Real-world access to MM clinical trials – international and national disparities in equity and access

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States (U.S.), with a median age at diagnosis of approximately 70 years.¹ Challenges exist in the delivery of MM treatment and clinical trial participation, with disparities arising according to patient characteristics including age, race/ethnicity, country of origin, and locality.^2-6 Here, the Multiple Myeloma Hub presents findings from four studies exploring these disparities at the national and international level.

Representing the wider MM population in clinical trials

Fatoki et al.² performed a systematic review to identify where randomized MM trials, with findings resulting in MM drug approvals by the Food and Drug Administration (FDA), had been conducted. The primary research aim was to determine MM trial characteristics including approval time; participating country characteristics, such as country income level and specific location based on ClinicalTrials.gov trial registration; approval rates; and the number of enrolled patients.²

The literature search aimed to identify all MM clinical trials that were conducted between 2005 and 2019, had achieved their primary endpoint, enrolled patients outside the U.S., and resulted in FDA approvals.

The primary outcomes of the study were

• to identify the median number of countries involved in clinical trials leading to FDA approval; and
• to group countries according to geographic region and income level.

Secondary outcomes included

• the proportion of non-U.S. countries with drug/regimen approval within 1, 3, and 5 years of FDA approval; and
• the median time from FDA approval to drug/regimen approval in trial countries vs other countries

Results

The study identified 18 MM clinical trials, each of which led to the approval of a drug or regimen by the FDA. Patients were enrolled from trial countries outside the U.S. in a median of 15 studies (range, 1–33 studies). Patients were enrolled from high-income countries all studies (18/18; 100%), relative to lower numbers in low-income countries, including:

• upper-middle income countries: 61%
• lower-middle-income countries: 28%
• low-income countries: 0%

Europe and Central Asia both enrolled patients to the highest portion of trials (16/18; 89%), followed by North America (14/18; 78%). One trial enrolled patients in sub-Saharan Africa; however, no trials enrolling patients in South Asia or the Caribbean were identified.

Of the 18 included clinical trials, 22% (4/18) received drug/regimen approval in all countries which enrolled patients within 1 year of FDA approval; this increased to 27% (4/15) at 3 years and 42% (5/12) at 5 years after FDA approval. The median time from FDA approval to trial country approval was 10.9 months (interquartile range [IQR], 4–12 months).

Discussion

MM trials leading to FDA approval are generally conducted in high-income countries, in regions such as Europe, Central Asia, and North America. Geography and national income-level can create profound discrepancies in the execution of clinical trials involving novel therapies and the likelihood of associated approvals, further highlighting the exclusion of patients with MM from low-income countries.

The impact of race and ethnic origin on clinical trial recruitment for MM patients

Casey et al.³ conducted an analysis of the ClinicalTrials.gov database to gather demographic and geographic data from clinical trials involving patients with MM.³ Data collected, including race, ethnicity, sex, and malignancy subtypes, were compared with real-world data on disease rates by race, ethnicity, and country-level mortality. The study was primarily focussed on identifying how the race and ethnic origin of patients with MM can impact clinical trial recruitment.

Results

This systematic review identified 61 studies, of which 29 reported information and data on race. After initial exclusion, a further 12 studies were reincluded as data on racial demographics was identified from clinical trial primary manuscripts and protocols. Data was extracted from a total of 41 and 20 clinical trials relating to race and ethnicity, respectively. Figure 1 outlines the inclusion and exclusion of all trials, studies were also excluded where data on race categorized patients as only White or non-White. A total of 13,731 patients were included across all identified clinical trials (including other haematologic malignancies), of whom 81.6% were White.

