Multiple myeloma clinical trials exclude patients with the highest-risk disease: a systematic review of trial exclusion criteria.

Patients with certain subsets of multiple myeloma continue to have poor outcomes and are in need of novel treatment approaches. Strict eligibility criteria for randomized controlled trials (RCTs) limit access to clinical trials and limit the external validity of trial results for these patients. We systematically reviewed RCTs in newly diagnosed myeloma from 2006 to 2023 to ascertain the prevalence of 12 key exclusion criteria and trends over time. 80 RCTs were included. Exclusion criteria included: age in 43 (51%) trials; projected life expectancy in 20 (24%); performance status in 74 (87%); non-secretory and/or oligosecretory disease in 47 (55%), hepatic function in 64 (79%), renal function in 63 (74%), hematological thresholds in 50 (59%), prior malignancy in 68 (80%), and neuropathy in 50 (59%). For 53 trials which had detailed exclusion criteria available, plasma cell leukemia was excluded in 21 (40%), extramedullary disease in 5 (9%) and CNS disease in 13 (25%). The percentage of studies invoking each of these exclusion criteria did not significantly improve over time on univariate regression analysis, and exclusion criteria relating to neuropathy have worsened. The restrictive eligibility criteria of most myeloma RCTs perpetuate a cycle where limited data exists to treat challenging myeloma subtypes.

Quadruplet regimens for patients with newly diagnosed multiple myeloma: A systematic review and meta-analysis.

Quadruplet regimens (anti-CD38 monoclonal antibodies (mAbs) with proteosome inhibitor (PI) and immunomodulatory (IMID) drugs) are increasingly being investigated in newly diagnosed multiple myeloma (NDMM). The objective of our study was to conduct a systematic review and meta-analysis to measure the efficacy and toxicity of quadruplet regimens utilized in NDMM. Embase, Medline, Web of Science, Cochrane Library, clinical trial registries, and meeting libraries from inception to January 24, 2024, in addition to ASCO conference abstracts 2024 were searched using terms reflecting MM and component of the quadruplet regimen. Included studies were randomized controlled trials (RCTs) that compared backbone regimens consisting of a PI and IMID versus the same regimen plus an anti-CD38 mAb in NDMM. We identified seven RCTs including 3716 patients. Compared to triplets, quadruplets increase the overall response rate (ORR, relative risk [RR] 1.03, 95% confidence interval [CI] 1.01-1.05), and progression free survival (PFS, hazard ratio [HR]] 0.55, 95% CI 0.46-0.66). Quadruplets increase the rates of minimal residual disease (MRD) negativity at 10-5 (RR 1.39, 95% 1.23-1.58) and at 10-6 (RR 1.62, 95% CI 1.36-1.94). Quadruplets improve overall survival (OS, HR 0.65, 95% CI 0.53-0.79). There was a slight increase in the rates of grade 3-4 infections (RR 1.22 [95% CI 1.07-1.39]) noted with quadruplets compared to triplets. Overall, in this meta-analysis quadruplets were associated with improved efficacy including ORR, MRD negativity, PFS and OS with a slight increase in infection rates. Quadruplet regimens represent a new standard of care particularly in transplant eligible NDMM.

Evaluating early intervention in smoldering myeloma clinical trials: a systematic review.

BACKGROUND: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. METHODS: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. RESULTS: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). CONCLUSION: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

Comparing the clinical trial efficacy versus real-world effectiveness of treatments for multiple myeloma: a population-based study.

Not available.

Dietary interventions in cancer: a systematic review of all randomized controlled trials.

BACKGROUND: Prior systematic reviews addressing the impact of diet on cancer outcomes have focused on specific dietary interventions. In this systematic review, we assessed all randomized controlled trials (RCTs) investigating dietary interventions for cancer patients, examining the range of interventions, endpoints, patient populations, and results. METHODS: This systematic review identified all RCTs conducted before January 2023 testing dietary interventions in patients with cancer. Assessed outcomes included quality of life, functional outcomes, clinical cancer measurements (eg, progression-free survival, response rates), overall survival, and translational endpoints (eg, inflammatory markers). RESULTS: In total, 252 RCTs were identified involving 31 067 patients. The median sample size was 71 (interquartile range 41 to 118), and 80 (32%) studies had a sample size greater than 100. Most trials (n = 184, 73%) were conducted in the adjuvant setting. Weight or body composition and translational endpoints were the most common primary endpoints (n = 64, 25%; n = 52, 21%, respectively). Direct cancer measurements and overall survival were primary endpoints in 20 (8%) and 7 (3%) studies, respectively. Eight trials with a primary endpoint of cancer measurement (40%) met their endpoint. Large trials in colon (n = 1429), breast (n = 3088), and prostate cancer (n = 478) each showed no effect of dietary interventions on endpoints measuring cancer. CONCLUSION: Most RCTs of dietary interventions in cancer are small and measure nonclinical endpoints. Although only a small number of large RCTs have been conducted to date, these trials have not shown an improvement in cancer outcomes. Currently, there is limited evidence to support dietary interventions as a therapeutic tool in cancer 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.

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.

Use of subjective minimizing language at hematology and oncology conferences: A systematic review.

BACKGROUND: Subjective minimizing language in oncology conferences may undermine patient-centered care and hinder comprehensive treatment strategies. Subjective terms like "safe," "tolerable," and "well-tolerated" can vary in interpretation among individuals, making it difficult to compare results across trials and potentially downplaying significant risks and limitations associated with treatments. METHODS: This study evaluates subjective minimizing language in major oncology conferences and its use in adverse event reporting. We conducted a search of three electronic databases, ASCO, ASH, and ESMO, for published abstracts from January 1, 2019, to December 31, 2021. This study included prospective cohort studies or clinical trials in humans that used safety terms like "safe," "well-tolerated," "tolerable," "no new safety signal," or "no new safety concern" in the abstract text. RESULTS: Out of 34,975 reviewed records, 5299 (15.2%) abstracts used subjective minimizing language terms. The analysis included 2797 (52.8%) abstracts meeting the inclusion criteria. The majority of studies were Phase 1 trials (45.5%), followed by Phase 2 (29.6%) and Phase 3 trials (7.4%). Solid tumors accounted for the most common disease category (56.5%), followed by malignant hematology following (37.1%). Subjective minimizing terms like "safe" (69.2%), "well-tolerated" (53.2%), "tolerable" (25.6%), and "no new safety signal/concerns" (10%) were used frequently. Of the abstracts using subjective minimizing language (n = 2797), 81.9% reported data on any grade adverse events (AEs). Grade I/II AEs were reported in 62.6% of abstracts, Grade III/IV AEs in 78%, and Grade V AEs (death related to AEs) in 8.8%. Discontinuation due to AEs occurred in 11.4% (SD 9.5%) of studies using subjective minimizing language terms. CONCLUSIONS: Frequent use of subjective minimizing language in major oncology conferences' abstracts may obscure interpretation of study results and the safety of novel treatments. Researchers and clinicians should provide precise and standardized information to avoid overstatement of benefits and understand the true impact of interventions on patients' safety and well-being.

Multiple Myeloma in Young Patients: A Scoping Review.

Data on the disease course, presenting features, outcomes, and prognosis of younger patients with multiple myeloma (MM) are lacking. Younger patients with MM have historically been considered to have better outcomes primarily based on better tolerance of treatment and lack of medical comorbidities, but the specific age range of this population has not been uniformly defined. Given the lack of consistent data reporting in patients considered to be young MM patients, we performed a scoping review to highlight the research currently available to start drawing conclusions about these patients and highlight unmet areas of need to focus on further investigation. We searched Embase, Cochrane Central Register of Controlled Trials, CINAHL Plus, Web of Science, and the OVID version of MEDLINE including broad terms that embody the concept of young patients with MM. Our final review included 201 studies which were then categorized according to age group, number of patients, outcomes, and comparators to older patients, along with location and database when available. We have chosen to categorize 3 age groupings: <50: young adults with MM (YA MM), 50 to 65: mid-life adults with multiple myeloma (ML MM) and 65+: older adults with multiple myeloma (OA MM). This review demonstrates the heterogeneity that exists in defining and describing young patients with MM, highlights the lack of studies specifically addressing the unique needs of younger patients, and emphasizes areas of future research unique to this population.