Molecular profiling in multiple myeloma

Multiple Myeloma (MM) is a malignant plasma cell disorder accounting for 1% of all malignant diseases and 10% of hematological malignancies. The annual incidence world-wide of MM is approximately 0.4 to 5 per 100.000, with high incidence rates in North America, Australia/New Zealand, Northern Europe, and Western Europe compared with Asian countries. Within the United States, the incidence in African Americans is about double that in Caucasians, whereas persons of Japanese and Chinese origin have lower rates. In the Netherlands the annual incidence of MM is 5 per 100.000 and increases progressively with age, the median age of diagnosis is 70 years. MM is characterized by clonal expansion of malignant plasma cells in the bone marrow. The myeloma plasma cell is a post-germinal centre plasma cell which has undergone somatic hypermutation and immunoglobulin class switching. MM cells secrete a monoclonal protein (M-protein) which can be detected in serum and/or urine. The M-protein is IgG in 50% of patients, and IgA in 30% of patients or consists of light chain (15%). In rare cases, secretion of IgD (1%–2%), IgM (0.2%), or IgE (even less frequent), or absence of secretion (non-secretory MM) is found. Osteolytic bone lesions are the hallmark of MM. Other characteristic clinical features include renal injury, anemia, hypercalcemia and immunodeficiency with recurrent infections. These features may result directly from mass accumulation of plasma cells in tissues (plasmacytomas) or indirectly from effects of the M-protein and/or cytokines secreted by the plasma cells. Furthermore a high level of M-protein can cause hyperviscosity, renal failure and neuropathy

A gene expression based predictor for high risk myeloma treated with intensive therapy and autologous stem cell rescue

Myeloma is characterized by a highly variable clinical outcome. Despite the effectiveness of high-dose therapy, 15% of patients relapse within 1 year. We show that these cases also have a significantly shorter post-relapse survival compared to the others (median 14.9 months vs. 40 months, p = 8.03 × 10(- 14)). There are no effective approaches to define this potentially distinct biological group such that treatment could be altered. In this work a series of uniformly treated patients with myeloma were used to develop a gene expression profiling (GEP)-based signature to identify this high risk clinical behavior. Gene enrichment analyses applied to the top differentially expressed genes showed a significant enrichment of epigenetic regulators as well as "stem cell" myeloma genes. A derived 17-gene signature effectively identifies patients at high risk of early relapse as well as impaired overall survival. Integrative genomic analyses showed that epigenetic mechanisms may play an important role on transcription of these genes

Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

This is a phase II dose escalation trial of carfilzomib in combination with thalidomide and dexamethasone for induction and consolidation in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The results of four dose levels are reported. Induction therapy consisted of four cycles of carfilzomib 20/27 mg/m2 (n=50), 20/36 mg/m2 (n=20), 20/45 mg/m2 (n=21), and 20/56 mg/m2 (n=20) on days 1, 2, 8, 9, 15, 16 of a 28-day cycle; thalidomide 200 mg on day 1 through 28 and dexamethasone 40 mg weekly. Induction therapy was followed by high-dose melphalan and autologous stem cell transplantation and consolidation therapy with four cycles of carfilzomib, thalidomide and dexamethasone in the same schedule except a lower dose of thalidomide (50 mg). Very good partial response rate or better and complete response rate or better after ind