Intergroupe Francophone Du Myelome Research Articles

Incidence and Prognostic Value of Chromosomal Abnormalities in Elderly Patients with myeloma: The IFM Experience on 1095 Patients

Abstract 994The outcome of patients with multiple myeloma (MM) is highly influenced by chromosomal abnormalities, and especially translocation t(4;14) and del(17p). However, these data have been mostly demonstrated in young patients, less than 65 years of age, treated with high-dose chemotherapy. Almost no data is available in elderly patients. In order to address this issue, we retrospectively analyzed patients over 66 years old, treated with various regimens in the Intergroupe Francophone du Myélome (IFM). Since chromosomal abnormalities are centrally analyzed in the IFM, we focused our analyses on 1890 patients (age=65–94, median=71 y). The patients were divided in two groups: 66–74 y (1239 patients) and over 75 y (651 patients). We first analyzed the incidence of the following abnormalities: del(13), del(17p) (defined by a deletion present in at least 60% of the plasma cells), and t(4;14). The incidence of del(13) was 43.6% in the first group, and 37% in the second one (p=.007). For del(17p), the incidences were 5.9% and 6.1%, respectively (p=NS). Finally, for t(4;14), the incidences were 10.9% and 8.3%, respectively (p=.09). When compared to patients < 65 y, we observed a highly significant lower incidence of t(4;14) in elderly patients (14% vs 10.9% vs 8.3%, p<.0001), vs no significant difference for del(13) and del(17p). Treatment and follow-up data were available for 1095 of these patients. Fifteen % of the patients were treated with high-dose chemotherapy (median age=66 y), 246 received melphalan-prednisone (MP), 434 receined MP-thalidomide (MPT), the others receiving various schemas, including MP-bortezomib (84 patients), lenalidomide-dexamethasone (118 patients), or intermediate-dose melphalan (45 patients). Global prognostic analyses showed that both t(4;14) and del(17p) influenced both the progression-free survival (PFS) and overall survival (OS). Even after stratification on treatment schema, both chromosomal abnormalities retained prognostic value: <10−6 for both t(4;14) and del(17p) for PFS, and <10−4 and <10−6 for OS, respectively. When restricted to the largest treatment group, i.e., patients treated with MPT, the respective p values were <10−4 and <0.002 for PFS, and <0.006 and <10−3 for OS. To conclude, this is by far the largest series analyzing the prognostic impact of chromosomal abnormalities in elderly patients. As demonstrated in younger patients, both t(4;14) and del(17p) negatively impact the PFS and OS survival of these elderly patients. Disclosures:Hulin:Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Facon:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Reply to W. Tapper et al

We appreciate the opportunity to reply to the comments by Tapper et al in relation to our study. To replicate our study, Tapper et al examined del(12p13.31) locus using fluorescent in situ hybridization in 256 patients newly diagnosed with multiple myeloma (MM), and found a trend for association with overall survival (P .06). After the publication of our work, we substantially increased the number of patients investigated for 12p13.31 deletion. The prognostic impact of this genetic lesion was confirmed in a larger cohort (n 455) of patients newly diagnosed with MM who were enrolled onto Intergroupe Francophone du Myelome clinical trials (Figs 1A and 1B). How can this apparent discrepancy between the study by Tapper et al and our study be explained? In

Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM 2008 Phase II Study

AbstractAbstract 624 Background:Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible MM patients (pts). Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response and survival in those pts are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Therefore, the IFM (Intergroupe Francophone du Myélome) decided to evaluate the Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) regimen as induction and consolidation therapy followed by Len maintenance in the transplant setting for newly diagnosed pts. Methods:This open-label phase II study was conducted at 10 IFM transplant centers, with enrollment between September and December 2009. Pts under 65 with symptomatic de novo MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (days 1, 4, 8, 11), Len 25 mg (days 1–14), and oral Dex 40 mg (days 1, 8 and 14). Stem cell collection was planned for all pts after high dose cyclophosphamide (3g/m2). All pts then proceeded to intensification prepared with melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts could receive two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 10–15 mg/day. All patients received, unless contraindicated, aspirin prophylaxis or alternative anticoagulation for prevention of deep-vein thrombosis (DVT), anti-viral therapy (valacyclovir) for herpes zoster prevention. Pts with ≥ grade 2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved 1 month after consolidation. The secondary endpoints were the response rate after 3 cycles of VRD, after ASCT and after consolidation; the safety profile of the program, the feasibility and quality of stem cell collection and dthe uration of response (DOR), PFS, OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells was performed before and after ASCT, and after consolidation. Toxicities were graded using the CTCAEv4. Patients:Thirty-one pts with symptomatic MM were enrolled. Baseline characteristics of the pts were: median age = 58 (range 33–65); 55% were women; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 13q deletion in 41% over 27 assessable pts; chromosome 17p del in 18% and t(4;14) translocation in 11%. Results:All pts but one remain on study program at data cut-off (01/08/10). The one pt had discontinued treatment at time of ASCT due to mobilization failure. Therefore, 31 pts are evaluable for response rates after induction therapy, 30 after ASCT and 13 after consolidation. All results are summarized in table 1. In Intent To Treat analysis, the overall response rate (ORR) after ASCT was 94%, including 32% VGPR, 13% CR and 23% sCR. Nine serious AEs were reported. There was no treatment-related mortality. The most common toxicities were: sensory PNY (45%), including 29% grade 1 and 16% grade 2; neuropathic pain (13%); GI tract symptoms (42%) including diarrhea (16%) and constipation (10%); fatigue (10%) and erythrodermia (9%). There was no grade 3/4 PNY. Grade 3/4 hematological toxicities included neutropenia (26%), and thrombocytopenia (6%). No DVT or pulmonary embolism was reported.Six of 31 pts (19%) have had difficulty with mobilization but only 1 pt did not undergo ASCT. Stem cell collection with plerixafor was successful in 4 pts. Median stem cell collection was 7.7 × 106 CD34+ cells/kg.Table 1:After InductionAfter ASCTAfter consolidationn%n%n%sRC413723526RC516413526RC+sRC92811351052VGPR8261032737≥ VGPR175421681789RP134282615ORR309729941894SD1313Total313018Out of trial131 Conclusions:VRD induction followed by ASCT and VRD consolidation produce high quality responses and is well tolerated in newly diagnosed MM pts under 65. Updated efficacy and safety data will be presented at the meeting. Disclosures:Roussel:Janssen: Consultancy, Research Funding, orator; Celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib, lenalidomide as induction and consolidation therapies in frontline MM pts. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

AbstractAbstract 3043 Introduction:The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods:Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results:As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29–76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion:VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35. Disclosures:Niederwieser:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences.

The purpose of this study was to update outcomes of autotransplantation trials for myeloma conducted by the Intergroupe Francophone du Myelome (IFM), the Southwest Oncology Group, and the University of Arkansas for Medical Sciences (Total Therapy [TT]). IFM90 (N = 194), IFM04 (N = 402), IFM9902 (N = 692), IFM9904 (N = 197), S9321 (N = 817), TT1 (N = 231), TT2 (N = 668), and TT3 (N = 303) were updated, and results were compared with original reports. Superior survival with single transplantation versus standard therapy in IFM90 was confirmed (P = .004), and a trend in favor of tandem versus single transplantation was maintained in IFM94 (P = .08). S9321 data were validated, with comparable survival in single transplantation and standard treatment arms (P = .35). A survival benefit from thalidomide maintenance in IFM9902 was not confirmed (P = .39) but emerged for the thalidomide arm of TT2 (P = .04). On multivariate analysis, survival was superior in TT2, TT3, and IFM9902 (all P < .001); tandem transplantations were superior to both single transplantations and standard therapies (P < .001), as were tandem transplantations with added thalidomide versus trials without thalidomide (P < .001). Postrelapse survival (PRS) was superior when initial event-free survival (EFS) exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib. These long-term follow-up data of transplantation trials provide a crucial framework of reference for outcome reporting of novel agent-based trials reportedly exhibiting remarkable short-term efficacy approaching high-dose therapy results.

Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myélome (IFM)

AbstractAutologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m2 × 4) and melphalan (200 mg/m2) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.

Analysis of Familial Dysglobulinemia: a Multicenter IFM Study.

