Faculty Bibliography

Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility.

PURPOSE/OBJECTIVE:To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. METHODS:A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. RESULTS:Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. CONCLUSION/CONCLUSIONS:These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.

Since the mid-1990s, the multiple myeloma treatment landscape has evolved considerably, which has led to improved patient outcomes and prolonged survival. In addition to discovering new, targeted agents or treatment regimens, the identification and validation of biomarkers has the potential to further improve patient outcomes. The International Staging System relies on a number of biochemical parameters to stratify patients into risk categories. Other biologically relevant markers that are indicative of inherited genetic variation (e.g., single-nucleotide polymorphisms) or tumor-acquired genetic events (e.g., chromosomal translocations or mutations) have been studied for their prognostic potential. In patients with high-risk cytogenetics, plasma cells (PC) undergo genetic shifts over time, which may partially explain why high-risk patients relapse and are so difficult to treat. Although novel agents have improved treatment outcomes, identification of markers that will enable clinicians to determine which treatment is most appropriate for high-risk patients following initial diagnosis represents an exciting frontier in the clinical management of multiple myeloma. Biomarkers based on quantitating PCs or factors that are secreted from them (e.g., serum free light chain) may also help to risk-stratify patients with asymptomatic multiple myeloma. Eventually, identification of novel biomarkers may lead to the creation of personalized treatment regimens that are optimized to target clonal PCs that express a specific oncogenomic profile. Although the future is exciting, validation will be necessary before these biologic and molecular beacons can inform decision-making processes in a routine clinical setting.

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

BACKGROUND:VSLI (Marqibo) is active in advanced non-Hodgkin lymphoma (NHL) and untreated aggressive NHL. Because of its favorable hematologic toxicity profile, VSLI might be useful in patients unable to tolerate myelosuppressive therapies. PATIENTS AND METHODS/METHODS:Twenty-two patients with heavily pretreated, advanced CD20(+) DLBCL or MCL were treated with VSLI 2.0 mg/m(2), without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m(2). ORR, complete response (CR), or partial response (PR), was the primary end point. Secondary end points included response duration, time to progression (TTP), and OS. Safety variables included adverse events and neurologic assessments. RESULTS:The ORR was 13 of 22 (59%); 6 patients achieved a CR (27%), and 7 patients achieved a PR (32%). Median response duration, TTP, and OS were 147 days, 121 days, and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. Grade 3 peripheral neuropathy, febrile neutropenia, and constipation were reported in 4, 2, and 1 patients, respectively. CONCLUSION/CONCLUSIONS:VSLI plus rituximab resulted in durable responses in patients with heavily pretreated advanced stage DLBCL and MCL. The toxicity profile was predictable and manageable with limited hematologic toxicity. Despite near-universal previous VCR exposure (96%) and doses of VSLI unachievable with standard VCR treatment, peripheral neuropathy and constipation were modest. This study supports further evaluation of VSLI as a component of DLBCL management.

Bendamustine is a unique bifunctional alkylating agent with promising activity in myeloma. Despite the increasing number of studies demonstrating its efficacy in both the upfront and relapse settings, including patients with renal insufficiency, the optimal use of bendamustine, in terms of dosage, schedule and combination with other agents, has yet to be defined. It is currently licensed for use as frontline treatment with prednisolone for patients with myeloma who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib. Studies in relapsed/refractory patients are currently ongoing with other combinations. Given the increasing data to date, the UK Myeloma Forum believes that bendamustine with steroids alone or in combination with a novel agent could be considered for patients with multiply relapsed myeloma. This document provides guidance for the use of bendamustine for patients with myeloma until the results of definitive studies are available.

The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.

The 14th International Myeloma Workshop Kyoto, Japan, 3-7 April 2013 The International Myeloma Workshop (IMW) is a biannual meeting that gathers experts in multiple myeloma (MM) from all over the world and scientists interested in clinical and biological aspects of myeloma. The 2013 IMW was held in Kyoto, Japan and presented an interesting program with an appealing section on newer imaging techniques as predictor of outcome in asymptomatic and symptomatic MM. During the meeting, the importance of newer functional imaging techniques as new ways of assessing bone disease and the extent of marrow infiltration by myeloma cells was highlighted. This short meeting report will provide a review of new and/or functional imaging techniques, such as magnetic resonance imaging (MRI), both axial and whole body (WB-MRI), dynamic contrast enhanced (DCE) MRI, diffusion weighted imaging (DWI) and PET integrated with computed tomography.