Jean-Luc Harousseau

A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma

Background The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. Methods Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation. Results The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P<0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 perce...

Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma

BACKGROUND High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkins lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment. METHOD A total of 215 patients with relapses of non-Hodgkins lymphoma were treated between July 1987 and June 1994. All patients received two courses of conventional chemotherapy. The 109 patients who had a response to chemotherapy were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55 patients). RESULTS The overall rate of response to conventional chemotherapy was 58 percent; among patients with relapses after chemotherapy, the response rate was 64 percent, and among those with relapses during chemotherapy, the response rate was 21 percent. There were three deaths from toxic effects among the patients in the transplantation group, and none among those in the group receiving chemotherapy without transplantation. The two groups did not differ in terms of prognostic factors. The median follow-up time was 63 months. The response rate was 84 percent after bone marrow transplantation and 44 percent after chemotherapy without transplantation. At five years, the rate of event-free survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation (P = 0.001), and the rate of overall survival was 53 and 32 percent, respectively (P = 0.038). CONCLUSIONS As compared with conventional chemotherapy, treatment with high-dose chemotherapy and autologous bone marrow transplantation increases event-free and overall survival in patients with chemotherapy-sensitive non-Hodgkins lymphoma in relapse.

International uniform response criteria for multiple myeloma

New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.

BACKGROUND High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation. METHODS We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival. RESULTS Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001). CONCLUSIONS 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.).

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study

BACKGROUND Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma. METHODS This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. FINDINGS 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. INTERPRETATION Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. FUNDING Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

Interferon Alfa-2b Combined with Cytarabine versus Interferon Alone in Chronic Myelogenous Leukemia

BACKGROUND Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. METHODS Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome-positive cells in the bone marrow) at 12 months. RESULTS The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon-cytarabine group (360 patients) as compared with the interferon group (361 patients) (P=0.02; relative risk of death, 0.64; 95 percent confidence interval, 0.44 to 0.93). After three years, the survival rate was 85.7 percent with interferon and cytarabine and 79.1 percent with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P=0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon and cytarabine (41 percent) and in 75 of 314 patients treated with interferon only (24 percent, P<0.001). CONCLUSIONS The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia.

Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial

PURPOSE To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma. PATIENTS AND METHODS Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate. RESULTS Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone. CONCLUSION Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

PURPOSE Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters. PATIENTS AND METHODS A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p). RESULTS We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients. CONCLUSION Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.

Prediction of Survival in Multiple Myeloma Based on Gene Expression Profiles Reveals Cell Cycle and Chromosomal Instability Signatures in High-Risk Patients and Hyperdiploid Signatures in Low-Risk Patients: A Study of the Intergroupe Francophone du Myélome

PURPOSE Survival of patients with multiple myeloma is highly heterogeneous, from periods of a few weeks to more than 10 years. We used gene expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers. PATIENTS AND METHODS In a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 patients with multiple myeloma. RESULTS The 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients into low-risk and high-risk groups. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan-Meier estimates of rates of survival at 3 years were 90.5% (95% CI, 85.6% to 95.3%) and 47.4% (95% CI, 33.5% to 60.1%), respectively, in our patients having a low risk or high risk independently of traditional prognostic factors. High-risk patients constituted a homogeneous biologic entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients were heterogeneous and displayed hyperdiploid signatures. CONCLUSION Gene expression-based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted antimitotics.

Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

PURPOSE This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. RESULTS Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. CONCLUSION The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.