Abstract 4891Multiple myeloma is a haematological malignancy which rarely occurs in a familial context. MGUS corresponds to the existence of a clone secreting a monoclonal immunoglobulin and can in some patients evolve to multiple myeloma. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of multiple myeloma, there are presently no identified genetic mechanisms which contribute to myelomagenesis, in particular in familial cases. The identification and study of families with several cases of dysglobulinemia should contribute to the determination of genetic factors predisposing to multiple myeloma. The aim of this study is to identify genetic factors predisposing to familial dysglobulinemia, thanks to the establishment of a DNA bank. Peripheral blood samples were collected both from patients with dysglobulinemia and from healthy family members and lymphoblastoid lines established for further studies. For this purpose, we have initiated a multicenter study aiming to identify families with several cases of dysglobulinemia, including both multiple myeloma and/or Monoclonal Gammapathy of Undetermined Significance (MGUS). This effort is supported by a French National Programme Hospitalier de Recherche Clinique (PHRC) and the French National Institute for Cancer Research (INCa)., and involves the French multicentric Myeloma groups, Intergroupe Francophone du Myélome (IFM) and Myeloma Autograft Group (MAG), in coordination with the Réseau des Hémopathies Familiales. This study was activated in Octobrer 2007 and as of April 2009, 72 families with at least two cases of dysglobulinemia (median 2, range 2-5) have been identified. Among 166 cases of dysglobulinemia, 100 were diagnosed as multiple myeloma, 49 as MGUS and the remainder as light chain amyloidosis or Waldenstrom's disease. The sex ratio was 1:1 for all groups. The median range at inclusion in this study was 64 years (range 33-85 years). The heavy chain subtype distribution was classical, with a majority of IgG cases. 42% of cases corresponded to cases involving parents and offspring and 54% corresponded to cases involving siblings. This study is ongoing in order to collect samples from 100 families and to initiate genetic analyses to identify predisposing factors. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Plus Dexamethasone (VD)Versus Reduced-dose bortezomib Plus Thalidomide Plus Dexametasone (vTD) as Induction Treatment Prior to Autologous Stem-Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM).

Abstract 354▪▪This icon denotes an abstract that is clinically relevant. IntroductionThe Intergroupe Francophone du Myelome (IFM) has shown that induction tteatment prior to ASCT with VD is superior to VAD in terms of complete response (CR) or CR plus very good partial response(VGPR) both before and after ASCT (Harousseau 2008 Joint ASH/ASCO session). The Italian group has presented impressive results with the three-drug combination VTD.(Cavo Blood 2008;112:)However in both studies, peripheral neuropathy (PN)was the most frequent adverse event (9% Grade 3) Patients and Methods.The IFM has conducted a randomized trial comparing four 21-day cycles of induction with VD(V1.3 mg/m2/d on days 1,4,8,11 plus D 40mg:d on days 1-4 and 8-11 for the first 2 cycles, on days 1-4 for the last 2 cycles) or vTD (v 1mg/m2 /d on days 1,4,8,11 plus thalidomide 100mg:d d1-21 plus dexamethasone same dosing as for VD). Results were assessed after cycle 2 and 4 and after ASCT. Responses were evaluated according to IMW uniform criteria . Samples for serum and urine electrophoreses were centralized (HAL,CHU Nantes). In the vTD arm, if after cycle 2, the response was. ResultsFrom 03/2008 to 01/2009, 205 patients with newly diagnosed symptomatic MM and up to 65 years of age were recruited and randomized at diagnosis (stratification according to β-2 microglobulin and presence of del(13) by FISH). The two groups were well balanced as regards initial prognostic parameters : age, ISS,β-2microglobulin,hemoglobin,calcium and creatinine levels, incidence of del(13),t(4.14) and del(17p.).As of August 15th, 191 patients are evaluable for response after cycle 4 ( 95 VD,96 vTD). According to investigators'assessment,the efficacy results are the following (VD vs vTD): CR rate 12%vs 14% (p = 0.68), ,≥VGPR 36%vs 50 % (p=0.047), ≥PR 81%vs 91%(p = 0.06),stable disease 12%vs 5%, progression/failure 7%vs 4%.In the vTD arm the doses of v and T were increased due to ≥3 6 %vs 2 % (p=0.17) ConclusionThe combination of reduced-dose bortezomid and thalidomide induces significantly more CR+VGPR than the VD with usual doses of V.Despite the addition of thalidomide, the incidence of PN was markedly reduced In the vTD arm with only 2% Grade ≥3 PN. vTD should be considered a new standard for induction treatment prior to ASCT Disclosures:Harousseau:Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:janssen cilag: Honoraria; celgene: Honoraria. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Achievement of at Least Very Good Partial Response Is a Simple and Robust Prognostic Factor in Patients With Multiple Myeloma Treated With High-Dose Therapy: Long-Term Analysis of the IFM 99-02 and 99-04 Trials

The prognostic impact of complete response (CR) achievement in multiple myeloma (MM) has been shown mostly in the context of autologous stem-cell transplantation. Other levels of response have been defined because, even with high-dose therapy, CR is a relatively rare event. The purpose of this study was to analyze the prognostic impact of very good partial response (VGPR) in patients treated with high-dose therapy. All patients were included in the Intergroupe Francophone du Myelome 99-02 and 99-04 trials and treated with vincristine, doxorubicin, and dexamethasone (VAD) induction therapy followed by double autologous stem-cell transplantation (ASCT). Best post-ASCT response assessment was available for 802 patients. With a median follow-up of 67 months, median event-free survival (EFS) and 5-year EFS were 42 months and 34%, respectively, for 405 patients who achieved at least VGPR after ASCT versus 32 months and 26% in 288 patients who achieved only partial remission (P = .005). Five-year overall survival (OS) was significantly superior in patients achieving at least VGPR (74% v 61% P = .0017). In multivariate analysis, achievement of less than VGPR was an independent factor predicting shorter EFS and OS. Response to VAD had no impact on EFS and OS. The impact of VGPR achievement on EFS and OS was significant in patients with International Staging System stages 2 to 3 and for patients with poor-risk cytogenetics t(4;14) or del(17p). In the context of ASCT, achievement of at least VGPR is a simple prognostic factor that has importance in intermediate and high-risk MM and can be informative in more patients than CR.

Autologous or reduced-intensity conditioning allotransplantation for de novo multiple myeloma

Recent pilot studies combining a cytoreductive autologous SCT (auto-SCT) with a reduced-intensity conditioning regimen (RIC) allograft have reported encouraging results in patients with de novo multiple myeloma up to the age of 65 years, with achievement of high CR rates and TRM rate inferior to 15%.1, 2 These results justified prospective trials comparing this auto/RIC allo-SCT tandem approach with double auto-SCT, which previously had been shown to be superior to single auto-SCT.3 Until now, only three prospective studies comparing the combination of auto-SCT followed by RIC allograft with tandem auto-SCT have been reported, one from the Intergroupe Francophone du Myelome,4, 5 one from Italy6 and one from Spain.7

New treatments in multiple myeloma: beyond optimal treatment

The prognosis of multiple myeloma (MM) has remained unchanged for three decades. The first improvement appeared in the 1990s when the Intergroupe Francophone du Myelome (IFM) 90 randomized trial showed the superiority of high-dose therapy supported by autologous stem cell transplantation (ASCT) compared with conventional dose chemotherapy in younger patients (<65 years of age) [1]. These results were confirmed by two other randomized studies [2–3]. But in less than 10 years, treatment of MM has dramatically changed due to the introduction of three novel agents: thalidomide, its analogue lenalidomide, and bortezomib. Compared with chemotherapeutic agents, these new compounds have different modes of action. They target not only the myeloma cell but also the microenvironment which is so important for myeloma cell survival and proliferation.

Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART): Consensus Statement

Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART): Consensus Statement

Molecular Prognosis in Multiple Myeloma: The IFM Experience.

