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Summary Background Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). Methods In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1–8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1–14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1–21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Findings Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5–23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8–37·8) in the KRd group and 34·4 months (30·1–not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83–1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3–4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [ Interpretation The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. Funding US National Institutes of Health, National Cancer Institute, and Amgen.

Background For pts with MM, HRQL is a key determinant of treatment choice in late-line therapies such as ide-cel, a BCMA-directed CAR T cell therapy. In KarMMa (NCT03361748), 54.2% of pts showed clinically meaningful improved HRQL from baseline to quarter (Q) 3, as measured by EQ-5D-5L; 8.5% experienced deterioration (Blood. 2020;136 [Suppl]:28–29). Analysis of HRQL in pts who received alternate, non-CAR T cell therapies could contextualize the impact of ide-cel on HRQL. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of largely community-based pts with newly diagnosed MM (NDMM) at study entry. It was used for a descriptive analysis assessing HRQL outcomes in triple-class exposed real-world pts who met KarMMa trial eligibility criteria but received alternate therapies. Method From 2009-2016, the Registry enrolled 3011 pts with symptomatic NDMM diagnosed ≤2 months prior to study entry at 250 community, academic, and government sites across the US. Pts agreed to complete HRQL forms at study enrollment and every Q of follow-up. Pts with RRMM included in this analysis met KarMMa eligibility criteria. HRQL was measured from the time of KarMMa eligibility (D1) using EQ-5D-3L and FACT-MM total score instruments. Results As of data cutoff (7 Feb 2020), 32 pts with RRMM from the Registry met KarMMa eligibility criteria. Median age was 64.1 y (range, 45.5–88.8). Median time to D1 since initial diagnosis was 3.4 y (range, 1.6–5.5); 24 pts (75%) had prior stem cell transplant; median prior lines of therapy was 7.5. At D1, pts initiated regimens that included IMiDs (n=20), proteasome inhibitors (n=15) and anti-CD38 monoclonal antibodies (n=7). HRQL form completion rate at Q3 was 64.7%. The baseline index score was 0.73 for Registry pts. Median EQ-5D-3L score (range) at D1 (n=21) was 0.761 (0.263–1) and 0.708 (0.263–1) at Q3 (n=11). At D1, 30% of pts experienced clinically meaningful improvement in EQ-5D-3L from baseline; 35% each experienced no change or deterioration in HRQL. By Q3, 20%, 30%, and 50% of pts experienced improvement from baseline, no change, and deterioration in HRQL, respectively. By Q3 post treatment initiation, a substantial proportion of ide-cel–eligible real-world pts with RRMM from the Connect MM Registry who received various alternate (non-CAR T cell) MM regimens experienced meaningful deterioration of HRQL (measured by EQ-5D-3L) from D1 over time. Conclusion In the context of the KarMMa trial, it was observed that a higher proportion of pts on ide-cel experienced meaningful improvement in HRQL (measured by EQ-5D-5L) and fewer pts experienced deterioration by Q3 after treatment. Limitations of this analysis may include small sample size and use of different versions of EQ-5D assessments. HRQL remains an important goal of MM treatment, and therapies that improve HRQL should be developed explicitly. These results support the need for replication in a larger pt sample and complement clinical trial findings.

Cancer survivors have lingering cognitive problems, however the anatomical basis for these problems has yet to be fully elucidated. Clinical studies as well as animal models of chemotherapy have pinpointed cell and volume loss to the hippocampus, however, few studies have performed shape analysis of the hippocampus on cancer survivors. This study used high-dimensional deformation mapping analysis to test whether localized hippocampal deformation differs in breast cancer survivors who received adjuvant chemotherapy coupled with hormone blockade therapy, and if deformation was related to subjective self-reported concerns and cognitive performance. 3 T MRI images were acquired from 16 pre-menopausal breast cancer survivors and 18 healthy controls without a history of cancer. Breast cancer survivors had undergone chemotherapy within the eighteen months prior to the study, and were receiving estrogen-blockade therapy at the time of the study. Automated high-dimensional deformation mapping was used to compare localized hippocampal deformation differences between groups. Self-reported subjective concerns were assessed using Neuro-QOL Cognitive Function assessment, whereas cognitive performance was evaluated using the NIH Toolbox Cognition Battery. Relative to healthy controls, cancer survivors showed significantly more inward hippocampal deformation, worse self-reported cognitive functioning, and inferior episodic memory test score. This study is the first of its kind to examine the relationship between hippocampal deformity and cognitive impairment in cancer survivors., Highlights • Cancer survivors demonstrated significant inward hippocampal deformation. • Survivors self-reported worse cognitive functioning. • Survivors performed worse than controls on a test of episodic memory.

