Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma.

BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

[Pomalidomide for multiple myeloma]. / Le pomalidomide dans le myélome multiple.

Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of "novel agents": proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This review focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy.

[Monoclonal gammopathies of undetermined significance do not systematically require a specialized consultation]. / Les gammapathies monoclonales de signification indéterminée ne nécessitent pas systématiquement un recours à une consultation spécialisée.

INTRODUCTION: Monoclonal gammopathy of undetermined significance (MGUS) is a frequent entity in the general population. The incidence rate of fortuitous discovery of a monoclonal component in asymptomatic patients is increasing nowadays. The majority of MGUS is being addressed to a hematologist for diagnosis or follow-up by their generalist practitioners. The management of MGUS consists of a clinical and biological surveillance as per published and validated international guidelines available for MGUS diagnosis and follow-up. MGUS thus may not necessarily need a specialized consultation and follow-up in a hematology ward, as we believe it could be performed by generalist practitioners. METHODS: We studied 190 patients addressed to our hematology department of Lille for diagnosis or follow-up of MGUS. RESULTS: Among the patients, 9.5% developed a malignant hemopathy (multiple myeloma or Waldenström macroglobulinemia). Among patients diagnosed with MGUS of IgG isotype and a monoclonal component <15 g/L, 96.2% showed no pejorative outcome: these represent simple and routine prognostic factors that can be assessed at diagnosis in order to predict the risk of progression. Those patients could have easily been followed by their generalist practitioner from the diagnosis of MGUS. CONCLUSION: A specialist's consultation would still be recommended for patients with pejorative factors at diagnosis, or if a clinical or biological event that could suggest progression occurs during follow-up, or in case of MGUS with complication, in which cases patients would need a specialized management in a hematology department.

[Smoldering multiple myeloma]. / Myélome multiple indolent.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell neoplasia, characterized by monoclonal plasma cell proliferation in the absence of end-organ damage, but with a high risk of progression to multiple myeloma. It has therefore to be distinguished from monoclonal gammapathy of undetermined significance (MGUS), which has a much lower risk of progression, but also from multiple myeloma, which remains an incurable disease and requires a specific treatment. The critical question in the management of SMM is whether an early therapeutic strategy could help delaying the progression to multiple myeloma, in order to lower the risk of serious complications related to this progression, or even to cure the disease. This early treatment could not be proposed to all SMM patients, who are indeed asymptomatic, and in whom the risk of toxicity could make it difficult to justify the potential benefit obtained. The challenge is to target early at diagnosis SMM patients with a high risk of progression, using available routine tests sufficiently reliable to warrant the therapeutic sanction which relies on it. Today however, apart from randomized studies, recommendations are to maintain therapeutic abstention in SMM patients.

Effect of streptozotocin-induced diabetes mellitus on release of vasoactive intestinal polypeptide from rodent small intestine.

Representative longitudinal muscle strips (6 x 10 mm) from proximal and distal small intestine were excised from control and streptozotocin-treated rats after one month of untreated and insulin-treated diabetes. Untreated diabetes significantly reduced tissue concentrations of vasoactive intestinal polypeptide (VIP) at both intestinal loci. Insulin treatment of the diabetic animals restored tissue VIP concentrations to control group levels, although the beneficial effect of insulin treatment was only significant in the duodenum. Spontaneous release of VIP was significantly attenuated by untreated diabetes at both intestinal sites. In the duodenum, insulin treatment of the diabetic animals restored VIP release to levels indistinguishable from control group values. In the ileum, insulin treatment produced levels of VIP release that were not significantly different from those of the control and untreated diabetic groups. Tetrodotoxin (5 x 10(-6) M) significantly--but incompletely--inhibited VIP release from control group animals at both intestinal sites. These observations indicate that diabetes mellitus significantly diminishes VIP tissue concentrations and release from intestinal myenteric nerves. These abnormalities improve with insulin treatment. However, the mechanisms of VIP release from proximal and distal intestine appear to differ not only in their response to the diabetic state, but also in their response to insulin treatment.