Does my patient with a serum monoclonal spike have multiple myeloma?

A monoclonal spike on serum protein electrophoresis is a frequent finding in the general population and pathognomonic of a plasma cell dyscrasia. In otherwise healthy individuals, it is diagnostic of two asymptomatic, premalignant conditions called monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) which carry a lifelong risk of progression to multiple myeloma (MM) or related malignancy. This article discusses the criteria for diagnosis of MGUS, SMM, and MM; current recommendations for follow-up and risk factors for progression to MM of patients with MGUS and SMM; and diagnostic evaluation of suspected MM transformation.

Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features.

The spread of multiple myeloma (MM) involves (re)circulation into the peripheral blood and (re)entrance or homing of MM cells into new sites of the BM. Hypoxia in solid tumors was shown to promote metastasis through activation of proteins involved in the epithelial-mesenchymal transition (EMT) process. We hypothesized that MM-associated hypoxic conditions activate EMT-related proteins and promote metastasis of MM cells.

Cell Trafficking in Multiple Myeloma.

Multiple myeloma (MM) is an incurable cancer of terminally differentiated plasma cells (PC) and represents the second most frequent hematologic malignancy in the western world. MM cells localize preferentially to the bone marrow where they interact closely with bone marrow stroma cells (BMSC) and extracellular matrix (ECM) proteins in a reciprocal pro-survival loop. Such a bone marrow niche guarantees a survival advantage for MM cells and has a crucial role in mediating drug resistance to chemotherapy agents.

The potential benefits of participating in early-phase clinical trials in multiple myeloma: long-term remission in a patient with relapsed multiple myeloma treated with 90 cycles of lenalidomide and bortezomib.

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year.

Management of myeloma-associated renal dysfunction in the era of novel therapies.

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM.

Tackling the readmission epidemic: a resident teaching service perspective.

Background: Readmission rates are projected to serve as quality measures that have the potential to negatively impact hospital and physician reimbursement. Individual physicians and hospitals are developing plans to reduce readmission rates. Successful plans should be based on specific data obtained from each individual type of practice.

Meningitis retention syndrome.

A 50-year-old Caucasian woman presented with signs and symptoms of meningitis preceded by a 3 day history of flu-like symptoms and progressive difficulty with urination. Cerebrospinal Fluid (CSF) analysis was consistent with aseptic meningitis. She was found to have a significant urinary retention secondary to atonic bladder.

Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib.

Drug resistance is a growing area of concern. It has been shown that a small, residual pool of leukemic CD34+ progenitor cells can survive in the marrow microenvironment of chronic myeloid leukemia (CML) patients after years of kinase inhibitor treatment. Bone marrow (BM) stroma has been implicated in the long-term survival of leukemic cells, and contributes to the expansion and proliferation of both transformed and normal hematopoietic cells.

Serum galactomannan and (1->3)-β-D-glucan assays for patients with multiple myeloma and Waldenstrom's macroglobulinemia.

We assessed the performance of galactomannan and (1→3)-β-d-glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1→3)-β-d-glucan assays were not falsely elevated in any patient. (1→3)-β-d-glucan assay results were uninterpretable in 24% of patients.

Epigenetics in Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow and a serum monoclonal immunoglobulin, known as IgM, in the circulation. Although indolent, it remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. Cytogenetic and molecular studies on gene-expression analysis at the mRNA level have demonstrated minimal changes in WM cells.

Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects.

Hematologic malignancies rely heavily on support from host cells through a number of well-documented mechanisms. Host cells, specifically mesenchymal stem cells (MSC), support tumor cell growth, metastasis, survival, bone marrow colonization, and evasion of the immune system. In multiple myeloma, similar to solid tumors, supporting cells have typically been considered healthy host cells.

Targeting the bone marrow in Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by widespread involvement of the bone marrow with lymphoplasmacytic cells. In approximately 20% of patients, the malignant clone also involves the lymph nodes and induces hepatosplenomegaly. The mechanisms by which the tumor cells home to the bone marrow and preferentially reside in the marrow niches are not fully elucidated.

Defining the role of TORC1/2 in multiple myeloma.

Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment to regulate multiple cellular processes. Rapamycin and its analogs have not shown significant activity in multiple myeloma (MM), likely because of the lack of inhibition of TORC2. In the present study, we investigated the baseline activity of the PI3K/Akt/mTOR pathway TORC1/2 in MM cell lines with different genetic abnormalities.

Novel agents in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow with lymphoplasmacytic cells and the detection of an IgM monoclonal gammopathy in the serum. WM is considered an incurable disease, with a median overall survival of 87 months. The success of targeted therapy in multiple myeloma has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias, including WM, both in the preclinical settings and as part of clinical trials.

The Medical Research Council Myeloma IX trial: the impact on treatment paradigms.

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs.

Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.

Purpose: Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM.

Management of relapsed and relapsed/refractory multiple myeloma.

Despite significant progress in the treatment of multiple myeloma (MM) over the past decade, this disease remains incurable and almost all patients ultimately experience relapse and become refractory to treatment over time. However, the outlook for patients with relapsed MM has improved markedly with the use of the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Moreover, the development of new drug classes based on preclinical rationale and the introduction of next-generation agents is likely to further expand treatment options and improve outcomes for relapsed MM.

Anti-angiogenic therapies in the treatment of Waldenstrom's Macroglobulinemia.

Bone marrow microenvironment has been shown to play a crucial role in supporting the pathogenesis and the progression of several B-cell malignancies, including Waldenstrom's Macroglobulinemia (WM). Among the different cell types within the bone marrow milieu, endothelial cells have been proven to support WM cells growth. Based on the understanding of bone marrow neo-angiogenesis in plasma cell dyscrasias, a number of anti-angiogenic molecules are now available for the treatment of these diseases.

BET bromodomain inhibition as a therapeutic strategy to target c-Myc.

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc.

The bone marrow microenvironment in waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a low-grade B-cell lymphoproliferative disorder characterized primarily by specific homing and growth of tumor cells within the bone marrow niches. The progressive growth of tumor cells throughout the bone marrow indicates that the tumor cells are capable of homing and adhering to specific niches that allow growth, survival and drug resistance. In this review we highlight the interaction of the tumor cells in WM and the bone marrow microenvironment including bone marrow stromal cells, endothelial cells and mast cells.

Managing multiple myeloma: the emerging role of novel therapies and adapting combination treatment for higher risk settings.

Novel therapies have transformed the treatment paradigm for multiple myeloma with significant improvements in survival now seen in both younger and older patients. Nonetheless, the disease is heterogeneous and high-risk patients in particular continue to have poor outcome. Moreover, the disease remains incurable.