Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma

Abstract

BACKGROUND High-dose chemotherapy with autologous stem cell transplantation has been the standard treatment for young patients with newly diagnosed myeloma. However, promising emerging data with the combination of lenalidomide, bortezomib and dexamethasone (RVD) have raised questions about the role of transplantation. METHODS We randomly assigned 700 patients to the RVD group (eight cycles; 350 patients) or to the transplant group (three cycles of RVD, followed by high-dose melphalan plus stem cell transplantation, followed by two additional cycles of RVD; 350 patients). Patients in both arms received maintenance lenalidomide for 1 year. The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the transplant versus the RVD group (median, 50 months vs. 36 months; hazard ratio, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified by International Staging System stage and cytogenetic risk profile. Transplantation versus RVD alone was associated with increased complete response (59% vs. 48%; P=0.006), and minimal residual disease negativity (79% vs. 65%; P<0.001). Overall survival was similar in both arms (4-year survival, 81% in the transplant group vs. 82% in the RVD group). Grade 3 or 4 neutropenia was significantly more common with transplantation than with RVD (92% vs. 47%), as were gastrointestinal adverse events (28% vs. 7%) and infections (20% vs. 9%). Rates of treatment-related deaths, second primary malignancies, thromboembolic events, and peripheral neuropathy were similar in the two treatment groups. CONCLUSIONS RVD plus transplant significantly prolonged progression-free survival as compared with RVD alone without overall survival difference.

Therapy Sequencing Strategies in Multiple Myeloma: Who, What and Why?

“…The median PFS was significantly longer in the ASCT group than in the group that received RVD alone (50 vs 36 months; hazard ratio [HR]: 0.65; p < 0.001), however, the OS at 4 years did not differ significantly between the two groups (81 and 82%, respectively) [7]. This transplant trial confirmed the findings of other published studies that address the role of ASCT [8,9].…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

How I treat myeloma with new agents

“…1,3,4 Two recent phase III trials comparing frontline ASCT vs ASCT at the time of first relapse showed that progressionfree survival (PFS) was improved in the front-line ASCT arm with the use of triplet, novel agent-based induction. 7,8 Nevertheless, especially in the French trial that compared frontline ASCT vs lenalidomidebortezomib-dexamethasone (RVD) and delayed ASCT, OS was similar in the 2 treatment groups, suggesting that delayed transplantation is feasible and does not have a detrimental effect on OS. 7 There is an ongoing cure vs control debate as to whether patients should receive an aggressive multidrug strategy with the aim of achieving CR, or a sequential disease control approach that emphasizes quality of life (QOL) as well as OS.…”

“…7,8 Nevertheless, especially in the French trial that compared frontline ASCT vs lenalidomidebortezomib-dexamethasone (RVD) and delayed ASCT, OS was similar in the 2 treatment groups, suggesting that delayed transplantation is feasible and does not have a detrimental effect on OS. 7 There is an ongoing cure vs control debate as to whether patients should receive an aggressive multidrug strategy with the aim of achieving CR, or a sequential disease control approach that emphasizes quality of life (QOL) as well as OS. These objectives are not mutually exclusive.…”

“…Nevertheless, recent data show that minimal residual disease (MRD)-negative status has a favorable prognostic impact, and it is known that frontline ASCT is associated with the higher rate of MRD negativity. 7,9 Based on response rates, depth of response, and PFS as surrogate markers for outcome, 3-drug combinations, including bortezomib and dexamethasone, are currently the standard of care as induction therapy prior to ASCT, but only limited data from prospective phase III trials are available to demonstrate that one combination is superior to the other. 1,4,10,11 Four to six courses of induction are recommended before proceeding to stem cell collection.…”