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Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer+ BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy. [ABSTRACT FROM AUTHOR]

CXCR4WHIM somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCRS338X mutation in WM. Following SDF-1a stimulation, CXCR4S338X WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4S338X-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4S338X WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4WT cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4S338X WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4WHIM versus CXCR4WT WM patients, and remained active despite ibrutinib therapy in CXCR4WHIM patients. Last, CXCR4S338X WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4WHIM mutations, and provide a framework for investigation of CXCR4 inhibitors in WM. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the examination of the presence of myelodysplastic syndrome (MDS)-associated phenotypic alterrations (MDS-PAs) in bone marrow (BM) samples from newly diagnosed patients referred immunophenotypic investigation of plasma cell (PC) neoplasia.

The article discusses the study on the serial exome analysis of disease progression in premalignant gammopathies. It notes the multiple myeloma (MM) characterized by progressive growth of malignant plasma cells where nearly all cases are preceded by asymptomatic monoclonal gammopathies (AMGs). The study involves whole-exome sequencing on tumor and germline DNA from 10 patients. It mentions that four of the patients progressed to clinical MM requiring therapy.

Radiological skeletal survey or computed tomography are currently applied to assess bone diseases in patients with monoclonal plasma cell disorders. Whole-body magnetic resonance imaging (whole-body MRI) allows detecting the infiltration of clonal cells in nearly the whole bone marrow compartment even before bone destruction has occurred. Those MRI results (i.e., patterns of bone marrow infiltration) have been demonstrated to be of prognostic significance in patients with symptomatic as well as asymptomatic multiple myeloma. We have therefore analyzed the findings of whole-body MRI in 137 consecutive individuals with monoclonal gammopathy of undetermined significance (MGUS). A focal infiltration pattern was detected in 23.4% of patients. Presence and number of focal lesions as well as value of M-Protein were of independent prognostic significance for progression into a symptomatic disease requiring systemic treatment (P=0.02; P<0.0001 and P=0.0005, respectively). Lower homogeneous signal intensities in T1-weighted images were related to a physiologically higher bone marrow cellularity in younger individuals (P=0.002). We conclude that whole-body MRI identifies patients with focal accumulations of presumably monoclonal cells in bone marrow with prognostic impact concerning the risk of progression into symptomatic disease. [ABSTRACT FROM AUTHOR]

To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene-expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL. [ABSTRACT FROM AUTHOR]

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit. [ABSTRACT FROM AUTHOR]

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months. [ABSTRACT FROM AUTHOR]

The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.Leukemia (2009) 23, 215–224; doi:10.1038/leu.2008.307; published online 20 November 2008 [ABSTRACT FROM AUTHOR]

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders. Leukemia (2008) 22, 1343–1353; doi:10.1038/leu.2008.123; published online 29 May 2008 [ABSTRACT FROM AUTHOR]

Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.Leukemia (2005) 19, 1729–1738. doi:10.1038/sj.leu.2403905; published online 11 August 2005 [ABSTRACT FROM AUTHOR]

We and others have shown that Mcl-1 was essential for the survival of human myeloma cells in vitro. Furthermore, this antiapoptotic protein is upregulated by interleukin-6, which plays a critical role in multiple myeloma (MM). For these reasons, we have evaluated the expression of Mcl-1 in vivo in normal, reactive and malignant plasma cells (PC), that is, myeloma cells from 51 patients with MM and 21 human myeloma cell lines (HMCL) using flow cytometry. We show that Mcl-1 is overexpressed in MM in comparison with normal bone marrow PC. In total, 52% of patients with MM at diagnosis (P=0.017) and 81% at relapse (P=0.014 for comparison with diagnosis) overexpress Mcl-1. Of note, only HMCL but not reactive plasmacytoses have abnormal Mcl-1 expression, although both PC expansions share similar high proliferation rates. Of interest, Bcl-2 as opposed to Mcl-1, does not discriminate malignant from normal PC. Finally, the level of Mcl-1 expression is related to disease severity, the highest values at diagnosis being associated with the shortest event-free survival (P=0.002). In conclusion, Mcl-1, which has been shown to be essential for the survival of human myeloma cells in vitro, is overexpressed in vivo in MM in relation with relapse and shorter survival. Mcl-1 represents a potential therapeutical target in MM.Leukemia (2005) 19, 1248–1252. doi:10.1038/sj.leu.2403784 Published online 5 May 2005 [ABSTRACT FROM AUTHOR]

Using a candidate gene approach, we analyzed the methylation status of the promoter-associated CpG islands of 11 well-characterized tumor suppressor genes by methylation-specific polymerase chain reaction in five multiple myeloma (MM) cell lines and 56 patients with malignant plasma cell disorders. The frequency of aberrant methylation among the patient samples was 46.4% for SOCS-1, 35.7% for p16, 214% for E-cadherin, 12.5% for DAP kinase and p73, 1.8% for p15, MGMT as well as RARβ, and 0% for TIMP-3, RASSF1A and hMLH1. We found at least one hypermethylated gene in 80.4% of the primary patient samples, while 33.9% harbored two or more hypermethylated genes. For the first time, we show that p73 may be hypermethylated in MM and thus be involved in the pathogenesis of plasma cell disorders. Hypermethylation of p16 at diagnosis was associated with a poorer prognosis. In patients with plasma cell leukemia, we found frequent simultaneous hypermethylation of p16, E-cadherin and DAP kinase. We conclude that aberrant methylation of tumor suppressor genes is a common event in malignant plasma cell disorders and that there is a correlation between methylation patterns and clinical characteristics in MM patients. [ABSTRACT FROM AUTHOR]

Primary light chain-associated amyloidosis (AL) is a plasma cell dyscrasia that causes morbidity via systemic tissue deposition of monoclonal light chains in the form of fibrils (amyloid). It is the most common form of systemic amyloidosis in Western countries and is rapidly fatal. Knowledge of the pathobiology of the underlying B cell clone is of primary importance for the design and optimization of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Recent studies have indicated a close relationship between inactivation of tumor suppressor genes (TSGs) and disease progression. The genes encoding the cyclin-dependent kinase inhibitors p16INK4A and p15INK4B are potent TSGs, and correlations between their inactivation and disease progression have also been reported in various malignancies. In this study, we analyzed the methylation status of p16INK4A and p15INK4B gene promoters in plasma cell dyscrasias (PCDs) by methylation-specific PCR (MSP). In analyses using DNAs extracted from bone marrow mononuclear cells (BM-MNCs), patients with multiple myeloma (MM) showed frequent hypermethylation of the p16INK4A gene (15/37, 41%), whereas p15INK4B gene methylation was not so frequent (5/37, 14%). Many patients whose BM-MNC showed dense methylation of the p16INK4A gene had extramedullary plasmacytoma (extra-PC), and all available extra-PC samples showed alterations of the p16INK4A gene (4; dense methylation, 1; homozygous deletion). In contrast to MM, hypermethylation of the p16INK4A gene was significantly infrequent in indolent PCDs (2/22, 9%, P= 0.0055). The infrequency in indolent PCDs was also confirmed by analyses using DNAs extracted from BM smears (1/29, 3%). It is possible that hypermethylation of the p16INK4A gene promoter contributes to progression to aggressive MM from indolent PCD, especially to extra-PC development. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including plasma cell disease, heavy or light chain (HLC) assays and immunoglobulin quantitation.