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The diagnosis and treatment of multiple myeloma has changed dramatically in the past decade. The disease definition has been updated to include highly specific biomarkers in addition to established markers of end-organ damage. The staging system has been revised to combine both measures of tumor burden and disease biology. Advances in therapy have resulted in a marked improvement in overall survival. New drugs introduced in the past few years include carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab. In this review, we outline the current approach to the diagnosis, prognosis, and management of multiple myeloma.

MGUS affects more than 5% of persons older than 70 years and shortens survival, as compared with age-matched controls. In a long-term study involving more than 1000 patients, those with IgM MGUS had a higher rate of progression to B-cell cancer than those with IgG MGUS.

Light chain cast nephropathy (LCCN) is a leading cause of acute kidney injury (AKI) in patients with multiple myeloma (MM) and is now defined as a myeloma defining event. While the long-term prognosis has improved with novel agents, short-term mortality remains significantly higher in patients with LCCN especially if the renal failure is not reversed. Recovery of renal function requires a rapid and significant reduction of the involved serum free light chain. Therefore, proper treatment of these patients is of the utmost importance. In this paper, we provide an algorithm for treatment of MM patients who present with biopsy-proven LCCN or in those where other causes of AKI have been ruled out. The algorithm is based on data from randomized trial whenever possible. When trial data is not available, our recommendations is based on non-randomized data and expert opinions on best practices. We recommend that all patients should enroll in a clinical trial if available prior to resorting to the treatment algorithm we outlined.

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. The mechanisms through which gut microbiota affect extramucosal tumors are poorly understood. Here the authors show that the gut microbiota promotes multiple myeloma by inducing differentiation and migration of Th17 cells in the bone marrow resulting also in increased recruitment of pro-tumorigenic eosinophils.

High cancer drug prices are a worsening trend in cancer care and are affecting patient care and our health care system. In the United States, the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000 to more than $100,000 by 2012, while the average household income has decreased by about 8% in the past decade. Further, although 85% of cancer basic research is funded through taxpayers’ money, Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries. Bound by the Hippocratic Oath, oncologists have a moral obligation to advocate for affordable cancer drugs. In this article, we discuss the high cost of cancer drugs, the reasons for these high prices, the implications for patients and the health care system, and potential solutions to the problem.

Monoclonal gammopathies comprise a spectrum of clonal plasma cell disorders that include monoclonal gammopathy of undetermined significance, multiple myeloma, and Waldenström macroglobulinemia. In this review, we outline the epidemiology, etiology, classification, diagnosis, and treatment of monoclonal gammopathy–associated peripheral neuropathy. Monoclonal gammopathy of undetermined significance is relatively common in the general population, with a prevalence of 3% to 4% among individuals older than age 50 years. Therefore, the presence of M protein in a patient with neuropathy does not automatically indicate a causal relationship. Monoclonal gammopathy–associated peripheral neuropathy is often a difficult diagnosis with limited treatment options. Studies addressing the optimal approach to diagnosis and management of this entity are limited. In addition to a review of the literature, we present a diagnostic approach to patients with monoclonal gammopathy–associated peripheral neuropathy and discuss available data and options for treatment.

Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.

Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant. In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 × 103 cells per mm3 or higher, and a platelet count of 80 000/mm3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1·3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1–14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1–21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one-sided stratified log rank test at a significance level of 0·02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228. Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0·712, 96% CI 0·56–0·906; one-sided p value 0·0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0·709, 95% CI 0·524–0·959; two-sided p value 0·025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group. In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile. NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.