Bernard Grosbois

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial

BACKGROUND In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. METHODS Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185. FINDINGS After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32). INTERPRETATION The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.

Anti-HMGCR Autoantibodies in European Patients With Autoimmune Necrotizing Myopathies: Inconstant Exposure to Statin

AbstractNecrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ⩽3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = −0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = −0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial.

In the 2005-01 trial, we have demonstrated that bortezomib-dexamethasone as induction therapy before autologous stem cell transplantation was superior to vincristine-adriamycin-dexamethasone. We conducted a post-hoc analysis to assess the prognostic impact of initial characteristics as well as response to therapy in patients enrolled in this study. Multivariate analysis showed that ISS stages 2 and 3 and achievement of response less than very good partial response (VGPR) both after induction therapy and after autologous stem cell transplantation were adverse prognostic factors for progression-free survival, the most important one being achievement of response less than VGPR after induction. Progression-free survival was significantly improved with bortezomib-dexamethasone induction therapy in patients with poor-risk cytogenetics and ISS stages 2 and 3 compared with vincristine-adriamycin-dexamethasone. In these 2 groups of patients, achievement of at least VGPR after induction was of major importance. This study is registered with EudraCT (https://eudract.ema.europa.eu; EUDRACT 2005-000537-38) and http://clinicaltrials.gov (NCT00200681).

Familial multiple myeloma: report of fifteen families

To further define the frequency, clinical and biological features of familial multiple myeloma we performed a retrospective study of related patients who presented with multiple myeloma. Most cases of familial multiple myeloma were observed in siblings (10/15), in whom the mean age at diagnosis was similar to unrelated multiple myeloma. In successive generations the mean age at diagnosis was lower. Monoclonal component was identical (IgG kappa) in seven families. Familial history of monoclonal gammopathy of undetermined significance was observed in three families. Five other prospective studies of 1263 patients identified four affected families (3.2 per 1000 cases of multiple myeloma), and raise the question of a genetic background in multiple myeloma.

Mature plasma cells as indicator of better prognosis in multiple myeloma. New methodology for the assessment of plasma cell morphology.

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Lack of Efficacy of 2-Chlorodeoxyadenoside in the Treatment of Splenic Lymphoma with Villous Lymphocytes

Splenic lymphoma with villous lymphocytes (SLVL) is a B-cell chronic lymphoproliferative disorder. Splenectomy and/or chlorambucil (CLB) are usually regarded as the most effective treatment in SLVL patients. However, a few patients relapse and the second line therapy remains questionable. Although 2-Cda has been evaluated in patients with chronic lymphoid leukemia (CLL) and hairy cell leukemia (HCL), it has been reported as the treatment of SLVL in only one case report. Therefore, we have evaluated its efficacy and toxicity in 7 SLVL patients. The median duration between diagnosis and treatment was 18 months (range, 1 to 59). The patients received 2-CdA (0.1 mg/kg/d) by venous infusion for 7 days with a median number of 1 cycle (range, 1 to 2) either as a first line therapy (one patient) or after a failure of other therapies (splenectomy, chemotherapy). Two patients achieved a complete response. The first one maintained his CR during a follow-up of 9 months and then relapsed; the second patient remained in CR after a follow-up of 20 months. Four patients achieved a partial response and relapsed after a median follow-up of 3.5 months (range, 1 to 4). One patient had no response. The treatment was not well tolerated with many infectious events. In the limits of our study, 2-Cda does not appear to be efficient therapy for SLVL and is not well tolerated for patients in relapse after splenectomy or resistant to CLB.

Analytical performance of the serum free light chain assay

Abstract Background: The Freelite™ system for nephelometric or turbidimetric measurement of serum free light chains (FLCs) has been available since 2001. It has been valuable for the management of patients with oligosecretory myeloma, light chain myeloma and AL amyloidosis. However, there are several limitations of the method. The goal of this study was to evaluate the analytical performance of the FLC assay. Methods: Titrated controls and clinical serum specimens were used to determine precision and post-dilution recovery. Results: As reported elsewhere, we found that the assay had several limitations, including poor post-dilution linearity and overestimation by nephelometry. Conclusions: These data demonstrate that the results of the FLC assay must be interpreted jointly by the clinician and the biologist, taking into account the individual patients clinical and biological characteristics. Clin Chem Lab Med 2010;48:73–9.

Systemic manifestations of monoclonal gammopathy

Systemic manifestations of monoclonal gammopathies (MG) are rare but extremely varied. This general review focuses on the hyperviscosity syndrome, neurological disorders, skin changes, the POEMS syndrome, and biological manifestations, with the exception of amyloidosis AL and cryoglobulinemia. The hyperviscosity syndrome usually involves a combination of general, hemorrhagic, ocular and central neurological disorders. The principal neurological manifestations are peripheral neuropathies, mainly due to IgM with anti-MAG activity. Skin disorders include overload dermatoses (xanthomatosis, mucinosis), neutrophilic dermatosis, urticaria, edema and the AESOP syndrome. The POEMS syndrome classically consists of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmocyte proliferation, and cutaneous manifestations. MG interference with assay methods can lead to false hyponatremia, hypoglycemia, hyperbilirubinemia, hypercalcemia and hypertransferrinemia. These systemic manifestations can reveal classical MG-related disorders such as monoclonal gammopathy of undetermined significance (MGUS), solitary plasmocytoma, multiple myeloma, and Waldenstroms disease. They are due either to the chemicophysical properties of the monoclonal immunoglobulin, or to its antibody activity (especially against autoantigens), with potential therapeutic implications.

Systemic lupus erythematosus and vaccination.

Patients with systemic lupus erythematosus (SLE) are frequently immunodepressed making them more vulnerable to infections. Preventive vaccination is therefore warranted but has often been withheld owing to fears of a link between infection and autoimmunity, and the possibility of inducing or exacerbating lupus after vaccination. The data published in the literature suggest that vaccination of lupus patient is safe, except for live vaccines. Their efficacy is lower than in healthy subjects but protection seems to be sufficient. But further large-scale studies are required to confirm these statements.

Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis

Mastocytosis (M) is a clonal myeloid-disabling disorder for which no curative therapy is currently available. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic purine analog cytoreductive treatment, for which efficacy is mostly reported in advanced M. Here we report, with a long-term follow-up period (>10 years) efficacy and safety in 68 adult patients with M (36 [53%] had indolent M and 32 [47%] had advanced M) treated by 2-CdA (0.14 mg/kg in infusion or subcutaneously, days 1-5; repeated at 4-12 weeks until 1 to 9 courses). Median 2-CdA courses number was 3.7 (1-9). The overall response rate was 72% (complete remission [R]/major/partial R: 0%/47%/25%) and according to indolent/advanced M was 92% (major/partial R: 56%/36%) and 50% (major/partial R: 37.5%/12.5%), respectively. Clinical improvement was observed for 10 of 11 mediator release and 6 of 7 mast cell infiltration-related symptoms including urticaria pigmentosa and organomegaly (P < .02). Serum tryptase levels decreased (P = .01). Median durations of response were 3.71 (0.1-8) and 2.47 (0.5-8.6) years for indolent and aggressive M, respectively. The most frequent grade 3/4 toxicities were lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%). 2-CdA appears to provide a significant efficacy with some toxicity in various M subtypes, mostly in indolent M, refractory to multiple symptomatic therapies.