How Can We Challenge the Status Quo in Myeloma Research?

Researchers and clinicians are attempting to increase access to and enrollment in clinical trials to better reflect the population of patients with multiple myeloma (MM).

The lack of information from underrepresented populations in clinical trials of MM has significant implications for current clinical knowledge. The drivers of disparities in MM clinical trial enrollment are multifactorial. Regardless, disparities create a knowledge gap related to the effectiveness and safety of treatments for these patient populations.

“Without data from diverse groups, it becomes challenging to develop personalized treatment approaches and tailor interventions to address the unique needs of underrepresented patients,” said Manshi R. Shah, MD, an Assistant Professor of Medicine at Rutgers Cancer Institute of New Jersey. “Consequently, clinical decision-making may be biased toward the majority of populations, leading to disparities in care and outcomes.”

Age-adjusted death rates from MM are estimated to have decreased by an average of 1.3% each year from 2011 to 2020.¹ These gains are likely due, at least in part, to the approvals and combinations of classes of drugs like proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies that have transformed the treatment of MM.

“It is important to keep in mind that although numbers have improved for everybody—the number of patients getting novel drugs, the number of patients getting to transplant, duration of treatment, survival—these underrepresented groups always lag behind,” said Sikander Ailawadhi, MD, a Professor of Medicine at the Mayo Clinic in Jacksonville, Florida. “There is never the same magnitude of improvement or benefit because these disparities exist.”

Who Is Underrepresented?

When underrepresented populations are discussed in MM, racial and ethnic minorities are often the first groups to come up.

Recent data from the Surveillance, Epidemiology, and End Results Program estimated that per 100,000 individuals, there would be 15.8 new cases of MM among Black patients compared with less than half that number (6.9 cases) among White patients.² Additionally, Black patients are more likely to have precursor conditions like monoclonal gammopathies of undetermined significance (MGUS) compared with White patients.³

Despite those finding, Black patients are less likely to get triplet therapy, transplant, and chimeric antigen receptor T-cell therapy,⁴ and they have a myeloma mortality rate that is twice that of White patients with MM.⁵

The Hispanic community is another racial/ethnic minority group where disparities related to MM are seen, pointed out Shahzad Raza, MD, a hematology specialist with the Cleveland Clinic. For example, one recent study found that MM-related in-hospital mortality is increased in Hispanic patients compared with non-Hispanic White and non-Hispanic Black patients.⁶ Hispanic patients may also have delayed initiation of treatment with bortezomib and low utilization of stem cell transplant.⁷

Both Black and Hispanic patients are underrepresented in global MM clinical trials. A pooled analysis of data from trials submitted to the US Food and Drug Administration supporting approval of MM therapies from 2006 to 2019 showed that Black patients comprised only 4% of the dataset. Hispanic patients also comprised just 4%.⁸

Certain racial/ethnic groups are not the only underrepresented populations in MM clinical trials. Another underrepresented group in the United States is elderly patients. MM occurs mostly in individuals aged 60 years or older, and the average age at diagnosis is 70.⁹ However, an analysis of data from therapeutic trials from 2000 to 2016 showed that the median age of trial participants was 62 years and 66% of participants were younger than 65.¹⁰

Additionally, patients diagnosed with MM at ages younger than 65 years have improved survival rates compared with those aged 65 years or older. Almost 70% of younger adults are alive at five years compared with 40% of older adults. Little progress has been made in terms of excess mortality in patients older than 75 years of age.¹¹

Individuals from rural geographic locations may also be underrepresented. Looking across cancer types, an analysis of 44 SWOG phase III or phase II/III treatment trials from 1986 to 2012 showed that less than one-fifth of enrolled participants were from rural locations.¹²

Finally, patients with advanced organ dysfunction or other comorbidities are also underrepresented.

“For example, 20% of myeloma patients show up with advanced kidney dysfunction, and they are never included in trials,” Dr. Ailawadhi said.

These patients are often excluded from trials whether or not there is knowledge of the “metabolic pathways and excretory routes on the investigational drug.”¹³ When these patients are excluded, trial enrollment will likely favor younger patients.

Barriers to Care

Access to care is a major challenge for underrepresented patients with MM, according to Dr. Shah.

“Financial barriers, lack of health insurance, geographical constraints, transportation issues, and limited availability of specialized health care providers in certain areas hinder these patients from accessing the necessary care,” Dr. Shah said. “Additionally, cultural and language barriers may further complicate communication and understanding, reducing the chances of receiving optimal treatment and support.”

According to Louis Williams, MD, a hematologist at the Cleveland Clinic, good comparative data about barriers to care for MM beyond what is highly generalizable are lacking.

To try to find out more, Dr. Williams and colleagues have begun an initiative to interview members of the Black community who decide to enroll in trials and those who do not.

“We are trying to be a bit more precise about what positive practices are driving enrollment,” Dr. Williams said. “There are a lot of studies of societal barriers and economic barriers, but very rarely are these [studies] translated into factors that drive patient decisions.”

Instead, Dr. Williams and colleagues are trying to focus on what he called “translational disparities research” to identify actions to bring to the bedside.

Similarly, Dr. Ailawadhi and colleagues recently conducted a survey study of approximately 500 patients with cancer who were seen at the Mayo Clinic in Jacksonville. Patients were asked for their thoughts about clinical trials.

“We noticed that the number one difference was awareness about clinical trials,” Dr. Ailawadhi said. “[Black] patients had significantly lower awareness.”

Dr. Ailawadhi pointed out that this lack of awareness was found even in a population of patients who had sought out care at a large cancer center, indicating a different mindset or level of health care literacy.

“Now think about patients in rural Iowa or those who go to smaller community centers. The opportunities, awareness, and information [are] going to be even less there,” Dr. Ailawadhi said. “This is a clear challenge for our already very demanding practices.”