CT, clinical trial; FDA, Food and Drug Administration; PM, primary manuscript.
Adapted from Casey, et al.³

Of the 41 studies identified, 16 included patients with MM, with a total of 7,287 patients; data on race and ethnicity were available in 75% and 50% of studies, respectively. Males were found to be underrepresented in MM clinical trials relative to the general population (55.3% vs 60.2%; p < 0.0001). From a geographical perspective, MM was the only haematologic malignancy shown to have adequate regional and state recruitment to clinical trials. Overall, 30% of all patients were recruited in the U.S.

In total, 27.4% of patients with MM in the U.S. identified as Black, with 4.7% of patients identified in clinical trials being of Black origin. All ethnic minorities identified were underrepresented relative to data on MM patients gathered from the U.S. Surveillance, Epidemiology and End Results (SEER) Program (Table 1).

Table 1. Race and ethnicity data for patients with MM identified from ClinicalTrials.gov relative to national SEER data*

CI, confidence interval; PI, pacific islander; SEER, Surveillance Epidemiology and End Results. *Adapted from Casey, et al.3
Demographic (95% CI), %	ClinicalTrials.org	SEER	Pearson’s Coefficient	p value
Black	4.7 (4.1–5.1)	27.4 (26.8–28)	1,659	<0.0001
White	80.3 (79.4–81.2)	68.7 (68.1–69.4)	359.2	<0.0001
Asian/PI	10.7 (10.0–11.4)	3.4 (3.2–3.6)	582.2	<0.0001
Native American	<0.1 (0.0–0.0)	0.2 (0.0–0.0)	109.0	<0.0001
Hispanic	2.9 (2.3–2.4)	17.5 (17.0–18.0)	558.5	<0.0001
Male	44.7 (54.1–56.5)	60.2 (59.6–60.9)	50.9	<0.0001

Discussion

Compared with real-world data, participants of pivotal clinical trials for MM are unrepresentative of the affected population; Black patients and those from ethnic minorities are significantly underrepresented.

Geographic and racial disparities in patients with MM accessing novel bispecific antigen and chimeric antigen receptor-T cell clinical trials in the U.S.

Answering a similar research question to the work of Casey et al.,³ Alqazaqi et al.⁴ conducted a review of clinical trials investigating chimeric antigen receptor (CAR) T-cell and bispecific-antibody therapies listed on ClinicalTrials.gov.⁴ Their objective was to determine if access was equitable for patients with MM across all geographical areas, in particular for Black populations who have a higher incidence of the disease.

Study design

A cross-sectional study of the ClinicalTrials.gov database was conducted, identified MM studies utilized CAR T-cell and bispecific-antibody therapies and were registered on the website up to and including January 31, 2022. Trials at all recruitment stages were incorporated, including those actively recruiting, completed, active but nonrecruiting, and suspended or terminated. Trials conducted at a single center in the U.S. were excluded. Search terms included:

• plasmacytoma
• MM
• plasma cell dyscrasia
• CAR-T
• chimeric antigen receptor T cells
• chimeric
• bispecific antibodies
• bispecific
• B-cell maturation antigen (BCMA)
• T-cell engager

Results

Of 162 studies identified, 69 multicentre trials were included in the final analysis, with a total of 7,896 patients enrolled or expected to be enrolled; 4,386 patients (55.5%) were involved with CAR T-cell clinical trials.

Using U.S. Census Bureau data, it was identified that only 35.9% of Black patients lived in a county with an open trial. Of the 10 U.S. states with the largest Black demographic (range, 18.6–41.4%), three (30%) had no CAR T-cell or bispecific-antibody open clinical trials, with a further 30% having less than three open studies. CAR T-cell trials were run across an average of 7.8 sites (range, 1–30 trials), compared with 8.7 sites for bispecific antibodies (range, 1–26 trials). Overall, 17 states (34%) had no CAR T-cell or bispecific-antibody clinical trials open.

No association with trial feasibility or availability of infrastructure was found In the states with the largest Black population, with most having at least one transplantation center. Of the studies identified, 96% were industry-sponsored, with safety-related, efficacy-related, and both safety- and efficacy-related primary outcomes in 59%,16%, and 23%, respectively.

