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

Update in the multiple myeloma treatment guideline 2018

Recently the guideline ‘Treatment multiple myeloma 2018’ was published. Below are the most important changes from the 2015 guideline. These changes concern the initial treatment of patients eligible for autologous stem cell transplantation, the initial treatment of patients who are not eligible for autologous stem cell transplantation and the patients with a relapse of the sickness. The changes are based on new clinical data that have become available from randomized phase 3 trials. The most recent version of the entire guideline can be found on the websites of both the NVvH and HOVON. The guideline will be adjusted per module. The expectation is that this will already happen in the coming months as several treatment combinations will be registered and hopefully also be available in the short term. This summary concerns patients who cannot be treated in a trial context. At all times treatment within a study context is preferable

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers