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.

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 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 prior to 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: 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/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 a primary endpoint in 20 (8%) and seven (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 non-clinical 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.

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.

Clinician preferences on treatment of smoldering myeloma: a cross-sectional survey.

Background: Smoldering myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) with a variable risk of progression. The management of high-risk SMM (HR-SMM) remains controversial, particularly with changes in diagnostic criteria that led to reclassifying of some patients with SMM to MM. This study aimed to assess clinician preferences for whether to treat patients with HR-SMM and/or patients with MM diagnosed solely by SLiM criteria (free light chain ratio >100, bone marrow plasma cell percentage >60, greater than two focal marrow lesions on MRI) through an electronic survey. Methods: This was a cross-sectional survey of clinicians, conducted via an anonymous online REDCap survey from May 16th to July 5th, 2023. The survey included questions on demographics, SMM surveillance practices, and management preferences for two clinical scenarios (HR-SMM and MM based solely on the free light chain ratio >100 criterion). Data was analysed descriptively via Microsoft Excel. Findings: A total of 146 clinicians completed the full survey, with 92% recommending against routine treatment for a patient with HR-SMM based on a single time point assessment, instead preferring active surveillance. For patients with MM diagnosed solely on the basis of a free light chain ratio >100, 61% recommended active treatment, while 37% recommended active surveillance. The most common reasons recommending against treatment of HR-SMM were toxicity, lack of demonstrated overall survival benefit, and low MM-defining event rates in clinical trials. Interpretation: The survey indicates that most clinicians recommend against routine treatment for HR-SMM. Active surveillance is the prevailing standard of care and it is therefore an appropriate control arm in future SMM trials. More randomised trials are needed to determine if early treatment of modern-era SMM offers a net benefit to patients. Funding: None.

Projecting complete redaction of clinical trial protocols (RAPTURE): redacted cross sectional study.

OBJECTIVES: To characterise redactions in clinical trials and estimate a time when all protocols are fully removed (RAPTURE). DESIGN: Redacted cross sectional study. SETTING: Published phase 3 randomised controlled trials from 1 January 2010 to ██████████████. PARTICIPANTS: New England Journal of Medicine, ██████████, and Journal of the American Medical Association. MAIN OUTCOME MEASURES: █████ ████████ ██████████████ ██████ ██████████ ████████ ████████ ██████████ ███████████ ████████████ ████████████ ████████████████████████ ██████████████████ RESULTS: ████████████████████ met the inclusion criteria, with 268 (56.7%) research protocols available and accessible. The rate of redactions in protocols has increased from 0 in 2010 to 60.8% in 2021 (P<0.001). The degree of data redaction has also increased, with the average cumulative redactions among industry funded trials rising from 0 in 2010 to 3.5 pages in 2021 (P<0.001). Modelling predicts that RAPTURE is expected to occur between 2073 and 2136. Redactions featured predominantly in ████████ sponsored trials and mostly occurred in the statistical design. CONCLUSIONS: This study highlights the rise in protocol redactions and predicts that, ██████████████████████████████████████████ will be entirely redacted between 2073 and 2136. A legitimate rationale for the redactions could ███ be found. A multipronged strategy against protocol redactions is required to maintain the integrity of science. AVAILABILITY: This paper is partially redacted, but for the sake of ███████████, a version without any redactions can be found in the supplementary material.

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma.

Importance: Cancer treatment can result in burdensome toxic effects that profoundly affect patient quality of life. In seeking to emphasize the efficacy of tested treatments, clinical trial reports may use subjective or minimizing terms to describe adverse events (AEs). Objective: To evaluate patterns of AE reporting in multiple myeloma (MM) randomized clinical trials (RCTs) published between 2015 and early 2023. Design, Setting, and Participants: For this cohort study, the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to assess the prevalence of minimizing terms in MM RCTs published between January 1, 2015, and March 1, 2023. Minimizing terms were defined as subjective terms used to favorably describe the safety profile of the intervention. The terms searched included convenient, manageable, acceptable, expected, well-tolerated, tolerable, favorable, and safe. Final data analysis was performed on July 21, 2023. Main Outcomes and Measures: The primary outcome was the occurrence of at least 1 minimizing term in an article. Univariate logistic regression analyses were performed to evaluate the association between the presence of at least 1 minimizing term and the actual incidence of grade 3 or 4 AEs, serious AEs, or grade 5 AEs. Results: Of the 65 RCTs included, 56 (86%) used minimizing terms when describing treatment-emergent AEs. The most frequently used minimizing terms were well-tolerated or tolerable in 29 trials (45%), manageable in 18 (28%), and acceptable in 16 (25%). Grade 3 or 4 AE rate in the examined RCTs ranged from 23% to 94%, with a median of 75% (IQR, 59%-82%). A univariate regression analysis demonstrated no association between the use of minimizing terms and grade 3 or 4 AE rates (odds ratio [OR], 1.35 [95% CI, 0.88-2.10] per 10% AE rate increase; P = .17) or grade 5 AE rates (OR, 3.16 [95% CI, 0.27-12.7] per 10% AE rate increase; P = .45). Conclusions and Relevance: These findings suggest that trial investigators and sponsors regularly use minimizing terms to describe toxic effects in MM trials, and use of this terminology may not reflect actual AE rates in these studies. Instead of using these terms, trial investigators should highlight event rates and patient-reported outcomes, to allow clinicians and patients to better evaluate the true tolerability of AEs.

