A Prognostic Survival Model Incorporating Patient-Reported Outcomes for Transplant-Ineligible Patients With Multiple Myeloma.

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.

Prevalence of geriatric impairments and frailty categorization among real-world patients with multiple myeloma: a prospective cohort study (MFRAIL).

There is limited knowledge regarding the prevalence of geriatric impairments and frailty among patients with multiple myeloma (MM) in a real-world setting. This study evaluated the distribution of frailty profiles among 116 patients with newly diagnosed or relapsed MM, using four common frailty scales. The proportion of patients classified as frail varied significantly, ranging from 15.5% to 56.9%, due to differences in how frailty was operationalized between each frailty measure. Functional, cognitive, and mobility impairments were common overall and irrespective of performance status. Analyses between frailty and treatment selection (dose reduction and doublet vs. triplet therapy) demonstrated significant differences in non-steroid MM drug dose reductions between frail vs. non-frail patients, as scored by the International Myeloma Working Group (IMWG) Frailty Index and Simplified Frailty Score (p < .05). A standardized approach to frailty assessment that is practical in application, and beneficial in guiding treatment selection and minimizing treatment related toxicity is necessary to provide optimal tailored care.

Treatment Pattern, Healthcare Resource Utilization and Symptom Burden Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study.

PURPOSE: This study aims to describe the treatment patterns, outcomes, health care utilization and symptom burden of triple class exposed (TCE) relapsed/refractory patents with multiple myeloma (MM) receiving a subsequent line of treatment (LOT). METHODS: This is a retrospective observational cohort study using administrative databases in Ontario, Canada. Outcomes were captured for TCE patients receiving a subsequent LOT and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), health care utilization, palliative care referral, and patient reported symptoms. RESULTS: Of the 16,777 patients diagnosed with MM between 2007-2021 in Ontario, 1358 (8%) patients were classified as TCE. Among the TCE MM patients, 489 (36%) received a subsequent LOT. The two most commonly administered therapies post TCE were carfilzomib/dexamethasone (n = 111, 22%) and pomalidomide/dexamethasone(n = 95, 19%). Median TTNT was 1.7 months (95%CI 1.2-2.4 months) and median OS 12.8 months (95%CI 10.8-16.5). Healthcare utilization was high with 276 (56%) of patients evaluated in an emergency department (ED) or admitted to hospital. There was high symptom burden as reported by patients with moderate-severe impairment in well-being, fatigue, pain and drowsiness noted in greater than 25% of the cohort. Palliative care referrals rates were low with only 10% (n = 48) patients referred to palliative care. Among the patients that died during study follow up, the majority died in hospital (n = 147,44%). CONCLUSION: Our study reports one of the largest series of real-world TCE patients published and demonstrates the poor outcomes of TCE patients receiving a subsequent LOT.

A structured oral chemotherapy teaching tool to improve adherence in adults with multiple myeloma: A pilot randomized controlled trial.

INTRODUCTION: Many of the newer treatments for adults with newly-diagnosed and relapsed multiple myeloma (MM) are orally administered. Adherence is a challenge, and little is known about strategies to optimize adherence. MATERIALS AND METHODS: Forty-seven patients initiating orally-administered anti-myeloma therapy were enrolled and randomized in a pilot study to receive either standard of care teaching or the Multinational Association of Supportive Care in Cancer Oral agent Teaching Tool (MOATT), a structured teaching tool. Adherence was measured electronically with a Medication Event Monitoring System (MEMS) cap. Optimal adherence was defined as an adherence rate of ≥90% over the six months study duration. Patients completed surveys regarding cancer therapy satisfaction and self-efficacy for medication management at one month and six months following the initiation of treatment in both arms. RESULTS: The mean adherence of patients over six months was 86.9%; 43.9% of the cohort were classified as non-adherent using the 90% threshold of adherence. Mean adherence was similar among standard of care teaching (87.9%) versus the MOATT intervention tool (85.6%) as was cancer therapy satisfaction and self-efficacy for medication management. DISCUSSION: In our pilot, the MOATT tool was not found to be feasible or acceptable. There were no preliminary differences noted between standard of care teaching versus the structured MOATT teaching tool with regards to overall adherence rates, cancer therapy satisfaction, or self-efficacy in medication management. Overall adherence rates were suboptimal in our study. Future research should work to identify aspects of educational interventions which are effective, and investigate different strategies which can be used to supplement patient education and potentially optimize medication adherence in patients with MM.

Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review.

Extra copies of chromosome 1q21 (+1q: gain = 3 copies, amp >= 4 copies) are associated with worse outcomes in multiple myeloma (MM). This systematic review assesses the current reporting trends of +1q, the efficacy of existing regimens on +1q, and its prognostic implications in MM randomized controlled trials (RCTs). Pubmed, Embase and Cochrane Registry of RCTs were searched from January 2012 to December 2022. Only MM RCTs were included. A total of 124 RCTs were included, of which 29 (23%) studies reported on +1q. Among them, 10% defined thresholds for +1q, 14% reported survival data separately for gain and amp, and 79% considered +1q a high-risk cytogenetic abnormality. Amongst RCTs that met the primary endpoint showing improvement in progression free survival (PFS), lenalidomide maintenance (Myeloma XI), selinexor (BOSTON), and isatuximab (IKEMA and ICARIA) were shown to improve PFS for patients with evidence of +1q. Some additional RCT's such as Myeloma XI+ (carfilzomib), ELOQUENT-3 (elotuzumab), and HOVON-65/GMMG-HD4 (bortezomib) met their endpoint showing improvement in PFS and also showed improvement in PFS in the +1q cohort, although the confidence interval crossed 1. All six studies that reported HR for +1q patients vs. without (across both arms) showed worse OS and PFS for +1q. There is considerable heterogeneity in the reporting of +1q. All interventions that have shown to be successful in RCTs and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention. A more standardized approach to reporting this abnormality is needed.

Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial.

Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .

Characteristics of post hoc subgroup analyses of oncology clinical trials: a systematic review.

BACKGROUND: Subgroup analyses in clinical trials assess intervention effects on specific patient subgroups, ensuring generalizability. However, they are usually only able to generate hypotheses rather than definitive conclusions. This study examined the prevalence and characteristics of post hoc subgroup analysis in oncology. METHODS: We systematically reviewed published subgroup analyses from 2000 to 2022. We included articles presenting secondary, post hoc, or subgroup analyses of interventional clinical trials in oncology, cancer survivorship, or cancer screening, published separately from the original clinical trial publication. We collected cancer type, year of publication, where and how subgroup analyses were reported, and funding. RESULTS: Out of 16 487 screened publications, 1612 studies were included, primarily subgroup analyses of treatment trials for solid tumors (82%). Medical writers contributed to 31% of articles, and 58% of articles reported conflicts of interest. Subgroup analyses increased significantly over time, with 695 published between 2019 and 2022, compared to 384 from 2000 to 2014. Gastrointestinal tumors (25%) and lymphoid lineage tumors (39%) were the most frequently studied solid and hematological malignancies, respectively. Industry funding and reporting of conflicts of interest increased over time. Subgroup analyses often neglected to indicate their secondary nature in the title. Most authors were from high-income countries, most commonly North America (45%). CONCLUSIONS: This study demonstrates the rapidly growing use of post hoc subgroup analysis of oncology clinical trials, revealing that the majority are supported by pharmaceutical companies, and they frequently fail to indicate their secondary nature in the title. Given the known methodological limitations of subgroup analyses, caution is recommended among authors, readers, and reviewers when conducting and interpreting these studies.

Real-world results of autologous stem cell transplantation in newly diagnosed multiple myeloma: a report from the Canadian Myeloma Research Group database.

Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients as part of initial therapy. Using the Canadian Myeloma Research Group (CMRG) national database, we examined the details and outcomes of ASCT performed as first-line therapy in eligible Canadian MM patients between 2007 to 2021. We included 3821 patients with 72% receiving CyBorD induction and 2061 patients receiving maintenance, consisting of lenalidomide +/- steroids in 78.3%. The median PFS and OS for patients given a single ASCT were 35.4 and 126 months. Those receiving a second induction regimen had significantly inferior outcomes, although when maintenance was used, results were comparable regardless of the number of induction regimens administered (median PFS 55.3 vs 51.1 months [p = 0.11]; median OS 158.6 vs not yet reached [p = 0.13]). Consolidation patients had a longer median PFS (55.3 vs 34.4 months [p = 0.001]), but no significant gain in median OS (p = 0.065). Patients who received lenalidomide-based maintenance experienced a median PFS of 53.7 months and OS of 159 months. In the multivariable analysis, use of any type of maintenance therapy vs no maintenance was associated with a lower risk of progression (HR 0.52 (95% CI 0.47-0.57)) and death (HR 0.58 (95% CI 0.51-0.67)). This real-world study demonstrates that, overall, first-line treatment sequence in transplant-eligible patients produces a median OS of ≥10 years. It also highlights the contribution of post-ASCT maintenance, particularly lenalidomide given until progression.

Cardiac Interventions in Patients With Active, Advanced Solid and Hematologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Invasive cardiac interventions are recommended to treat ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndromes, multivessel coronary disease, severe symptomatic aortic stenosis, and cardiomyopathy. These recommendations are based on randomized controlled trials that historically included few individuals with active, advanced malignancies. Advanced malignancies represent a significant competing risk for mortality, and there is limited evidence to inform the risks and benefits of invasive cardiac interventions in affected patients. We review the benefit conferred by invasive cardiac interventions; the periprocedural considerations; the contemporary survival expectations of patients across several types of active, advanced malignancy; and the literature on cardiovascular interventions in these populations. Our objective is to develop a rational framework to guide clinical recommendations on the use of invasive cardiac interventions in patients with active, advanced cancer.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

INTRODUCTION: Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. METHODS AND OBJECTIVE: We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. RESULTS: We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. CONCLUSION: Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

Cancer-specific mortality in multiple myeloma: a population-based retrospective cohort study.

Survival has improved in patients diagnosed with multiple myeloma (MM) over the last two decades; however, there remains a paucity of data on the causes of death in MM patients and whether causes of death change during the disease trajectory. We conducted a retrospective population-based study to evaluate the rates of MM-specific versus non-MM cause of death and to identify factors associated with cause-specific death in MM patients, stratified into autologous stem cell transplant (ASCT) and non-ASCT cohorts. A total of 6,677 patients were included, 2,576 in the ASCT group and 4,010 in the non-ASCT group. Eight hundred and seventy-three (34%) ASCT patients and 2,787 (68%) non-ASCT patients died during the follow-up period. MM was the most frequent causes of death, causing 74% of deaths in the ASCT group and 67% in the non-ASCT group. Other cancers were the second leading causes of death, followed by cardiac and infectious diseases. Multivariable analysis demonstrated that a more recent year of diagnosis and novel agent use within 1 year of diagnosis were associated with a decreased risk of MM-specific death, whereas a history of previous non-MM cancer, older age, and the presence of CRAB criteria at diagnosis increased the risk of non-MM death. Our data suggests that despite improvement in MM outcomes in recent years, MM remains the greatest threat to overall survival for patients. Further advances in the development of effective MM therapeutic agents in both ASCT and non-ASCT populations and patient access to them is needed to improve outcomes.

Redefining attrition in multiple myeloma (MM): a Canadian Myeloma Research Group (CMRG) analysis.

While most patients diagnosed with multiple myeloma (MM) receive initial therapy, reported attrition rates are high. Understanding attrition rates and characteristics of patients not receiving subsequent therapy is useful for MM stakeholders. We performed an analysis of attrition rates in a large disease-specific database of patients with newly diagnosed MM who received at least one line of therapy between Jan 1/10-Dec 31/20. Attrition was defined as failure to receive a subsequent line of therapy despite progression of MM or due to death. A total of 5548 patients were identified, 3111 autologous stem cell transplant (ASCT) patients and 2437 non-ASCT. In the ASCT cohort, the attrition rate was 7% after line 1, 12% after line 2, and 23% after line 3. In non-ASCT patients, the attrition rate was 19% after line 1, 26% after line 2, and 40% after line 3. Death was the dominant contributor to attrition across all cohorts, with a minority of patients alive with progressive disease in the absence of further therapy at each line. Multivariable analysis identified older age, shorter time to progression, and inferior response as independent risk factors for attrition. Our data show that attrition rates increase with each line of therapy and are higher in non-ASCT patients but are appreciably lower than previously reported. This study supports a revision of the previous definition of attrition, demonstrating that most patients who do not receive subsequent therapy are either continuing their current therapy and/or are in remission off-treatment rather than being irreversibly lost to attrition.

