Clinical Trials In Multiple Myeloma Research Articles

EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

Characteristics of Clinical Trials for Multiple Myeloma and CAR-T Cell Therapy: A Cross Sectional Analysis

Background: In recent decades novel CAR-T cell therapies have proven efficacious in the treatment of multiple myeloma, leading to FDA approval. As CAR-T cell therapies continue to be developed in clinical trials, it is important to assess trends over time that can inform drug development and relate to equitable access and representation. This cross-sectional study was conducted to analyze the characteristics of clinical studies for multiple myeloma and CAR-T cell therapy registered in ClinicalTrials.gov (CTG). Methods: All multiple myeloma clinical studies registered on CTG from September 27, 2007 to July 15, 2023 were identified using Advanced Search feature in ClinicalTrials.gov. Trial characteristics were assessed through relative frequency calculations. Odds ratio and 95% confidence intervals were determined for key characteristics and significance of findings. Results: Out of the 390,301 studies registered in CTG during this period, a mere 0.63% (2,457 studies) were conducted for multiple myeloma, compared to 1.61% (6,287 studies) for lymphoma and 1.46% (5,699 studies) for leukemia. Among these multiple myeloma studies, 85.47% (2,100 studies) were interventional and 14.82% (364 studies) were observational. Further, a total of 184 studies for CAR-T cell therapy in multiple myeloma were found in CTG registered during this period. Among these, 124 studies are still ongoing, constituting around 12.53% of the total 990 ongoing multiple myeloma studies. In multiple myeloma, around 51.98% (1276 studies) were industry sponsored, while 12.75% (313 studies) received funding from the National Institutes of Health (NIH) and other U.S. federal agencies (FA). The remaining 36.7% (901 studies) were funded by all others including individuals, universities and other research organizations. Similar funding trends were observed for 984 ongoing clinical studies. Notably, there were statistically significant differences in funding trends for CAR-T cell therapy within multiple myeloma studies. Industry funded a higher percentage for CAR-T cell therapy, 66.3%, compared to the overall 51.98% multiple myeloma studies that were industry sponsored. Further, NIH/ FA provided funding in 12.5% studies for CAR-T for CAR-T cell therapy, compared to a much lower 4.9% of all multiple myeloma studies. Interestingly, the premature discontinuation rates for CAR-T cell therapy clinical studies in multiple myeloma were significantly lower than those observed in overall multiple myeloma studies (OR 0.33; CI 0.177 to 0.611; p<0.01). This is promising for adherence in a heavily pretreated population. However, the proportion of studies with unknown status were significantly higher when compared to the overall multiple myeloma studies. (OR 2.84; 95% CI 1.94 to 4.18; p<0.01). There was no statistically significant difference between the unknown status and premature discontinuation rates of CAR-T cell therapy studies in multiple myeloma are myeloma compared to those in lymphoma. Conclusion: This cross-sectional study demonstrates that CAR T-cell therapy for multiple myeloma remains of prominent interest to industry followed by NIH and other U.S. funding organizations. There were significant trends noted that can inform drug development policy and relate to access and representation in trials. While the trends in the study discontinuation trends are promising, there is a need to address the proportion of studies with unknown status. Improved reporting and research into clinical trial funding and design will optimize efforts in developing cellular therapies for patients with myeloma.

The Validity of a Synthetic Control Arm Derived from Historical Multiple Myeloma Clinical Trials

Introduction While randomized phase III clinical trials (RCTs) are the gold-standard for establishing drug efficacy in the United States, external control arms (ECAs) may be valuable for both early and late phase drug development. An ECA is a collection of patients with the disease of interest who were treated outside of a clinical trial of interest (ie, target trial) and whose outcomes are compared to those of the target trial patients' to evaluate comparative drug efficacy and/or safety. ECAs created through rigorous statistical non-experimental methods such as matching patient-level characteristics may provide early estimates of comparative efficacy in advance of RCTs and offset prospective enrollment of control patients in randomized studies. We evaluate the validity of using a matched ECA to estimate the comparative efficacy of an experimental drug in relapsed refractory multiple myeloma (r/r MM). Methods From the anonymized Medidata Enterprise Data Store (MEDS), we identified historic RCTs in r/r MM containing patients exposed to an experimental drug as well as an active control drug (ie, a corticosteroid). Arbitrarily, we selected one trial to serve as the “target trial”. For the remaining trials, we collapsed all corticosteroid control patients into a single pool to construct an ECA. Using propensity score (PS) optimal full matching, we identified corticosteroid ECA patients by selecting from the candidate patients those whose baseline demographic and clinical attributes were similar to patients receiving the experimental drug in the target trial. Using the Kaplan-Meier (KM) estimator and a Cox proportional hazards regression, we first compared overall survival time (OS) of patients in the experimental drug arm vs control arm in the target trial. We then compared the OS in the experimental drug arm vs the ECA. Results We found fewer than five historic clinical trials from MEDS which were open-label RCTs conducted from 2010-2017. They enrolled r/r MM patients aged ≥18 years who had received more than two prior lines of therapy, one of which was lenalidomide and bortezomib. The target trial contained 300 patients in the investigational drug arm and 152 patients in the control arm. Using the PS matching, we identified 183 patients from the control arms in pooled trials that were matched with 290 patients in the investigational drug arm in the target trial (i.e., ECA). These ECA patients were then upweighted to be matched with 290 patients in the investigational drug arm in the target trial. Full matching successfully attenuated baseline differences between the investigational drug and ECA arms. Figure 2 shows the KM curves of OS (investigational vs control) in the target trial. Median OS was 13.25 months vs. 8.52 months (log-rank p<0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.60-0.92). Figure 2 shows the KM curves of OS, after full matching, using the ECA. Median OS was 13.51 months vs. 8.75 months (log-rank p<0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.58-0.94). Conclusions In this methodologic validation study, we have demonstrated that it is possible to produce an ECA from historical clinical trials data using propensity score methods which replicates the comparative efficacy estimate from a target without introducing bias. That is, the ECA, which was well balanced with the investigational arm with respect to baseline patient attributes, returned nearly identical estimates of comparative efficacy as assessed by OS of both target trial control arm and ECA against the target trial experimental arm. This work illustrates that it is possible to create a valid ECA even when historical data size is limited and to do so without excessive exclusion of non-matched patients. That the treatment effect on OS estimated in comparison to the randomized control was very closely matched by that of the ECA suggests this approach to ECAs may be used to (1) estimate comparative efficacy of therapies that have only been studied in single arm settings and/or (2) augment or replace a randomized control arm in future trials when ethically or practically challenging. Figure 1A. Kaplan-Meier OS estimates of target trial experimental (N=300) vs. control arm (N=152) Figure 1B. Kaplan-Meier OS estimates of target trial experimental (N=290) vs. ECA (N=290)

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma

ImportanceCancer 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).ObjectiveTo evaluate patterns of AE reporting in multiple myeloma (MM) randomized clinical trials (RCTs) published between 2015 and early 2023.Design, Setting, and ParticipantsFor 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 MeasuresThe 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.ResultsOf 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 RelevanceThese 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.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Creating Equitable and Inclusive Clinical Trials for Multiple Myeloma

Black and Latino/Hispanic populations are disproportionately impacted by multiple myeloma (MM) in the United States and are underrepresented in many clinical trials. The Multiple Myeloma Research Foundation sponsored a 1-day workshop of 46 experts spanning the ecosystem of MM research and care, including government, academia, nonprofits, pharma/biotech, community partners, and retail pharmacy. Specific, tangible steps to overcome the well-documented barriers to improving the diversity and inclusivity of clinical trials were discussed, including broadening inclusion/exclusion criteria, reducing the financial and other burdens of trial participants, selecting diverse study sites, including implicit bias training, and taking steps to empower patients.

P-079 Impact of treatment effect on measurable residual disease (MRD) and progression-free survival (PFS): an aggregate data analysis from randomized clinical trials in multiple myeloma (MM)

P-079 Impact of treatment effect on measurable residual disease (MRD) and progression-free survival (PFS): an aggregate data analysis from randomized clinical trials in multiple myeloma (MM)

Impact of treatment effect on MRD and PFS: an aggregate data analysis from randomized clinical trials in multiple myeloma

Impact of treatment effect on MRD and PFS: an aggregate data analysis from randomized clinical trials in multiple myeloma

A patient survey indicates quality of life and progression-free survival as equally important outcome measures in multiple myeloma clinical trials

A patient survey indicates quality of life and progression-free survival as equally important outcome measures in multiple myeloma clinical trials

Listening to What Matters Most: Consumer Endorsed Patient Reported Outcome Measures (PROMs) for Use in Multiple Myeloma Clinical Trials: A Descriptive Exploratory Study.

Patients with multiple myeloma (MM) experience some of the highest levels of symptom burden of all hematological malignancies. Therefore, assessment of quality of life (QoL) is critical for the delivery of patient-centered cancer care. Patient reported outcome measures (PROMs) are commonly used to measure QoL in people with MM. However, it is unknown whether measures used, are appropriate and informative to address issues that matter most to patients. This exploratory study was designed to establish consumer endorsed PROMs to measure QoL in people with MM. This was a descriptive, exploratory study. Participants were invited to provide feedback on the acceptability, appropriateness, and practicability of ten commonly used PROMs via telephone-based, semi-structured interviews and surveys. Data were analyzed using a manifest content analysis approach and descriptive statistics. 26 individuals participated in the study. Participants emphasized the importance of selecting a suite of PROMs that captures the diversity of quality-of-life experiences and priorities reported over the course of treatment, while minimizing the burden of completing PROMs. Based on these criteria, a suite of three PROMs - the MyPOS, the Brief Fatigue Inventory, and COST-FACIT were endorsed by study participants. To our knowledge, this is the first study of its kind to establish a suite of consumer-endorsed PROMs for use in clinical trials in patients with MM. Ensuring that the patient voice is at the center of advances in cancer treatment is a hallmark of quality cancer care.

Follow up duration of phase III Multiple Myeloma Clinical Trials: A systematic review.

Long-term follow-up of multiple myeloma (MM) clinical trials are needed to assess long-term outcomes. We aimed to investigate the length of follow-up of all phase III MM clinical trials. Median follow-up duration of clinical trials of newly diagnosed MM was longer when compared to relapsed/refractory MM clinical trials (42.7 vs. 20.5 months, respectively). The follow-up duration of phase III clinical trials in MM is relatively short when compared to the improved outcomes in the current era. Efforts should be made to facilitate long-term clinical trials follow-up and/or publication of results of updated results.

Racial bias in multiple myeloma clinical trials: Racial minorities continue to miss out on treatment advances.

e20009 Background: Adequate representation of participants based on race and ethnicity in a clinical trial helps ensure the results' generalizability. There is a disparity in the participation of minorities in oncology clinical trials despite higher incidence and disease burden in them. The incidence of Multiple Myeloma (MM) in AA (African American) is twice as compared to White, and they are twice as likely to die from MM compared to White. Methods: We queried ClinicalTrials.gov in February 2023 for all completed interventional trials with the published results for Multiple Myeloma in the US. Demographic data were collected from all the studies. If not available, the primary manuscript was searched using the trial number. We excluded the studies involving other malignancies and conducted outside of the USA. Trials on prevention, diagnostics, supportive care, and antibiotics were also excluded. Incidence data of Multiple myeloma was obtained from the SEER database for each ethnicity and race. Results: Out of 194 trials included in our study, 133 (68.56%) reported at least either race or ethnicity. Of these trials, 83 (42.78) reported race, 124 (63.91) reported ethnicity, and 77 (39.69) reported both race and ethnicity. 5.67% of the trial participants were reported as Hispanic race. White, AA, and Asian represented 79.82%, 11.36%, and 3.10% of the trial participants, respectively. The number of trials reporting race or ethnicity has increased when comparing the trials conducted between 2001-2011 and 2012-2022 (58.3% vs. 90.3%); OR 6.4; 95% CI 2.77-17.98; p<0.001. Participation of Asians increased (2% vs. 5.5%; p<0.0005), while there were slight changes among AA (11.7% vs. 10.6%, p=0.1475), Hispanic (5.4% vs. 6%; p=0.3863), and White (80.8% vs. 77.8%, p=0.208) between 2001-2011 and 2012-2022. Conclusions: Despite ongoing efforts to improve the diversity of minorities in oncology trials, they are still under-enrolled in multiple myeloma. More studies and interventions are needed to address this disparity. [Table: see text]

