Adam J. Waxman

Racial disparities in incidence and outcome in multiple myeloma: a population-based study

Multiple myeloma (MM) is the most common hematologic malignancy in blacks. Some prior studies suggest inferior survival in blacks; others suggest similar survival. Using the original 9 Surveillance, Epidemiology, and End Results registries, we conducted a large-scale population-based study including 5798 black and 28 939 white MM patients diagnosed 1973-2005, followed through 2006. Age-adjusted incidence rates, disease-specific survival, and relative survival rates were calculated by race, age, and time period of diagnosis. Mean age at diagnosis was 65.8 and 69.8 years for blacks and whites, respectively (P < .001). Incidence among blacks was m twice that among whites; this disparity was greater among patients < 50 years (P = .002). Over the entire study period, disease-specific and relative survival rates were higher in blacks than whites (P < .001). For whites, 5-year relative survival rates increased significantly 1973-1993 to 1994-1998 (26.3% to 30.8%; P < .001) and 1994-1998 to 1999-2005 (30.8% to 35.0%; P = .004). Survival improvements among blacks were smaller and nonsignificant (1973-1993 to 1999-2005: 31.0% to 34.1%; P = .07). We found (1) a younger age of onset among blacks; (2) better survival in blacks 1973-2005; and (3) significant survival improvement among whites over time, with smaller, nonsignificant change seen among blacks, possibly due to unequal access to and/or disparate responsiveness to novel therapies.

Multiple Myeloma Precursor Disease

Recent data indicate that multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma. Currently, multiple myeloma is a clinical diagnosis based on manifestations including hypercalcemia, renal failure, anemia, and bone lesions, whereas MGUS and smoldering myeloma are diagnosed based on laboratory abnormalities. Current clinical markers allow for more individualized risk stratification and counseling of these patients. However, there is a dearth of biomarkers and molecular imaging techniques capable of (1) accurately identifying patients with disease biology corresponding with high risk of progression; (2) elucidating the mechanism of transformation to multiple myeloma; and (3) forming a framework for development of targeted therapies. This case presentation and review discusses the current understanding of myeloma precursor disease and future opportunities for improving personalized management of patients with MGUS or smoldering myeloma, as well as the potential for developing early treatment strategies designed to delay and prevent development of multiple myeloma.

Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future.

Recent studies show that multiple myeloma (MM) is consistently preceded by an asymptomatic precursor state. Smoldering MM (SMM) is a MM precursor defined by an M-protein concentration >or= 3 g/dL and/or >or= 10% bone marrow plasma cells, in the absence of end-organ damage. Compared with individuals diagnosed with monoclonal gammopathy of undetermined significance (MGUS), patients with SMM have a much higher annual risk of developing MM. However, based on clinical observations, the natural history of SMM varies greatly, from stable MGUS-like disease to highly progressive disease. Using conventional clinical markers, SMM patients can be stratified into 3 risk groups. Importantly, because of considerable molecular heterogeneity, we currently lack reliable markers to predict prognosis for individual SMM patients. Furthermore, until recently, potent drugs with reasonable toxicity profiles have not been available for the development of early MM treatment strategies. Consequently, current clinical guidelines emphasize the application of close clinical monitoring followed by treatment when the patient develops symptomatic MM. This review focuses on novel biomarkers, molecular profiles, and microenvironmental interactions of interest in myelomagenesis. We also discuss how the integration of novel biologic markers and clinical monitoring of SMM could facilitate the development of early treatment strategies for high-risk SMM patients in the future.

Classifying ultra-high risk smoldering myeloma.

Multiple myeloma (MM) always evolves from a precursor state, either monoclonal gammopathy of undetermined significance or smoldering MM (SMM).1, 2 These precursor states are defined by the absence of MM-related organ damage (‘CRAB’ features: hypercalcemia, renal failure, anemia and bone disease).3 SMM has a highly variable clinical behavior, where some patients have an imminent risk of developing CRAB features and others have a substantially lower risk.4, 5 A recent study has demonstrated that the treatment of high-risk SMM patients with lenalidomide and dexamethasone resulted in fewer CRAB events and improved the overall survival.6 This provocative study suggests that treatment of high-risk SMM may be beneficial. However, identifying patients at ultra-high risk of progression (>80% at 2 years) has proven difficult.7 Both the Mayo Clinic and PETHEMA models fail to define such a high-risk group.4, 5, 8 Furthermore, the PETHEMA model employs a flow cytometry technique, which is not widely available or validated. Genomic approaches have also failed to identify ultra-high risk groups.9, 10, 11 Notably, a recent small study highlighted a fair degree of discordance among these models in SMM.12 Bone marrow plasma cell (BMPC) infiltration of 60% in SMM patients is associated with a 95% risk of developing MM within 2 years.13 A major limitation remains that these models have not been validated in other populations.

Proteasome inhibitor associated thrombotic microangiopathy

A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug‐induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin—7.5 g dL−1, platelet count—20 × 109/L, LDH—698 U L−1, creatinine—3.12 mg dL−1. No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348–E352, 2016.

Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis

Importance Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE. Objective To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies. Data Sources PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171” through January 1, 2017. Study Selection Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis. Data Extraction and Synthesis Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE. Main Outcomes and Measures Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded. Results A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively. Conclusions and Relevance Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

High prevalence of polyclonal hypergamma-globulinemia in adult males in Ghana, Africa†‡

Chronic antigenic stimulation is associated with hypergamma‐globulinemia. Higher rates of hypergamma‐globulinemia in tropical populations are maintained even with migration to temperate regions. We conducted a population‐based screening study to assess the prevalence and risk factors for hypergamma‐globulinemia in Ghana, Africa. 917 Ghanaian males (50–74 years) underwent in‐person interviews and health examinations. Serum from all persons was analyzed by electrophoresis performed on agarose gel; serum with a discrete/localized band was subjected to immunofixation. 54 persons with monoclonal proteins were excluded and 17 samples were insufficient for analysis. Using logistic regression and Chi‐square statistics we analyzed patterns of hypergamma‐globulinemia. Among 846 study subjects, the median γ‐globulin level was 1.86 g/dL. On the basis of a U.S. reference, 616 (73%) had hypergamma‐globulinemia (>1.6 g/dL) and 178 (21%) had γ‐globulin levels >2.17 gm/dl. On multivariate analyses, lower education status (P = 0.0013) and never smoking (P = 0.038) were associated with increased γ‐globulin levels. Self‐reported history of syphilis was associated with hypergamma‐globulinemia. We conclude that three quarters of this population‐based adult Ghanaian male sample had hypergamma‐globulinemia with γ‐globulin levels >1.6 g/dL. Future studies are needed to uncover genetic and environmental underpinnings of our finding, and to define the relationship between hypergamma‐globulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma. Am. J. Hematol., 2011.

Racial disparities in incidence and survival among 37,977 blacks and whites with multiple myeloma.

8115 Background: Multiple myeloma (MM) is the most common hematologic malignancy in blacks. Prior studies suggest poorer survival among blacks than whites; however, some smaller hospital-based studies suggest similar survival in equal access health systems. We conducted a large-scale, population-based study to evaluate racial disparities in MM incidence and MM-specific survival. Methods: Data were obtained from the National Cancer Institutes Surveillance, Epidemiology and End Results-9 Registry, covering new diagnoses of MM from 1973-2005 with follow-up through 2006. Age at diagnosis was grouped into three strata (<50, 50-69, and 70+ years). Incidence rates were calculated using SEER*Stat. Cumulative MM-specific survival was assessed by the Kaplan-Meier method and the log-rank test. Results: 37,977 MM patients (5,798 blacks; 28,939 whites) were identified. Mean age at diagnosis was 65.7 years for blacks and 70.0 years for whites (p<0.001). Incidence was 2-fold higher in blacks than whites (10.9 and 4.9 p...

A Case Study Progression to Multiple Myeloma

Multiple myeloma consistently is preceded by precursor states, which often are diagnosed incidentally in the laboratory. This case report illustrates the clinical dilemma of progression from precursor to full malignancy. The article also discusses future directions in management and research focusing on myelomagenesis.