Discussion

Patients with MM from Black populations are not equitably represented by the geographic distribution of CAR T-cell and bispecific-antibody clinical trials across the U.S. A large number of U.S. states with high a proportion of Black populations either have no, or significantly fewer, open clinical trials compared with the national state average. Actions must be taken to help ensure that CAR T-cell and bispecific-antibody clinical trials reflect national demographics to deliver unbiased and relevant healthcare to patients with MM.

Disparities in MM clinical trials among older patients

White et al.⁵ performed an analysis of structured data from a national patient electronic health record, including 280 U.S. cancer clinics. Included patients were ≥18 years of age, diagnosed with MM between January 2011 and December 2016, and had received at least one line of therapy within 90 days of diagnosis.

The primary outcome was clinical trial participation in any of the first five lines of therapy. Overall rate of trial participation was compared between adults ≥70 and <70 years of age. Variables including age, sex, race, ethnicity, geographic region, treatment setting, baseline Eastern Cooperative Oncology Group (ECOG) Performance Status, and organ function were analyzed.

The study identified 4,522 eligible patients, the median age was 69 years (IQR, 61–77 years) and median follow-up time was 4.5 years; 54% of patients were male. Overall, <3% of older adults with MM participated in clinical trials compared with 3.9% of the overall population. Patients ≥70 years of age were half as likely to participate in clinical trials than those <70 years of age.

Patients with MM who enrolled in clinical trials were more likely to be

• younger (median age, 63.5 years vs 69.0 years; p < 0.001);
• male (62.9% vs 53.4%; p = 0.012); and
• non-Hispanic White (82.4% vs 65.8%; p < 0.001).

A subanalysis of patients ≥70 years demonstrated lower rates of enrolment among

• patients ≥75 years vs <75 years (2.1% vs 4.3%; p = 0.003);
• females vs males (2.2% vs 3.3%; p < 0.01);
• non-Hispanic Black or Hispanic patients vs non-Hispanic White patients (2.2% and 0% vs 3.4%; p < 0.001);
• ECOG Performance Status ≥2 vs 0–1 (1.5% vs 5.1%; p < 0.001); and
• impaired baseline glomerular filtration rate of ≤45 ml/min vs >45 ml/min (1.9% vs 3.8%; p = 0.03).

Rates of clinical trial participation for different lines of treatment can be seen in Figure 2.

*Adapted from White, et al.⁵

Discussion

Older adults, especially those above the age of 70, are under-represented in MM clinical trials and less likely to be recruited. Patients over 70 years of age are often frail, heavily pretreated, more likely to have received multiple lines of therapy, and have a higher risk of progressive disease. Further to this, non-White patients ≥70 years are even less likely to be recruited to clinical trials. It is imperative that clinical trials are conducted to include this sub-population of patients with MM; given their lower uptake in trials, there is a need for the development of strategies to increase active recruitment in older adults with MM.

In a recent editorial by Chandhock and Sekkers,⁶ the need for equity within cancer research, encompassing the earliest phases of drug development and clinical trials, was discussed. The editorial accompanies the previously mentioned article by Casey et al.,³ expanding its comment on the over-representation of individuals of European descent in trials and under-representation of Hispanic Black populations in genome-wide association studies aiming to identify targets for cancer drug development.

Global multicentre clinical trials have advanced our knowledge of MM treatments and increased population sizes for greater statistical power and significance, while reducing the overall duration of trials.

Conclusion

The studies discussed above demonstrate the national and international barriers to clinical trial recruitment for patients whose demographics are representative of real-world populations. Further to this, countries participating in clinical trials do not always benefit from the approval of trial drugs and regimens, in particular low-income countries, which are also far less likely to participate in clinical trials.

Attempts to address these imbalances are essential to ensure that MM clinical trials and treatment are equitable for all patients, producing results that accurately translate to real-world clinical settings.