Eligibility criteria and enrollment of a diverse racial and ethnic population in multiple myeloma clinical trials

AbstractThe narrow eligibility criteria may contribute to the underrepresentation of racial and ethnic subgroups in cancer clinical trials. We conducted a retrospective pooled analysis of multicenter global clinical trials submitted to the US Food and Drug Administration between 2006 and 2019 to support the approval of the use of multiple myeloma (MM) therapies that analyze the rates and reasons for trial ineligibility based on race and ethnicity in MM clinical trials. Race and ethnicity were coded per Office of Management and Budget standards. Patients flagged as having screen failures were identified as ineligible. Ineligibility rates were calculated as the percentage of patients who were ineligible compared with the screened population within the respective racial and ethnic subgroups. Trial eligibility criteria were grouped into specific categories to analyze the reasons for trial ineligibility. Black patients (24%) and other (23%) race subgroups had higher ineligibility rates than White patients (17%). The Asian race had the lowest ineligibility rate (12%) among all racial subgroups. Failure to meet the hematologic laboratory criteria (19%) and treatment-related criteria (17%) were the most common reasons for ineligibility among Black patients and were more common in Black patients than in other races. Failure to meet disease-related criteria was the most common reason for ineligibility among White (28%) and Asian (29%) participants. Our analysis indicates that specific eligibility criteria may contribute to enrollment disparities for racial and ethnic subgroups in MM clinical trials. However, the small number of screened patients in the underrepresented racial and ethnic subgroups limits definitive conclusions.

Accounting for the High Enrollment of African Americans on Winship Cancer Institute's Myeloma Clinical Trials.

Thirty-four percent of Multiple Myeloma (MM) clinical trial participants at Winship Cancer Institute (Winship) are African American (AA); however, AAs make up only 4.5 percent of myeloma clinical trial participants in the United States. Given our high enrollment, we aimed to measure AAs' trust in providers and identify if clinical trial enrollment barriers exist. A member of the ethics research team surveyed AA patients who had consented to a MM clinical trial at Winship. Three validated surveys were used: Trust in Medical Research (TMR); Human Connection (THC) which measures how much patients feel they are heard and valued by their physicians; and the Duke Intrinsic Religiosity Scale (DUREL) which measures strength of religious engagement and belief. The survey also included questions about the impact of side effects, distance to the trial center and trial related costs on the decision to participate in clinical trial. Ninety-two percent (61/67) of patients approached consented. The mean TMR score and the mean THC score were significantly higher (P-value < 0.001) than the results obtained in key national surveys (TMR 14.9 compared to 11.65; THC 57.7 compared to 54.6). These two surveys were significantly correlated, meaning trust and human connection increase or decrease in tandem. The 3 religiosity subscale results showed high religiosity (3.84, 4.36, and 4.35 with 5 being the highest score). The mean scores of the importance of the investigational agent's side effects, trial costs, and distance to trial center on the decision to enroll in a clinical trial were also high (8.5, 7.8, and 6.5, respectively, with 10 being the most important). In our study population, high trust and human connection overcame other trial participation barriers: strong religious beliefs and concerns about side effects, costs, and travel distance. We present a roadmap to guide investigators to increase human connection, and hopefully trust.

The prevalence and outcomes of frail older adults in clinical trials in multiple myeloma: A systematic review