Context Symptom cluster research expands cancer investigations beyond a focus on individual symptoms in isolation. Objectives We conducted a prospective longitudinal study of sleep, fatigue, depression, anxiety, and perceived cognitive impairment in patients with breast cancer undergoing chemotherapy. Methods Patient-reported outcome measures were administered prior to chemotherapy, at Cycle 4 Day 1, and six months after initiating chemotherapy. Participants were divided into four groups and assigned a symptom cluster index (SCI) score based on the number/severity of symptoms reported at enrollment. Results Participants ( N = 80) were mostly women (97.5%) with Stage II (69.0%) breast cancer, 29–71 years of age. Scores on all measures were moderately-highly correlated across all time points. There were time effects for all symptoms, except sleep quality (nonsignificant trend), with most symptoms worsening during chemotherapy, although anxiety improved. There were no significant group × time interactions; all four SCI groups showed a similar trajectory of symptoms over time. Worse performance status and quality of life were associated with higher SCI score over time. Conclusion With the exception of anxiety, the coherence of the symptom cluster was supported by similar patterns of severity and change over time in these symptoms (trend for sleep quality). Participants with higher SCI scores prior to chemotherapy continued to experience greater symptom burden during and after chemotherapy. Early assessment and intervention addressing this symptom cluster (vs. individual symptoms) may have a greater impact on patient performance status and quality of life for patients with higher SCIs.

Background The recurrence score (RS) based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low. There is little information from prospective clinical trials, however, regarding outcomes for patients with a high RS treated with chemotherapy regimens including taxanes and/or anthracyclines. Methods Women with hormone-receptor-positive, HER2-negative, axillary-node-negative breast cancer and a high RS of 26-100 were assigned to receive endocrine therapy plus a chemotherapy regimen selected by the treating physician. Results Among the 9719 eligible women, 1389 (14%) had a RS of 26-100.The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-FU in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). The estimated rates of freedom from recurrence of breast cancer at a distant site were 93.0% (standard error [SE]+0.8%) at 5 years and 86.8% (SE + 1.7%) at 9 years. In contrast, the projected rates of freedom from distant recurrence in this population if treated with endocrine therapy alone was estimated to be 78.8% (SE ± 14.0%) at 5 years and 65.4% (SE ± 10.4%) at 9 years when estimating outcomes based on the treatment effect of chemotherapy noted in the HER2-negative cohort of the B20 trial. Five-year rates of freedom from distant recurrence ranged from 92.3% to 95.5% for all chemotherapy regimens with the exception of CMF (88.5%). Conclusions The estimated rate of freedom from distant recurrence in women with a RS of 26-100 treated with a variety of adjuvant taxane and/or anthracycline-containing chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Clinical trial identification NCT00310180. Legal entity responsible for the study ECOG-ACRIN Cancer Research Group. Funding USA National Cancer Institute, Genomic Health. Disclosure All authors have declared no conflicts of interest.

Introduction:Despite recent therapeutic advances, lung cancer is a difficult disease to manage. This study assessed clinicians’ perceptions of care difficulty, quality of life (QOL), and symptom reports for their lung cancer patients compared with their patients with breast, prostate, and colon cancer.Methods:This report focused on secondary analyses from the Eastern Cooperative Oncology Group (ECOG) Symptom Outcomes and Practice Patterns (SOAPP) study (E2Z02); outcome measures included clinician ratings of 3106 solid tumor patients. Univariate analyses focused on patterns of disease-specific perceptions; multivariable analyses examined whether disease-specific differences persisted after covariate inclusion.Results:In univariate comparisons, clinicians rated lung cancer patients as more difficult to treat than other solid tumor patients, with poorer QOL and higher symptom reports. After covariates were adjusted, the odds of clinicians perceiving lower QOL for their lung cancer patients were 3.6 times larger than for patients with other solid tumors (odds ratio = 3.6 [95% confidence interval, 2.0–6.6]; p < 0.0001). In addition, the odds of clinicians perceiving weight difficulties for their lung cancer patients were 3.2 times larger (odds ratio = 3.2 [95% confidence interval, 1.7–6.0]; p = 0.0004). No other outcome showed significant differences between lung versus other cancers in multivariable models.Conclusion:Clinicians were more pessimistic about the well-being of their lung cancer patients compared with patients with other solid tumors. Differences remained for clinician perceptions of patient QOL and weight difficulty, even after controlling for such variables as stage, performance status, and patient-reported outcomes. These continuing disparities suggest possible perception bias. More research is needed to confirm this disparity and explore the underpinnings.

Purpose Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown. Methods Here we present an analysis of HCRU and clinical outcomes in a cohort of patients from the Connect MM registry, the largest, ongoing, observational, prospective US registry of patients with symptomatic newly diagnosed MM. In this study, patients with newly diagnosed MM who completed induction and single ASCT without subsequent consolidation received lenalidomide-only maintenance (n = 180), any maintenance (n = 256), or no maintenance (n = 165). HCRU (hospitalization, surgery/procedures, and concurrent medications [growth factors, bisphosphonates, or neuropathic pain medication]) was assessed starting from 100 days post-ASCT for up to 2 years. Findings Although the rates of hospitalization per 100 person-years were similar across groups at the end of years 1 and 2, the median duration of hospitalization was numerically longer with no maintenance. The rates of use of growth factors, bisphosphonates, and neuropathic pain medication were generally similar in all 3 groups. The receipt of any maintenance was associated with significantly reduced use of neuropathic pain medications during year 1. Of note, lenalidomide-only maintenance was associated with significantly longer progression-free survival (54.5 vs 30.4 months; hazard ratio [HR] = 0.58; 95% CI, 0.43–0.79; P = 0.0005) and overall survival (OS) (median OS not reached in either group; HR = 0.45; 95% CI, 0.28–0.73; P = 0.001) compared with no maintenance. Likewise, the group treated with any maintenance had significantly longer median progression-free survival (44.7 vs 30.4 months; HR = 0.62; 95% CI, 0.47–0.82; P = 0.0008) and OS (median OS not reached in either group; HR = 0.50; 95% CI, 0.33–0.76; P = 0.001) than did the group that did not receive maintenance. Implications These findings suggest that in this largely community-based study population, post-ASCT maintenance therapy, including lenalidomide-only maintenance, improves clinical outcomes without negatively affecting HCRU. ClinicalTrials.gov identifier: NCT01081028.

Decrements in cognitive function are common in cancer patients and other clinical populations. As direct neuropsychological testing is often not feasible or affordable, there is potential utility in screening for deficits that may warrant a more comprehensive neuropsychological assessment. Furthermore, some evidence suggests that perceived cognitive function (PCF) is independently associated with structural and functional changes on neuroimagery, and may precede more overt deficits. To appropriately measure PCF, one must understand its components and the underlying dimensional structure. The purpose of this study was to examine the dimensionality of PCF in people with cancer. The sample included 393 cancer patients from four clinical trials who completed a questionnaire consisting of the prioritized areas of concerns identified by patients and clinicians: self-reported mental acuity, concentration, memory, verbal fluency, and functional interference. Each area contained both negatively worded (i.e., deficit) and positively worded (i.e., capability) items. Data were analyzed by using Cronbach's alpha, item-total correlations, one-factor confirmatory factor analysis, and a bi-factor analysis model. Results indicated that perceived cognitive problem items are distinct from cognitive capability items, supporting a two-factor structure of PCF. Scoring of PCF based on these two factors should lead to improved assessment of PCF for people with cancer.

Fatigue, pain, distress, and anorexia are four commonly encountered symptoms in cancer. To evaluate the usefulness of a single-item screening for these symptoms, 597 ambulatory outpatients with solid tumors were administered a self-report screening instrument within the first 12 weeks of chemotherapy. Patients rated the severity of each symptom on a 0-10 scale, at its worst over the past three days, with higher ratings associated with higher symptom levels. From this sample, 148 patients also completed a more comprehensive assessment of these symptoms. Two criteria were used to determine optimal cut-off scores on the screening items: 1) the sensitivity and specificity of each screening item to predict clinical cases using receiver-operating characteristics analysis and 2) the proportion of patients at each screening score who reported that some relief of the target symptom would significantly improve their life. Optimal cut-off scores ranged from 4 to 6 depending on the target symptom (area under the curve range=0.68-0.88). Use of single-item screening instruments for fatigue, pain, distress, and anorexia may assist routine clinical assessment in ambulatory oncology practice. In turn, such assessments may improve identification of those at risk of morbidity and decreased quality of life due to excess symptom burden.