Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
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Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “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,” the researchers said. “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.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.