Multiple myeloma (MM) is an incurable blood cancer that primarily affects older adults. Several frailty tools have been developed to address the heterogeneity of aging in this population. Uptake of these measures has been variable, leading to a gap in knowledge regarding the proportion of enrolled trial participants considered frail and uncertainty in the treatment-related effects and outcomes among this high-risk population. We performed a systematic review of therapeutic interventional MM clinical trials reporting on frailty. We included 43 clinical trials (24 randomized controlled trials and 19 non-randomized trials) which met eligibility criteria. Frailty was increasingly incorporated in studies in more recent years with 41.9% of included studies being reported in the last two years. Commonly used frailty tools included the International Myeloma Working Group (IMWG) frailty index (41.8%), and the simplified frailty score (39.5%). Frailty status was categorized with 3 levels as (frail, intermediate fit, or fit) in 51.2% of the studies and dichotomized (frail, non-frail) in 18.6% of studies. Frailty prevalence greatly varied across trials ranging from 17.2% to 73.6% of the cohort. Of the included studies, 72.0% conducted subgroup analysis (planned or post-hoc) based on frailty status. Most studies demonstrated a consistent benefit of MM interventions among the frail and non-frail populations, however in general, frail patients had worse outcomes compared to the fit. Although frailty is increasingly being incorporated in MM clinical trials, due to the variation in both the definition and categorization of frailty, there remains heterogeneity in the prevalence of frailty and its potential associated impact on outcomes.

Minority groups underrepresented in hematologic cancer trials

Minority groups underrepresented in hematologic cancer trials

Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for novel therapeutic strategies to treat MM. The isoprenoid biosynthetic pathway (IBP) is responsible for the post-translational modification of proteins belonging to the Ras small GTPase superfamily, such as Ras, Rho and Rab family members. Given the important roles these GTPase proteins play in various cellular processes, there is significant interest in the development of inhibitors that disturb their prenylation and consequently their activity in MM cells. Numerous preclinical studies have demonstrated that IBP inhibitors have anti-MM effects, including the induction of apoptosis in MM cells and inhibition of osteoclast activity. Some IBP inhibitors have made their way into the clinic. For instance, nitrogenous bisphosphonates are routinely prescribed for the management MM bone disease. Other IBP inhibitors, including statins and farnesyltransferase inhibitors, have been evaluated in clinical trials for MM, while there is substantial preclinical investigation into geranylgeranyl diphosphate synthase inhibitors. Here we discuss recent advances in the development of IBP inhibitors, assess their mechanism of action and evaluate their potential as anti-MM agents.

Toxicity Reporting Is Inconsistent and Incomplete, and Subjective Minimizing Language Is Common in Acute Leukemia Clinical Trials: A Systematic Review of Randomized Controlled Trials Presented at ASH between 2017-2021

Introduction: Despite calls for greater transparency in reporting harms in cancer clinical trials, data on drug toxicity continues to be obscured by incomplete reporting and use of subjective, minimizing language. Subjective terms such as "acceptable" or "tolerable" toxicity are commonly employed in peer-reviewed publications in oncology (Gyawali et al. BMJ 2018). The use of subjective language that minimizes harms in clinical trials can adversely impact informed consent and shared decision-making by overlooking the fact that only individual patients can determine if a therapy is tolerable. The scope of this problem in clinical trials in hematologic malignancies and at medical conferences, however, remains unknown. To further assess this issue, we conducted a systematic review of abstracts presented at ASH annual meetings from 2017-2021 to characterize toxicity reporting and use of subjective, minimizing language in phase 3 clinical trials in acute leukemia. Methods: Following a pilot phase to identify and define minimization terms, we conducted a systematic search of all ASH abstracts from 2017-2021. Phase 3 randomized controlled trials in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) were included; subset analyses, long-term follow up studies and supportive care trials were excluded. Subjective, minimizing language was defined a priori as use of "acceptable", "tolerable", "manageable", "favorable", "feasible" "safe", and/or "limited" in reference to treatment-related adverse events (AE), which falsely suggested that patients deemed the therapy as such without evaluating patient experiences. Primary toxicity outcome assessment included fatal AE (FAE), serious AE (SAE), and use of common terminology criteria for AE (CTCAE), as well as absent and incomplete AE reporting, defined in Table 1A. Complete severe AE reporting was defined as reporting of cumulative rates (per 100 patients; %) of CTCAE grade ≥3 toxicities or cumulative SAE. An across-disease assessment was performed including phase 3 clinical trials in multiple myeloma and lymphoma from the same time period. Results: 341 studies in acute leukemia underwent abstract screening, of which 40 met inclusion criteria. Study characteristics are reported in Table 1A. AE reporting was variable across trials. Ten trials (25%) provided no information on AE in their abstract, and 6 (15%) had incomplete AE reporting. Subjective, minimizing language was used to describe AE data in 16 trials (40%), with "tolerable" and "acceptable" being the most frequently used terms, and a total of 26 (65%) studies had either absent AE reporting or used minimizing terms (Table 1A). Minimizing language was seen across a range of different study types, including trials in patients with adult and pediatric leukemia, trials of systemic therapies and stem cell transplantation, and trials in frontline and relapsed/refractory settings. Severe toxicities were reported in 10 of the 16 trials that used minimizing language (62.5%) and FAE in 6 of 16 (37.5%). In experimental arms of trials using minimizing terms, rates of CTCAE grade ≥3 AE or SAE ranged from 17-97.3%, and rates of fatal AE from 0-19.5% (Table 1B). FAE and severe AE rates were similar or numerically higher in abstracts that used minimizing terms compared to those abstracts that did not. A total of 65 abstracts reporting results of randomized clinical trials in multiple myeloma and lymphoma (including Hodgkin and non-Hodgkin lymphoma) were available for across-disease assessment and demonstrated similar high rates of absent and incomplete AE reporting, as well as subjective, minimizing terms, used to describe a wide range of severe AE (Table 1B). Discussion: This systematic review of ASH abstracts highlights inconsistent, incomplete, and often absent toxicity reporting, as well as frequent use of subjective, minimizing language. The findings suggest that formal toxicity minimization and subjective minimizing terms are common. Conference abstracts often form the first impression of a clinical trial and can have a disproportionate influence on physician perspectives, thus impacting clinical practice. These findings will inform a larger systematic review to inform policy to improve reporting transparency at hematology and oncology conferences. #co-senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Use and Reporting of Cytogenetics in Phase III Multiple Myeloma Clinical Trials

