4% vs 3.7%. Treatment was discontinued due to adverse events in 11% vs 9%. The incidence of invasive second primary cancers was 1.5 vs 1.1 cases/100 patient-years (P = .37); acute myeloid leukemia occurred in four patients vs one patient. Treatment-related death occurred in six vs two patients.
The investigators concluded: “Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches.” They noted: “[The progression-free survival] benefit must be weighed against the increased risk of 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.” ■
DISCLOSURE: The study was supported by Celgene, Janssen, and funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and the French National Research Agency. For full disclosures of the study authors, visit www.nejm.org.
1. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.
Parameswaran N. Hari, MD, MRCP
Luciano J. Costa, MD, PhD
Over the past 20 years, the Intergroupe Francophone du Myelome (IFM) and Dr. Michel Attal have pioneered the use of autologous hematopoietic cell transplantation (AHCT) for multiple myeloma in a series of randomized studies. ...!-->!-->!-->!-->