Thierry Facon

The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than th...

This phase I/II dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1-4; carfilzomib was administered intravenously on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to nine cycles of CMP. In the phase I, dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase II portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase I portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase II portion of the study, 44 patients were enrolled at the MTD. Among 50 e...

Pseudomembranous conjunctivitis (PMC) is a rare ophthalmic lesion usually caused by infectious agents such as streptococcus, Klebsiella, Chlamydia, or adenovirus. It can also be associated with skin lesions of toxic epidermal necrolysis (TEN) and graft-versus-host-disease (GVHD). We report the pathological study of a patient with PMC and GVHD who had a conjunctival biopsy before death. This allowed us to differentiate this form of PMC from PMC of infectious origin, and to find within the epithelium characteristic features of acute GVHD and mononuclear cells expressing natural-killer markers. This suggests that this form of PMC resulted from a very acute, cytotoxic form of GVHD. Because PMC in bone marrow recipients can be related to infections, TEN, or acute GVHD, a systematic pathological study is required to guide the therapy.

To analyze prognostic factors for allogeneic bone marrow transplantation (BMT) in multiple myeloma. One hundred sixty-two reports of allogeneic matched sibling-donor transplants in multiple myeloma received by the European Group for Blood and Marrow Transplantation (EBMT) registry between 1983 and early 1993 were analyzed for prognostic factors. End points were complete remission, survival, and duration of complete remission. Following BMT, 44% of all patients and 60% of assessable patients entered complete remission. The overall actuarial survival rate was 32% at 4 years and 28% at 7 years. The overall relapse-free survival rate of 72 patients who were in complete remission after BMT was 34% at 6 years. Favorable pretransplant prognostic factors for survival were female sex (41% at 4 years), stage I disease at diagnosis (52% at 4 years), one line of previous treatment (42% at 4 years), and being in complete remission before conditioning (64% at 3 years). The subtype immunoglobulin ...

High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard of care for eligible newly diagnosed MM patients. Several randomized studies demonstrated a survival advantage for patients undergoing transplantation, compared with conventional chemotherapy. Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response rates and survival in those patients are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Nevertheless, this approach is currently challenged by the promising results of long-term treatment with novel agents. Recent data suggest that the upfront combination of a proteasome inhibitor plus one immunomodulatory drug (IMiD) is highly effective. The most promising 3-drug association might be Bortezomib, Lenalidomide and dexamethasone (VRD). Adjunction of...

To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death. Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827). The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and advers...

The three-drug combination of lenalidomide, bortezomib, and dexamethasone (RVD) has shown significant efficacy in multiple myeloma (MM). The Intergroupe Francophone du Myélome (IFM) decided to evaluate RVD induction and consolidation therapies in a sequential intensive strategy for previously untreated transplantation-eligible patients with MM. In this phase II study, 31 symptomatic patients age < 65 years were enrolled to receive three RVD induction cycles followed by cyclophosphamide harvest and transplantation. Patients subsequently received two RVD consolidation cycles and 1-year lenalidomide maintenance. Very good partial response rate or better at the completion of induction, transplantation, and consolidation therapy was 58%, 70%, and 87%, respectively. Maintenance upgraded responses in 27% of patients. Overall, 58% of patients achieved complete response, and 68% were minimal residual disease (MRD) negative by flow cytometry. The most common toxicities with RVD were neurol...

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective international trials. At diagnosis, a geriatric assessment had been performed to assess comorbidities, cognitive and physical status. An additive scoring system (range 0-5), based on age, comorbidities, cognitive and physical conditions, was developed to identify 3 groups: fit (score=0, 39%); intermediate-fitness (score=1, 31%), and frail (score≥2, 30%). The 3-year overall survival was 84% in fit patients, 76% in intermediate-fitness patients (HR 1.61, 95%CI 1.02-2.56, p=0.042) and 57% in frail patients (HR 3.57 CI 95% 2.37-5.39, p<0.001). The cumulative incidence of grade ≥3 non-hematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR 1.23, 95%CI 0.89-1.71; p 0.217) and 34.0% (HR 1.74, 95%CI 1.28-2.38; p<0.001) in frail patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fit...

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) can be safely administered to patients with end stage relapsed/refractory multiple myeloma (RRMM). However, we observed a shorter median PFS and OS for these patients when characterized with adverse cytogenetics (deletion 17p and translocation (4;14)) in the IFM 2009-02 trial. We then sought to determine whether MM with adverse cytogenetic would benefit greater to Pom-Dex if exposed earlier in the multicenter IFM 2010-02. The ITT population included 50 patients, with median age 63 years, 38% ≥65. The TTP was 2.8 months; interestingly, with a striking difference according to presence of t(4;14) compared to del(17p), 7.3 versus 2.8 months; similarly to the DOR, 8.3 and 2.4 months, and the ORR, 32% versus 15%, respectively. Interestingly, the OS was prolonged after Pom-Dex, particularly in t(4;14) given the short TTP, suggesting that patients were rescued at relapse with further lines of therapy. Pomalidomide plus low...

This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression. Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone. Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.

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.

Age is a strong prognostic factor in multiple myeloma. The overall survival is shorter in patients older than 66 years, and even shorter in those older than 75 years. Whether age is also a prognostic parameter in patients younger than 66 years treated homogeneously with intensive approaches is unknown. To address this issue, we retrospectively analyzed a series of 2316 patients treated homogeneously with 3-4 cycles of induction chemotherapy followed by a high-dose melphalan course, without any consolidation or maintenance. We show that patients older than 60 years have a statistically significant shorter overall survival. The analysis of prognostic parameters did not show a higher incidence of high-risk cytogenetics, but a higher incidence of International Staging System (ISS) stages 2 and 3, mainly due to higher β2-microglobulin levels. This study is the first to demonstrate the impact of age in the outcome of 'young' patients with multiple myeloma, and suggests that this parameter should be included in the stratification factors for future prospective clinical trials.

The outcomes were analyzed retrospectively of 59 cases of non-Hodgkin lymphoma (NHL) that included prominent splenic involvement (LPS). Forty-three patients had low-grade NHL, and 16 had intermediate or high-grade NHL. Forty of the 59 patients underwent splenectomy. Four patients died postoperatively before any treatment, and 10 others received no chemotherapy or radiation therapy. Twenty-nine splenectomized and 16 patients whose spleens were not removed received chemotherapy or radiation therapy. One or more cytopenias were present in 45 patients (77%). Five (18%) of the 28 patients who initially were cytopenic underwent splenectomies that did not correct their blood disorders. The median actuarial survival was 108 months in splenectomized patients and 24 months in those not treated surgically (P = 0.0001). For the 40 splenectomized patients, a normal postoperative platelet count, an initial hemoglobin level of 110 g/l or more, and a postoperative hemoglobin level 110 g/l or more were associated with prolonged survival. These results suggest that cytopenias are frequent in LPS and that their reversal is observed after early splenectomy in 82% of cases. The absence of cytopenia after early splenectomy is associated with prolonged survival.

... Stéphane Depil,; Claire Mathiot,; Xavier Leleu,; Anne Sophie Moreau,; Jean-Luc Faucompré,; Bernadette Hennache,; Francis Bauters,; Régis Bataille,; ... Kyrtsonis, MC, Vassilakopoulos, TP, Papadogiannis, A., Tzenou, T., Dimopoulou, MN, Siakantaris, MP, Kokoris, SI, Dimitriadou, ...

The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT.