Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

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.

Bone marrow involvement by anaplastic large cell anaplastic large cell (ALC) lymphoma can be difficult to detect on routine morphologic examination alone. In a series of 42 patients with ALC lymphoma, the authors analyzed: (1) the usefulness of a limited panel of monoclonal antibodies directed against CD30 (Ber-H2, HRS4) and epithelial marrow involvement on routinely processed biopsy specimens; and (2) the prognostic significance of bone marrow involvement as detected on both morphologic and immunohistochemical grounds. On conventional examination, 17% of the patients were found to have bone marrow involvement at diagnosis. However, after immunohistochemical analysis, occult malignant cells were detected in 23% of the patients with negative bone marrow biopsy on routine histology. The low percentage of positive cases on routine morphologic examination compared to immunohistochemical examination was related to: (1) the scarcity of neoplastic cells which were scattered among hematopoietic cells; (2) the difficulty of distinguishing malignant cells from immature hematopoietic elements; and (3) the absence of alteration of the reticulin network. The authors observed a significant association between marrow infiltration and the presence of hematologic abnormalities (mostly anemia or cytopenias) at diagnosis, both in children and adult patients. More importantly, a significant lower survival was seen in patients with bone marrow involvement compared to those without bone marrow involvement. Immunohistochemistry with anti-CD30 and anti-EMA antibodies should be performed systematically in bone marrow biopsies from patients with ALC lymphoma to reliably identify the presence of bone marrow involvement that appears to carry a poor prognosis.

High-dose therapy (HT) has been reported to induce a high response rate in multiple myeloma (MM). However, the impact of such strategy on overall survival is difficult to assess. Indeed, prospective studies testing the effect of HT versus conventional chemotherapy (CC) have never been reported. In order to address this issue, from September 1990 to May 1993, 200 patients aged under 65 years with stage II/III DS previously untreated MM were randomized, at diagnosis, to receive CC (VMCP/BVAP) or HT (high dose melphalan and total body irradiation, supported with unpurged autologous bone marrow, collected after two cycles of VMCP/BVAP). Maintenance treatment with a-interferon was used in both arms. The analysis was performed as of June 1994, on an intention-to-treat basis, with a median follow-up of 28 months from diagnosis. Patient characteristics of each group (CC = 100 patients; HT = 100 patients) were similar and no significant differences were found with regard to age (57 years; SD = 6), stage DS (I1 = 5 I ; 111 = 149), Ig isotype (IgG = 11 1; IgA = 56; BJ = 28; IgD = 4), Pl-Microglobulin (4.8 mg/l; SD = 4), and bone marrow plasmacytosis (38%; SD = 25). Seventythree of 100 patients enrolled in the HT arm were actually treated with autologous bone marrow transplantation (ABMT) and 23 patients did not receive ABMT for the following reasons: six for bad performance status, six for organ failure, ten for insufficient bone marrow collection and five for early death. Two toxic deaths occurred after ABMT (Streptococcus infection). Response rate was significantly higher in the HT arm than in the CC arm (p < 0.001). Indeed, 23/100 patients achieved complete remission (CR), 15/100 very good partial response (VGPR 2 90%), 41/100 PR, 8/100 minimal response (MR) and 13/100 remained with a progressive disease (PD) in the HT arm, versus 41100 CR, 10/100 VGPR, 42/100 PR, 17/100 MR and 27/100 PD in the CC arm. HT was also found to improve event-free survival (EFS). Indeed, the three-year postdiagnosis probability of EFS was 35% (95% CI = 20-50) in the ABMT arm versus 15% (95% CI = 435) in the CC arm (p < 0.05). The three-year postdiagnosis probability of survival was 64% (95% CI = 49-76) in the ABMT arm versus 15% (95% CI = 2-5 1) in the CC arm 0, < 0.05). In multivariate analysis among various factors tested (age, stage DS, M component, P2-Microglobulin, albumin, LDH, plasmacytosis, treatment arm, response (CR + VGPR/PR/others), two factors were found to significantly affect survival: P,-Microglobulin ( p < 0.05) and response ( p < 0.00 1). Indeed, the three-year postdiagnosis probability of survival was 91% for patients in CR or VGPR (n = 52), 41% for patients in PR (n = 83) and 0% for patients in MR or with PD (n = 65) (p < 0.001). Finally, the Intergroupe Frangais du Myelome (IFM) trial demonstrates that ABMT improves response rate, EFS and survival in MM. Furthermore, this study demonstrates that attainment of a higher CR rate should be the major objective of future prospective trials.

310 High dose therapy with autologous stem cell transplantation (ASCT) is a standard treatment for young patients with myeloma. Some residual disease responsible for relapse is always present after ASCT. Effective maintenance treatment would be required to prevent relapse. However, such treatment is still to be defined. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide (LEN) for maintenance after transplantation. Patients, under 65 years of age, with non-progressive disease after a first line ASCT (performed within the last 6 months) were randomized to receive consolidation with LEN (25 mg/d, 21 days/month, for 2 months) followed by maintenance with either placebo (Arm A) or LEN (10 to 15 mg/d) until relapse (Arm B). From July 2006 to August 2008, 614 patients were randomized. Patient's characteristics of each group were similar with regard to age (57 years), ISS stage, FISH analysis, induction regimen (VAD / bortezomib-dex / others = 49%/44%/7%), diagnosis-randomization interval (10 months), and response at time of randomization. The first pre-planned interim analysis was performed on the 4th of September 2009 with a median follow up of 24 months from randomization (ASCO 2010, abstract 8018). The independent data and safety monitoring committee recommended to unblind the trial due to the PFS superiority of arm B (primary end point). On the 6th of July 2010, the trial was unblinded and the final analysis was performed with a median follow up of 34 months from randomization and 44 months from diagnosis. Consolidation with LEN improved the very good partial response rate (VGPR) (p<0.0001). Maintenance with LEN improved the progression-free survival: median 24 months from randomization and 34 months from diagnosis in arm A, versus 42 months from randomization and 52 months from diagnosis in arm B (HR=0.5, p<10−8). This benefit was observed across all stratified subgroups of patients including beta-2 microglobulin level, (< or > 3 mg/l) cytogenetic profile (del 13, + or -), and response after transplantation (CR/VGPR or not). In multivariate analysis, PFS was related to maintenance with LEN (p<0.0001), and to the achievement of CR/VGPR after consolidation with LEN (p<0.01). Maintenance treatment with LEN was not associated with resistance of the disease at time of progression: the median interval between progression and death was similar in both arms (12 months). With the current follow-up, the 5-year post diagnosis overall survival remains extremely high and similar in the 2 treatment groups: 83%. Maintenance treatment with LEN was well tolerated. The definitive interruption rate for serious adverse events during maintenance was similar in both arms (Arm A=5%, Arm B=8%, NS). The IFM 2005-02 trial demonstrates that lenalidomide is an effective and well tolerated maintenance treatment after transplantation for multiple myeloma patients. Disclosures: Attal: celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Off Label Use: maintenance treatment with Revlimid. Facon:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy. Roussel:celgene: Consultancy; johnson and johnson: Consultancy. Avet-Loiseau:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Harousseau:celgene: Consultancy; johnson and johnson: Consultancy.