Multiple myeloma is the second most common hematological malignancy and remains incurable despite high dose chemotherapy. Patients experience survival periods of few months to more than ten years. We used gene-expression profiles of malignant plasma cells obtained at diagnosis to develop and validate biomarkers to predict disease prognosis. Gene-expression profiling was realized on 250 bone marrow samples obtained from patients less than 66 years, treated according to the Intergroupe Francophone du Myelome (IFM) 99 clinical trials, based on double intensive treatments. The median follow-up time was 3 years and 55 patients died from their disease during this period. Supervised methods were performed to identify expression signatures associated with survival in a training group of 182 patients. From these genes, a classifier of prognosis was developed in the training group and validated in an independent validation group of 68 patients. Univariate Cox proportional hazards model at a significant level of p<0.05 and selection procedure from BRB ArrayTools at a significant level of p<0.001 were used to select 50 genes associated with survival. Resampling and permutation tests were performed in an rigorous internal validation procedure and 28 genes with a permutation p<0.005 and a resampling mean p<0.01 were retained. To reduce gene list instability, multiple training/test partitions (100) were performed and the 15 most stable genes were used to build a survival predictor. For each patient, a score based on the first component of principal component analysis was calculated. The patients were ranked according to their score and divided according to the median (low-risk and high-risk). The model was highly significantly associated with survival in the training group (p<0.001) and it was confirmed in the validation group (p<0.001). The relative risk of death for high-risk patients was 8.46 (95% confidence interval (CI) = 3.3 to 21.6) in the training group and was 15.3 (95% CI = 2 to 116.5) in the validation group. Various biological variables including serum beta2-microglobulin, serum albumin, combined in the International Staging System (ISS), the deletions/monosomy of chromosome 13 (del13) and the t(4;14)(p16;q32) have emerged as relevant prognostic factors in MM. The 15-gene prognostic classifier was independent of ISS (p<0.001) with an adjusted hazard ratio of death =7.5 (95% CI = 3.09 to 18.2), of del13 (p<0.001) with an adjusted hazard ratio of death =8.8 (95% CI = 3.7 to 21), and of t(4;14) (p<0.001) with an adjusted hazard ratio of death =9.3 (95% CI = 3.9 to 22.1). These results demonstrate that this molecular predictor is very powerful to identify different categories of patients based on expected survival, and thus may be clinically useful to design therapeutic trials. [Display omitted]

Timing of Second Autologous Transplantations in Multiple Myeloma: Results of a Multicenter Sequential Randomized Clinical Trial.

Background: Autologous stem cell transplantation (ASCT) is now considered standard therapy in young patients (<65 years) with multiple myeloma (MM). The Intergroupe Francophone du Myelome conducted a randomized trial of the treatment of MM with high-dose chemotherapy followed by either one or two successive ASCTs. The probabilities of event-free-survival and overall survival were doubled with a double transplant. However, no randomized trial has compared tandem transplant up-front with a strategy including planned second ASCT at relapse or progression. Therefore, we performed a multicenter, sequential, randomized trial designed to assess the optimal timing of a second ASCT.Methods: From May 2003 to April 2006, 140 patients with symptomatic MM (de novo) and less than 60 years of age, were randomly assigned to receive either tandem transplantation up-front (within 6 months of the first transplantation) [Arm A, n=69] or one ASCT followed by a consolidation therapy with thalidomide (day +90, 100 mg/per day during 5 months) [Arm B, n=71]. Patients included in the arm B received a second transplant in case of disease progression on consolidation therapy, or in case of relapse in responders. Clinical characteristics of each group were similar. In both arms of the study, ASCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m2) and G-CSF. Data were analyzed on an intent-to-treat basis.Results: With a median follow-up of 23 months (range: 6–34), the 2-year overall survival was 55% in the arm A and 75% in the arm B. Survival curves were not different (P=0.28, log-rank test). The 2-year event-free survival was 41% in the arm A and 60% in the arm B (P=0.4, log-rank-test). In the arm B, relapse-free survival of ≥ 16 months following the first transplantation was an important predictor of overall survival (p< 0.001).Conclusion: Data from the present study suggest that up-front single ASCT followed by a consolidation therapy with thalidomide and a second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Longer follow-up is needed before definite conclusions can be given concerning the optimal timing of second autologous transplantations in patients with MM.

Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma

The Intergroupe Francophone du Myélome (IFM) initiated 2 trials in 1999 to study patients with high-risk (beta2-microglobulin level greater than 3 mg/L and chromosome 13 deletion at diagnosis) de novo multiple myeloma. In both protocols, the induction regimen consisted of vincristine, doxorubicin, and dexamethasone (VAD) followed by first autologous stem cell transplantation (ASCT) prepared by melphalan 200 mg/m(2). Patients with an HLA-identical sibling donor were subsequently treated with dose-reduced allogeneic stem cell transplantation (IFM99-03 trial), and patients without an HLA-identical sibling donor were randomly assigned to undergo second ASCT prepared by melphalan 220 mg/m(2) and 160 mg dexamethasone with or without anti-IL-6 monoclonal antibody (IFM99-04 protocol). Two hundred eighty-four patients-65 in the IFM99-03 trial and 219 in the IFM99-04 trial-were prospectively treated and received at least one course of VAD. On an intent-to-treat basis, overall survival (OS) and event-free survival (EFS) did not differ significantly in the studies (medians 35 and 25 months in the IFM99-03 trial vs 41 and 30 months in the IFM99-04 trial, respectively). With a median follow-up time of 24 months, the EFS of the 166 patients randomly assigned in the tandem ASCT protocol was similar to the EFS of the 46 patients who underwent the entire IFM99-03 program (median, 35 vs 31.7 months), with a trend for a better OS in patients treated with tandem ASCT (median, 47.2 vs 35 months; P = .07). In patients with high-risk de novo MM, the combination of ASCT followed by dose-reduced allogeneic transplantation was not superior to tandem dose-intensified, melphalan-based ASCT.

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.

Maintenance Treatment with Thalidomide after Autologous Transplantation for Myeloma : First Analysis of a Prospective Randomized Study of the Intergroupe Francophone du Myelome (IFM 99 02).

High dose therapy (HDT) supported with autologous stem cell transplantation has been introduced in the management of aggressive myeloma. However, after single or tandem transplantation, almost all patients ultimately relapse. New strategies are required to control any residual disease after HDT. The Intergroupe Francophone du Myelome (IFM) initiated a trial designed to evaluate the impact of maintenance treatment with Thalidomide on the duration of response after HDT.From April 2000 to October 2003, 1004 myeloma patients at diagnosis under the age of 65 years were enrolled in the IFM 99 protocol. 780 of them, without or with only one adverse prognostic factor (beta-2 microglobuline >3 mg/l or deletion of chromosome 13), were enrolled in the IFM 99 02 protocol. They were to receive the following treatment: 1) 3–4 cycles of the VAD regimen; 2) a first autologous transplant prepared with Melphalan 140 mg/m2; 3) a second autologous transplant prepared with Melphalan 200 mg/m2. Patients without progressive disease 2 months after the second transplant were randomized to receive: no maintenance treatment (arm A), maintenance treatment with Pamidronate (arm B) or maintenance treatment with Thalidomide and Pamidronate (arm C).As of May 2004, 580 patients (74%) have been randomized: 195 in arm A, 190 in arm B and 195 in arm C. Clinical characteristics of each group were similar. The median follow-up from diagnosis was 26 months (range: 6–50)Thalidomide was found to improve the Progression-free survival (PFS; p<0.007) and the Event-free-survival (EFS; p<0.01).Indeed, the 40-months post-diagnosis probability of PFS was 70% (95% CI= 42–80) in the Thalidomide arm versus 53% (95% CI= 37–65) in arm A, and 52% (95% CI= 36–68) in arm B.Most patients (60%) enrolled in arm A and B received Thalidomide at time of relapse. The overall survival was similar in the 3 treatment groups.Among the 580 randomized patients, 2 factors were found to be associated with a longer EFS : low beta-2-microglobulin at diagnosis (p<0.01) and treatment arm (p<0.01). Deletion of chromosome 13 (FISH analysis) was not related to EFS.In conclusion, the first analysis of the IFM9902 trial strongly suggests that Thalidomide is an effective maintenance treatment after high dose therapy for myeloma. The next analysis (November 2004) will be presented during the meeting.

Multiple Myeloma

High-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies. While it is now clear that dose-intensification improves the outcome in younger patients, long-term remissions are obtained in a minority of patients. Therefore, the impact of novel agents as part of front-line therapy is the objective of ongoing trials. Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies. In Section I, Dr. John Shaughnessy describes recent data obtained with GEP of CD138-purified plasma cells from patients with MM. His group has already shown that overexpression of the Wnt signaling inhibitor DKK1 by MM plasma cells blocks osteoblast differentiation and contributes to the development of osteolytic bone lesions. Recent data allow identification of four subgroups of MM in which GEP is highly correlated not only with different clinical characteristics and outcome but also with different cytogenetic abnormalities. In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses. In the context of intensive therapy with tandem autotransplantations, this model appears to be more powerful than current prognostic models based on standard biologic variables and cytogenetics. Understanding why the dysregulation of these three genes is associated with a more aggressive behavior of the disease will help to define new therapeutic strategies. In Section II, Dr. Jean-Luc Harousseau presents recent results achieved with tandem autologous SCT (ASCT) and with reduced intensity conditioning (RIC) allogeneic SCT. ASCT is now considered as the standard of care in patients up to 65 years of age. The IFM (Intergroupe Francophone du Myelome) has recently shown that double ASCT is superior to single ASCT. Current results of three other randomized trials confirm that double ASCT is superior, at least in terms of event-free survival. However, patients with poor prognostic features do poorly even after tandem ASCT. Strategies to further improve the outcome of ASCT include more intensive therapies and the use of novel agents such as thalidomide and immunomodulatory analogs (IMiDs) or bortezomib. Results of allogeneic SCT remain disappointing in MM even with T cell-depleted grafts. Preliminary results of a strategy combining ASCT to reduce tumor burden and RIC allogeneic SCT are encouraging, although the follow-up is still short. However, again, patients with chromosome 13 deletions have poor results with RIC. Longer follow-up of ongoing multicentric studies will help to clarify the indications of RIC. In Section III, Dr. Paul Richardson summarizes current knowledge of novel targeted therapies in MM. A better understanding of interactions between MM cells and bone marrow stromal cells and of the signaling cascades whereby cytokines mediate proliferation, survival, drug resistance and migration of MM cells provide the rationale for testing novel agents in relapsed/refractory MM. Increased angiogenesis coupled with the known anti-angiogenesis activity of thalidomide justified its use in refractory MM. The remarkable responses initially achieved prompted a number of clinical studies in different indications and the development of more potent IMIDs. Among them CC-5013 (Revlimid) has been tested in Phase I/II studies and a randomized Phase III study has just been completed. Blockade of NF-kappa B using the proteasome inhibitor bortezomib (Velcade) may mediate anti-MM activity by inhibiting interleukin (IL)-6 production in stromal cells and other mechanisms of action have been shown in preclinical studies. Based on the promising results of the Phase II trial, a large randomized trial of bortezomib versus dexamethasone has been completed. Studies of bortezomib combined with other drugs are ongoing. Arsenic trioxide has a number of properties showing that it targets MM cells interacting with the microenvironment. Clinical studies are ongoing as well. Other agents in MM have already been or will probably be translated soon from the bench to the bedside.

Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy

Recently, we have described the biological correlations associated with the main translocations involving the 14q32 chromosomal region, that is, t(14q32), in patients with multiple myeloma (MM). We have now extended the analysis to the prognostic value of these chromosomal rearrangements in 168 consecutive patients with newly diagnosed MM receiving intensive chemotherapy within clinical trials of the Intergroupe Francophone du Myelome (IFM). Patients with t(4;14) displayed a poor outcome (short event-free survival and short overall survival), whereas those with t(11;14) displayed long survival. On the other hand, patients with neither t(4;14) nor t(11;14) presented an intermediate outcome. Importantly, chromosome 13 abnormalities (C13As) significantly influence the prognosis of this latter group. In contrast, C13As affected the outcome of the other patients to a much lesser extent, either because of an almost constant association (in the t(4;14) group) or because of a lack of any significant prognostic impact (in the t(11;14) group; only one event occurred in the 10 patients with t(11;14) and C13As). Considering that t(4;14) and t(11;14) (1) are the only (so far recognized) true, recurrent t(14q32)'s, (2) are linked to specific immunoglobulin isotypes, and (3) display specific outcomes, they represent distinct entities corresponding to a specific oncogenesis and prognosis. These data emphasized the interest in analyzing these two translocations by fluorescence in situ hybridization in prospective therapeutic trials in order to consider these translocations as distinct entities.

Randomized trial experience of the Intergroupe Francophone du Myélome

This article summarizes clinical results of the Intergroupe Francophone du Myélome (IFM) trials: high-dose therapy (HDT) supported with autologous stem cells improves survival, melphalan 200 mg/m 2 is the best preparative regimen, unpurged peipheral blood stem cells (PBSC) are the recommended source of stem cells to support HDT, and tandem transplants significantly improve survival. Although these results are encouraging, the current IFM 99 protocol will evaluate innovative strategies with the goal to improve long-term survival.