Tony Reiman

International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index

PURPOSE Emerging evidence suggests muscle depletion predicts survival of patients with cancer. PATIENTS AND METHODS At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models. RESULTS Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001). CONCLUSION CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Purpose: Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). Experimental Design: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively. Results: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05). Conclusion: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.

Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy Toxicity

Purpose: Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Experimental Design: Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Results: Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Conclusion: Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition.

Body composition in patients with non–small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis

BACKGROUND The prominent clinical feature of cachexia has traditionally been understood to be weight loss; however, in recognition of the potential for divergent behavior of muscle and adipose tissue, cachexia was recently defined as loss of muscle with or without loss of fat mass. Detailed assessments are required to verify body composition in patients with cancer cachexia. DESIGN We adopted a population-based approach to study body composition in patients with cancer, with the use of diagnostic computed tomography images acquired for cancer diagnosis and follow-up. A prospective cohort of 441 patients with non-small cell lung cancer, who were referred consecutively to a regional medical oncology service in Alberta, Canada, was evaluated. RESULTS At referral (median time to death: 265 d), mean body mass index (BMI; in kg/m(2)) was 24.9, with 47.4% of patients being overweight or obese. Only 7.5% overall were underweight as conventionally understood (BMI < 18.5). Analysis of computed tomography images showed extremely high heterogeneity of muscle mass within all strata of BMI. The overall prevalence of severe muscle depletion (sarcopenia) was 46.8% and was present in patients in all BMI categories. A much higher proportion of men (61%) than women (31%) met the criteria for sarcopenia. CONCLUSIONS Wasting of skeletal muscle is a prominent feature of patients with lung cancer, despite normal or heavy body weights. The significance of muscle wasting in normal-weight, overweight, and obese patients as a nutritional risk factor, as a prognostic factor, and as a predictor of cancer treatment toxicity is discussed in this article.

Randomized Controlled Trial of the Effects of Aerobic Exercise on Physical Functioning and Quality of Life in Lymphoma Patients

PURPOSE Lymphoma patients commonly experience declines in physical functioning and quality of life (QoL) that may be reversed with exercise training. PATIENTS AND METHODS We conducted a randomized controlled trial in Edmonton, Alberta, Canada, between 2005 and 2008 that stratified 122 lymphoma patients by major disease type and current treatment status and randomly assigned them to usual care (UC; n = 62) or 12 weeks of supervised aerobic exercise training (AET; n = 60). Our primary end point was patient-rated physical functioning assessed by the Trial Outcome Index-Anemia. Secondary end points were overall QoL, psychosocial functioning, cardiovascular fitness, and body composition. RESULTS Follow-up assessment for our primary end point was 96% (117 of 122) at postintervention and 90% (110 of 122) at 6-month follow-up. Median adherence to the supervised exercise program was 92%. At postintervention, AET was superior to UC for patient-rated physical functioning (mean group difference, +9.0; 95% CI, 2.0 to 16.0; P = .012), overall QoL (P = .021), fatigue (P = .013), happiness (P = .004), depression (P = .005), general health (P < .001), cardiovascular fitness (P < .001), and lean body mass (P = .008). Change in peak cardiovascular fitness mediated the change in patient-rated physical functioning. AET did not interfere with chemotherapy completion rate or treatment response. At 6-month follow-up, AET was still borderline or significantly superior to UC for overall QoL (P = .054), happiness (P = .034), and depression (P = .009) without an increased risk of disease recurrence/progression. CONCLUSION AET significantly improved important patient-rated outcomes and objective physical functioning in lymphoma patients without interfering with medical treatments or response. Exercise training to improve cardiovascular fitness should be considered in the management of lymphoma patients.

International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

PURPOSE The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis

Background: Erythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy. Methods: We conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups. Results: We identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25). Interpretation: Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.

Class III β-Tubulin Expression and Benefit from Adjuvant Cisplatin/Vinorelbine Chemotherapy in Operable Non–Small Cell Lung Cancer: Analysis of NCIC JBR.10

Purpose: High class III β-tubulin (bTubIII) expression in advanced non–small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non–small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial. Experimental Design: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII “low” or “high” using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups. Results: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance. Conclusions: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.

International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.