Frailty and survival among veterans treated with abiraterone or enzalutamide for metastatic castration-resistant prostate cancer.

INTRODUCTION: Abiraterone and enzalutamide are treatments for metastatic castration-resistant prostate cancer (mCRPC). Due to a lack of head-to-head trials, they are prescribed interchangeably. However, the drugs have different pharmacokinetics and thus may have differing efficacy and adverse effects influenced by patient functional status and comorbid diseases. Additionally, mCRPC mainly affects older adults and since the prevalence of frailty increases with age, frailty is an important patient factor to consider in personalizing drug selection. MATERIALS AND METHODS: We conducted a retrospective observational study of US veterans treated with abiraterone or enzalutamide for mCRPC from September 2014 to June 2017. Frailty was assessed using the Veterans Affairs Frailty Index (VA-FI), which utilizes administrative codes to assign a standardized frailty score. Patients were categorized as frail if VA-FI scores were > 0.2. The primary outcome was difference in overall survival (OS) between the two treatment groups. Cox regression modeling and propensity score matching was used to compare between abiraterone and enzalutamide treatments. RESULTS: We identified 5,822 veterans, 57% of whom were initially treated with abiraterone and 43% with enzalutamide. Frail patients (n = 2,314; 39.7%) were older, with a mean age of 76.1 versus 74.9 years in the non-frail group (n = 3,508; 60.3%, p < 0.001) and had shorter OS compared to non-frail patients regardless of treatment group (18.5 vs. 26.6 months, p < 0.001). Among non-frail patients there was no significant difference in OS between abiraterone and enzalutamide treatment (27.7 vs 26.1 months, p = 0.07). However, frail patients treated with enzalutamide versus abiraterone had improved OS (20.7 vs 17.2 months, p < 0.001). In a propensity score matched analysis of frail patients (n = 2,070), enzalutamide was associated with greater median OS (24.1 vs 20.9 months, p < 0.001). In patients with dementia, enzalutamide was associated with longer OS (19.4 vs. 16.6 months, p = 0.003). DISCUSSION: In this study of 5822 US veterans with mCRPC, treatment with enzalutamide was associated with improved OS compared to abiraterone among frail veterans and veterans with dementia, but not among non-frail veterans. Future studies should evaluate interactions between frailty and cancer treatments to optimize selection of therapy among frail adults.

Dynamic frailty risk assessment among older adults with multiple myeloma: A population-based cohort study.

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007-2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each landmark interval (1-yr, 2-yr, 3-yr post diagnosis). The association of frailty with overall survival (OS) both at baseline and at each landmark interval as well as factors associated with worsening frailty status over time were evaluated. Overall, 4617 patients were included. At baseline, 39% of the patients were categorized as moderately frail or severely frail. Among those who had 3 years of follow-up, frailty categorization changed post diagnosis in 93% of the cohort (78% improved and 72% deteriorated at least at one time point during the follow up period). In a landmark analysis, the predictive ability of frailty at the time of diagnosis decreased over time for OS (Harrell's C Statistic 0.65 at diagnosis, 0.63 at 1-yr, 0.62 at 2-yr, and 0.60 at 3-yr) and was inferior compared to current frailty status at each landmark interval. Our study is one of the first to demonstrate the dynamic nature of frailty among older adults with MM. Frailty may improve or deteriorate over time. Current frailty status is a better predictor of outcomes than frailty status at time of diagnosis, indicating the need for re-measurement in this high-risk patient population.