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.

The story of the development of generic lenalidomide: How one company thwarted the Hatch-Waxman Act to generate billions of dollars in revenue.

Lenalidomide (Revlimid®) was originally approved by the Food and Drug Administration (FDA) in 2005, however, a generic version was not available until 2022. In that time, the price of lenalidomide has increased more than 20 times, and in 2021 alone, it accounted for >$5.8 billion dollars in Medicare Part D spending. This was a direct consequence of legal tactics employed by the manufacturer to thwart development of generic formulations of lenalidomide. In this report, we review the clinical development of lenalidomide, provide background on generic drug manufacturing in the United States (US), describe the steps that the manufacturer took to prevent entry of generic lenalidomide into the US market, and advocate for legislative reform of the FDA approval process and patent law protections in the US.

Randomised controlled trials evaluating anticancer therapies in haematological cancers: an overview of global research activity.

Background: Design, results, and interpretation of oncology randomised controlled trials (RCTs) have changed substantially over the past decade. In this study, we describe all RCTs evaluating anticancer therapies in haematological cancers published globally during 2014-2017 with comparisons with solid tumours RCTs. Methods: A PubMed literature search identified all phase 3 RCTs of anticancer therapy for haematological cancers and solid tumours published globally during 2014-2017. Descriptive statistics, chi-square tests and the Kruskal-Wallis test were used to compare RCT design results, and output between haematological cancers and solid tumours as well as for different haematological cancer subtypes. Results: 694 RCTs were identified; 124 in haematological cancers and 570 in solid tumours. Overall survival (OS) was the primary endpoint in only 12% (15/124) of haematological cancer trials compared to 35% (200/570) in solid tumours (p < 0.001). Haematological cancer RCTs evaluated the systemic novel therapy more often than the solid tumour RCT (98% versus 84%, p = 0.002). Use of surrogate endpoints like progression-free survival (PFS) and time to treatment failure (TTF) were more common in haematological cancers than solid tumours (47% versus 31%, p < 0.001). Within haematological cancers, the use of PFS and TTF was more prevalent in chronic lymphocytic leukaemia and multiple myeloma as compared to others (80%-81% versus 0%-41%, p < 0.001). Seventy-eight percent of haematologic trials were funded by industry as compared to 70% of solid tumour trials. Only 4% (5/124) of haematologicalcancer trials were led by investigators in upper-middle and lower-middle-income countries as compared to the 9% of solid tumour trials. Conclusion: The fact that only 12% of haematological cancer RCTs are designed to show improvements in OS is of grave concern for the field and the care of future patients. This is further compounded by the highly prevalent use of alternative primary endpoints that are rarely valid surrogates for OS in haematological cancers.

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.

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis.

Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

Incidence of second primary malignancies in patients with multiple myeloma receiving anti-CD38 monoclonal antibodies: A systematic review and meta-analysis.

Anti-CD38 monoclonal antibodies (mAbs) are commonly used for treating newly diagnosed and relapsed/refractory (r/r) multiple myeloma (MM). However, concerns have been raised about the occurrence of second primary malignancies (SPMs) in patients receiving anti-CD38 mAbs. Assessing the safety data for rare adverse events like SPMs is challenging because individual clinical trials are typically focused on the primary endpoint. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) published between January 2005 and April 2022, including patients with newly diagnosed or r/r MM. Our aim was to compare SPM rate with the use of anti-CD38 mAb-based regimens with other anti-myeloma regimens. After a median follow-up of 35.3 months (range: 8.2-56.2), we found that exposure to anti-CD38 mAbs was associated with an increased risk of developing SPMs compared to the control group (6.8% vs. 5.2%; Peto odds ratio [OR]: 1.53 [95% confidence interval (CI): 1.20-1.95]; I2= 0%, p-value for heterogeneity= 0.44). This increased risk was primarily driven by non-melanoma cutaneous cancers (92 vs. 47; Peto OR: 1.77 [95% CI: 1.25-2.51]; I2 = 0%, p-value for heterogeneity = 0.54). However, there was no significant difference in the incidence of solid tumors (including malignant melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) or hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27]). In conclusion, the use of anti-CD38 mAb-based combination regimens is associated with a higher risk of non-invasive cutaneous SPMs, but not solid tumors or hematologic SPMs. The increased occurrence of non-invasive cutaneous SPMs may be due to enhanced monitoring resulting from longer treatment duration with anti-CD38 mAbs.

Detecting Selection Bias in Observational Studies-When Interventions Work Too Fast.

This Viewpoint discusses the limitations that observational studies have in drawing causal inferences.