INTRODUCTION Multiple myeloma (MM) is an incurable neoplasm arising from mature plasma cells in the bone marrow. Different genetic aberrations including translocations and deletions have been described in MM especially involving immunoglobulin heavy chain locus in chromosome 14. Such translocations include t(4;14), t(14;16), and t(14;20) in addition to del13q and del1p32. These events are associated with poor prognosis and are under investigation for novel therapeutic approaches. Identification of these events can be detected by either metaphase cytogenetics or by fluorescent in situ hybridization (FISH). We aimed to study the use and reporting of cytogenetics in phase III clinical trials of MM. METHODS We performed a cross-sectional study by retrieving interventional MM phase III clinical trials from clincaltrials.gov. All phase III interventional MM clinical trials were included. NCT number, article title, publication date, initiation year, number of enrolled patients funding source, location, cytogenetics performed, and the percentage of unknown/missing cytogenetics were extracted. Descriptive statistics, the Mann-Whitney U test, and the Spearman correlation test were used to analyze the data. Statstical analysis was done with SPSS® Statistics. RESULTS Of 271 phase III clinical trials, 101 studies performed cytogenetics testing. Full-text publications with results were available for 87% of those studies (n=88/101). The total number of patients enrolled was 53,411 with a median number of 455 (IQR= 430) per trial. The median publication year was 2017 (IQR= 8) and the median study initiation year was 2011 (IQR=9). del(17p) was the most commonly performed and/or reported cytogenetic abnormality in 93 trials (92%), followed by t(4;14) in 90 trials (89%), t(14;16) in 66 trials (63%), 1q gain in 15 trials (15%), del13q in 14 trials (14%), and t(14;20) in 8 trials (8%). Missing cytogenetics data were reported in 71 trials and a total of 9831 patients with a median of 23.37% (IQR= 38.33%) missing cytogenetic results per trial. [Figure.1] The later the initiation date of the trial significantly correlated with a lower missing cytogenetics percentage (p-value <0.05). The number of enrolled patients, trial location, and funding type did not correlate with missing cytogenetics percentage. CONCLUSIONS Less than half of MM trials reported the use of cytogenetics in testing for enrolled patients. When reported approximately 1 of 4 enrolled patients had an unknown/missing cytogenetics profile. A trend of improvement indicated by lower percentage of missing cytogenetics testing was noted in recently conducted clinical trials. Efforts should be made to minimize missing cytogenetics data in enrolled MM patient in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal