First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium.

Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.

Renal failure among multiple myeloma patients utilizing carfilzomib and associated factors in the "real world".

Carfilzomib, a next-generation proteasome inhibitor, improves outcomes in patients with multiple myeloma (MM); however, a proportion of those treated develop renal failure due to adverse event, comorbidity, or myeloma progression. The rate of renal failure and associated risk factors remains unknown in real-world populations. Adults with relapsed/refractory MM who received carfilzomib between the years 2013 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Renal failure was defined using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes and procedure codes for dialysis. Patients with a pre-existing diagnosis of renal failure were excluded to distinguish an adverse event from comorbidity. Multivariate cox regression analysis was performed to identify the variables independently associated with the development of renal failure among MM patients utilizing carfilzomib. A total of 1950 patients were included in the analysis. Renal failure developed in 22% of patients during the study period. The median time to development of renal failure from first carfilzomib administration was 1.6 months (range < 0.1-23.3). Increasing age (adjusted hazard ratio [aHR] 1.01 per year, p = 0.018), pre-existing heart failure (aHR 1.50, p = 0.005), and pre-existing chronic kidney disease (aHR 2.00, p < 0.001) were associated with a higher risk of developing renal failure. Renal failure occurred in up to 22% of patients on carfilzomib therapy. The exact cause and mechanism of renal failure cannot be determined from our study and may be multifactorial. Future studies are needed to further understand the cause of renal failure among patients on carfilzomib and devise strategies to mitigate the risk.

Symptom burden in transplant ineligible patients with newly diagnosed multiple myeloma: a population-based cohort study.

Not available.

Transplant-ineligible newly diagnosed multiple myeloma: Current and future approaches to clinical care: A Young International Society of Geriatric Oncology Review Paper.

Multiple myeloma is the second most common hematological malignancy in the USA and Europe. Despite improvements in the 5-year and overall survival rates over the past decade, older adults (aged ≥65 years) with multiple myeloma continue to experience disproportionately worse outcomes than their younger counterparts. These differences in outcomes arise from the increased prevalence of vulnerabilities such as medical comorbidities and frailty seen with advancing age that can influence treatment-delivery and tolerance and impact survival. In general, geriatric assessments can help identify those patients more likely to benefit from enhanced toxicity risk-prediction and aid treatment decision-making. Despite the observed benefits of geriatric assessments and other screening frailty tools, provider and systems-level barriers continue to influence the overall perception of the feasibility of geriatric assessments in clinical practice settings. Clinical trials are underway evaluating the efficacy and safety of various multiple myeloma therapies in less fit/frail older adults, with a minority examining fitness-based/risk-adapted approaches. Thus, significant gaps exist in knowing which myeloma therapies are most appropriate for older and more vulnerable adults with multiple myeloma. The purpose of this Review is to discuss how geriatric assessments can be used to guide the management of transplant-ineligible patients; and to highlight frontline therapies for standard-risk and high-risk cytogenetic abnormalities [i.e., t(4;14), t(14;16), and del(17p)] associated with multiple myeloma. We also discuss the current shortcomings of the existing clinical approaches to care and highlight ongoing clinical trials evaluating newer fitness-based approaches to managing transplant-ineligible patients.

Burden of Treatment Among Older Adults With Newly Diagnosed Multiple Myeloma.

BACKGROUND: Multiple myeloma is an incurable hematologic malignancy with significant recent treatment advances; however, the magnitude of treatment burden among patients in the first year after diagnosis has yet to be fully researched and reported. PATIENTS AND METHODS: Patients with multiple myeloma newly diagnosed between 2007 and 2013 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Treatment burden was captured as the number of total days with a health care encounter (including acute care and outpatient visits), oncology and nononcology physician visits, and the number of new prescriptions within the first year after diagnosis. Logistic regression was used to identify factors associated with high treatment burden. RESULTS: A total of 3065 patients were included in the analysis. There was a substantial burden of treatment within the first year after diagnosis (median, 77 days; interquartile range, 55-105 days), which was highest during the first 3 months. Patients with high comorbidities (adjusted odds ratio [aOR] 1.27 per 1-point increase in Charlson comorbidity index, P < .001), poor performance status (aOR 1.85, P < .001), myeloma-related end organ damage, particularly bone disease (aOR 2.28, P < .001), and those who underwent autologous stem-cell transplantation (aOR 2.41, P < .001) were more likely to have a higher treatment burden. CONCLUSION: There is considerable burden of treatment in patients with newly diagnosed multiple myeloma within the first year after diagnosis, particularly within the first 3 months. Future tailored interventions aimed at optimizing this treatment burden when possible while simultaneously providing support to manage it may improve patient-centered care.

Disparities in treatment patterns and outcomes among younger and older adults with newly diagnosed multiple myeloma: A population-based study.

INTRODUCTION: Multiple myeloma, a cancer of older adults, has seen significant improvement in therapeutic options over the past two decades. Uncovering disparities in treatment patterns and outcomes is imperative in order to ensure older adults, who are underrepresented in clinical trials, are benefitting from these advances. METHODS: Adults with newly diagnosed multiple myeloma (NDMM) were identified using linked provincial administrative databases between 2007 and 2017 in Ontario, Canada. Trends in rate of no treatment, novel drug and autologous stem cell transplant (ASCT) usage was evaluated within one year following diagnosis along with the associated early mortality (<12 months) for the aforementioned cohorts among younger (≤65 years) and older adults (>65 years) with NDMM. RESULTS: A total of 8841 adults with NDMM were identified. Rates of no treatment decreased in both age groups during the study period; however still remain considerably high among older patients (from 34.9% in 2007 to 27.4% in 2017) with high associated early mortality in the older untreated group (54.1% 1 yr mortality over study period). Despite increased usage of novel drugs in both age groups, early mortality decreased among younger patients utilizing novel drugs (16.1% to 5.6%) but remained high and stagnant in older patients using novel drugs (18.2% 1 yr mortality over study period). ASCT utilization increased in both age groups during the study period with decreasing early mortality among older patients undergoing ASCT (from 26.3% in 2007 to 1.1% in 2017). CONCLUSION: While several improvements have been made, rates of no treatment and early mortality among patients not treated and those started on novel drugs remains a concern in older adults with NDMM.

Maintenance therapy in transplant ineligible adults with newly-diagnosed multiple myeloma: A systematic review and meta-analysis.

BACKGROUND: The role of maintenance therapy in transplant ineligible multiple myeloma (MM) patients following a period of fixed duration induction therapy remains unclear. OBJECTIVES: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) examining maintenance therapy compared to observation. METHODS: We conducted a comprehensive search including MEDLINE, Embase, and the Cochrane database up to February 28, 2020, for RCTs comparing maintenance therapy to observation in newly diagnosed transplant ineligible MM patients. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. We performed meta-analyses using a random-effects model and assessed certainty using GRADE methodology. MAIN RESULTS: We included five RCTs with a total of 1139 patients. Patients receiving maintenance therapy had improved progression-free survival (PFS) compared to observation (Hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.38 to 0.62, high certainty); however, there was no difference in overall survival (HR 0.96, 95% CI 0.76-1.2, moderate certainty). Adverse events were higher in the maintenance group compared to observation (very low to moderate certainty). CONCLUSION: Maintenance therapy increases PFS in transplant ineligible MM patients following a fixed period of induction therapy; however, this must be weighed against the increased risk of adverse events.

Geriatric Assessment and Frailty Scores Predict Mortality in Myeloma: Systematic Review and Meta-analysis.

The incidence of multiple myeloma is increasing as the proportion of older adults is growing rapidly. A critical evaluation of the evidence available is needed to guide the management of older patients with myeloma. A systematic review was conducted to report the prognostic value of geriatric assessment and frailty scores in older patients with multiple myeloma. We conducted a literature search in February and August 2018. Two researchers extracted the data and assessed the quality of the studies. Geriatric assessment and frailty scores were defined as those evaluating at least 2 geriatric domains. Main outcomes were mortality or toxicity. We estimated the pooled hazard ratios (HR) with 95% confidence intervals (CIs) using a random-effects model. We screened titles and abstracts of 1672 citations for eligibility. Seven studies were included in the qualitative analysis, of which 3 were included in the meta-analysis. Two studies reported similar risks of hematologic adverse events in intermediate-fit and in frail patients compared to frail, but a significantly increased risk of nonhematologic adverse events in frail patients compared to fit patients. In meta-analysis, a significantly increased HR for death was observed in patients with activity of daily living score ≤ 4 (pooled HR = 1.576; 95% CI, 1.051-2.102; χ2 = 0.87; P = .647; I2 = 0). Patients classified as frail showed higher risk of death than fit patients (pooled HR = 2.169; 95% CI, 1.002-2.336; χ2 = 3.02; P = .221; I2 = 33.7%). GA and frailty score are effective in predicting mortality in older adults with myeloma.

Development of a Medicare Health Outcomes Survey Deficit-Accumulation Frailty Index and Its Application to Older Patients With Newly Diagnosed Multiple Myeloma.

Purpose: To develop a frailty index using the Rockwood Accumulation of Deficits approach for the Medicare Health Outcomes Survey (MHOS) and apply it in a subset of older patients with newly diagnosed multiple myeloma. Methods: Data from 2,692,361 patients without cancer, > 66 years of age, in SEER-MHOS linked databases between 1998 and 2009 were analyzed. A frailty index was constructed, resulting in a 25-item scale; cutoff values were created for individuals classified as frail. This frailty index was then applied to 305 patients with newly diagnosed myeloma in the database to predict overall survival. Results: In the derivation cohort of patients without cancer, the median age was 74 years and the mean frailty index was 0.23 (standard deviation, 0.17). Among patients without cancer, each 10% increase in frailty index (approximately three to four more deficits) was associated with a 40% increased risk for death (adjusted hazard ratio, 1.397; 95% CI, 1.396 to 1.399; P < .001). In the cohort of patients with newly diagnosed myeloma, the median age was 76 years an d the mean frailty index was 0.28 (standard deviation, 0.17). Each 10% increase in frailty index was associated with a 16% increased risk for death (adjusted hazard ratio, 1.159; 95% CI, 1.080 to 1.244; P < .001). Fifty-three percent of patients with multiple myeloma were considered frail. The estimated median overall survival of patients considered frail was 26.8 months, compared with 43.7 months (P = .015) for those who were not. Conclusion: The MHOS-based frailty index was prognostic for patients with multiple myeloma in predicting overall survival.

Novel Treatments for Multiple Myeloma: What Role Do They Have in Older Adults?

Multiple myeloma is a malignant plasma cell disease, which typically affects older patients, with a median age at diagnosis of 70 years. The recent introduction of novel drugs and ongoing improvements in supportive care have significantly contributed to overall better management and outcomes for patients with multiple myeloma. Autologous stem-cell transplantation has been a standard part of therapy for myeloma patients for many years, first in younger patients and increasingly in older, and may still be considered in selected older patients with myeloma. In addition, in both newly diagnosed patients and in the relapsed/refractory setting, a number of novel agents tested in large phase III trials have yielded improvements in overall outcomes. As clinical trials under-enrol older patients and have stringent exclusion criteria, the data and results from them may not be generalizable to all older adults. In this review, we examine the treatment options for older adults with myeloma with a specific focus on the currently available data on novel agents in this cohort. The clinical efficacy and unique toxicity profile of each novel agent must be considered prior to the treatment plan in older adults.

The relationship of CD34+ dosage and platelet recovery following high dose chemotherapy and autologous CD34+ reinfusion in multiple myeloma.

Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for multiple myeloma (MM), yet the impact of transplanted CD34+ cell dose remains unresolved, especially in patients over the age of 65 years. Data was collected from 207 consecutive ASCT patients to determine the relationship between CD34+ infusion count and short-term and long-term platelet recovery. For MM patients under the age of 65 years (n=155), CD34+ dosage correlates with time to platelet engraftment (p<0.001) and platelet count at 30 days (p=0.003), but not with long-term platelet counts at 180 or 360 days from the CD34+ reinfusion. For MM patients aged 65 years or older (n=46), CD34+ dosage did not correlate with time to platelet engraftment, but did correlate with both short-term and long-term platelet counts at 30 (p<0.001), 180 (p=0.021), and 360 days (p=0.005). Exploratory regression analysis was done to explore platelet stability following the current minimum CD34+ dosage reinfusion. For MM patients under the age of 65 years, the minimum standard CD34+ dosage of 2×106cells/kg was sufficient for a timing to platelet engraftment of <21 days and short-term platelets count ≥150×109/L at 30 days. Alternatively, for MM patients aged 65 years or older, the CD34+ dosage of 2×106cells/kg was insufficient for platelet counts ≥150×109/L at 30 and only marginally attainable at 360 days suggesting that in elderly MM patients a higher CD34+ dosage may be required for platelet recovery and possibly long-term platelet stability.

EspP, an Extracellular Serine Protease from Enterohemorrhagic E. coli, Reduces Coagulation Factor Activities, Reduces Clot Strength, and Promotes Clot Lysis.

BACKGROUND: EspP (E. coli secreted serine protease, large plasmid encoded) is an extracellular serine protease produced by enterohemorrhagic E. coli (EHEC) O157:H7, a causative agent of diarrhea-associated Hemolytic Uremic Syndrome (D+HUS). The mechanism by which EHEC induces D+HUS has not been fully elucidated. OBJECTIVES: We investigated the effects of EspP on clot formation and lysis in human blood. METHODS: Human whole blood and plasma were incubated with EspP(WT )at various concentrations and sampled at various time points. Thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aPTT), coagulation factor activities, and thrombelastgraphy (TEG) were measured. RESULTS AND CONCLUSIONS: Human whole blood or plasma incubated with EspP(WT) was found to have prolonged PT, aPTT, and TT. Furthermore, human whole blood or plasma incubated with EspP(WT) had reduced activities of coagulation factors V, VII, VIII, and XII, as well as prothrombin. EspP did not alter the activities of coagulation factors IX, X, or XI. When analyzed by whole blood TEG, EspP decreased the maximum amplitude of the clot, and increased the clot lysis. Our results indicate that EspP alters hemostasis in vitro by decreasing the activities of coagulation factors V, VII, VIII, and XII, and of prothrombin, by reducing the clot strength and accelerating fibrinolysis, and provide further evidence of a functional role for this protease in the virulence of EHEC and the development of D+HUS.

Optimal Manual Exchange Transfusion Protocol for Sickle Cell Disease: A Retrospective Comparison of Two Comprehensive Care Centers in the United Kingdom and Canada.

Chronic red blood cell (RBC) transfusion is employed for a wide range of sickle cell disease complications, ranging from primary and secondary stroke prophylaxis to prevention of painful vaso-occlusive episodes. Currently different methods are employed by centers for chronic transfusion that include simple, automated and partial manual RBC exchange transfusion. A retrospective cohort study of two different manual RBC exchange transfusion methods was conducted between two comprehensive care centers in Toronto, ON, Canada and London, United Kingdom in 19 and 21 sickle cell disease adults, respectively. London used a weight-based protocol, while Toronto used a unit-based method. Our results indicated that sickle cell disease patients utilizing a weight-based method are more often unable to achieve the prescribed Hb S (HBB: c.20A > T) target compared to the unit-based method (90.0 vs. 53.0% in the weight-based and unit-based methods, respectively, p = 0.0123). On multivariable logistic regression, none of the covariates examined was found to influence the ability to achieve the prescribed Hb S target after accounting for the exchange transfusion method. Mean interval of exchange sessions, session duration, total units of packed RBC, volume of blood used by body weight each year, the mean post exchange hematocrit [or packed cell volume (PCV)] and ferritin change were similar in both cohorts. In conclusion, the unit-based method was more effective at maintaining the prescribed Hb S target.

Crystal structure of the passenger domain of the Escherichia coli autotransporter EspP.

Autotransporters represent a large superfamily of known and putative virulence factors produced by Gram-negative bacteria. They consist of an N-terminal "passenger domain" responsible for the specific effector functions of the molecule and a C-terminal "ß-domain" responsible for translocation of the passenger across the bacterial outer membrane. Here, we present the 2.5-Å crystal structure of the passenger domain of the extracellular serine protease EspP, produced by the pathogen Escherichia coli O157:H7 and a member of the serine protease autotransporters of Enterobacteriaceae (SPATEs). Like the previously structurally characterized SPATE passenger domains, the EspP passenger domain contains an extended right-handed parallel ß-helix preceded by an N-terminal globular domain housing the catalytic function of the protease. Of note, however, is the absence of a second globular domain protruding from this ß-helix. We describe the structure of the EspP passenger domain in the context of previous results and provide an alternative hypothesis for the function of the ß-helix within SPATEs.