Clinicians have to be thinking about the right trial at the right time, present the information nicely, and make time to answer patients’ questions, he said.

Even if awareness is increased and a wider variety of patients are offered enrollment on a clinical trial, the cards may still be stacked against certain populations.

“Eligibility criteria in trials may disproportionately exclude certain populations, especially the Black population, who at diagnosis may have a higher burden of disease and, therefore, more evidence of organ dysfunction, which further limits their representation and potentially exacerbates disparities in research findings,” Dr. Shah said.

One recent study found that inclusion parameters that determine who can and cannot be enrolled may be disproportionately excluding minority patients. Black patients (25%) and patients from “other” (24%) racial subgroups had higher ineligibility rates compared with White (17%) and Asian (12%) patients.¹⁴ Specifically, Black patients more often failed to meet hematologic lab criteria and treatment-related criteria.

Barriers to effective care often begin long before a patient may be approached for clinical trial enrollment.

“No matter your race or ethnicity, your age, or whether you are in a rural or urban environment, if you don’t have access to primary care or other health care screenings, you are more likely to be diagnosed later in the disease course than someone with regular appointments where a provider runs a [complete blood count (CBC)] or chemistry,” said Sagar Lonial, MD, FACP, a Professor and Chair in the Department of Hematology and Medical Oncology at Emory University School of Medicine and Chief Medical Officer at Winship Cancer Institute of Emory University.

What Is Being Done

Increased emphasis on diversity and inclusion in clinical trials, community engagement, and education programs; culturally tailored interventions; and collaborations with community organizations have helped improve representation and access to care.

The myeloma program at Emory has focused on partnering closely with physician colleagues around the state, partnerships the institute has been building for 20 years, Dr. Lonial said.

“Treatment plans we recommend can often be given locally, and anything that can only be done by us here, we keep here,” Dr. Lonial said. “That kind of partnership is why our clinical trial enrollment is 30%.”

More specifically, 34% of MM clinical trial participants at Winship Cancer Institute are Black. A survey study examining this high rate of enrollment found that scores on the Trust in Medical Research and Human Connection surveys were significantly higher than in national surveys. In their discussion of these findings, the study’s researchers wrote that “the high correlation between trust and human connection among our study population may suggest that a way to increase trust levels of [Black] patients is to increase human connection, or the feeling of being heard and valued by the provider.”¹⁵

At the Mayo Clinic in Jacksonville, Dr. Ailawadhi said that approximately two-thirds of all patients seen in the myeloma clinic are enrolled on clinical trials.

“My concept is if patients come to us, we have to offer them a clinical trial if they are in need of a change of treatment,” Dr. Ailawadhi said. “It is ultimately up to the patient to decide to go on trial, but I believe if we present trials and make a case for trials, patients are not against participating.”

Offering all patients access to trials is especially important, he said, as studies have shown that when given equal access, outcomes for Black patients are at least as good as if not superior to those of White patients.^16,17

Some efforts to better include underrepresented racial/ethnic groups are not only looking to increase access to all MM trials but also designing trials specifically for those populations.

In 2022, researchers at the City of Hope in Duarte, California, announced that they were “casting a wide net” to reach patients with smoldering MM—specifically Black patients—for enrollment in a trial looking at leflunomide, an older rheumatoid arthritis drug. The trial will compare outcomes in Black and White patients but will look beyond skin color and examine participants’ neighborhood, social structure, experiences of discrimination, and ancestry. To recruit for the trial, a multiethnic advisory council spearheaded outreach in communities with large Black populations and used culturally responsive educational materials.¹⁸

Dr. Williams mentioned both the PROMISE and SMRT trials as examples of studies designed at least in part to answer questions related to these specific patient populations.

PROMISE was designed to determine clinical/genomic alterations present in patients with MGUS or smoldering MM who are at high risk for developing MM, particularly Black individuals with or without a family history of MM.¹⁹ The SMRT study is looking at racial differences in smoldering MM. Researchers at Memorial Sloan Kettering Cancer Center and New York University will study biomarkers and genomic sequencing to see how the transformation into MM differs in people of European or African descent.²⁰

Cooperative study groups and industry sponsors are also trying to address how inclusion criteria can be broadened to incorporate a wider population of patients on clinical trials.

Some trials are beginning to allow for benign ethnic neutropenia, a condition where people of African descent may have genetically lower white blood cell counts. A National Cancer Institute-sponsored trial of belantamab mafodotin combined with carfilzomib, pomalidomide, and dexamethasone for relapsed or recurrent MM requires an absolute neutrophil count of at least 1, except in the case of benign ethnic neutropenia where it can be 0.75.²¹

The recently activated SWOG S2209 trial has modified inclusion criteria that will, for example, allow patients with any kidney dysfunction (outside of dialysis). Clinical trials typically demand a hemoglobin level above 8 g/dL, but this trial has been modified to 7 g/dL and allows for a platelet count as low as 50,000 and neutrophils above 0.75 instead of 1. The study is also allowing the use of growth factor and transfusion if cytopenias are considered secondary to bone marrow involvement in MM.

“In these patients, the counts are low because of the disease, but we often say if your counts are low you can’t go on trial,” Dr. AIlawadhi said. “Instead, we are saying if the disease is causing it, you can get help. We don’t want a patient to not go on a trial because they have a lot of disease. I want to put them on the trial [precisely] because of that.”

The study will also include patient-reported outcome measures in English and Spanish.²²

In addition, Dr. Ailawadhi said SWOG 2209 will allow up to one cycle of treatment to be done in the community. He and others credit this type of change in access to the rapid adoption of telemedicine seen in response to the COVID-19 pandemic.

“There is a light at the end of the tunnel in that studies have shown that outcomes are not different between these populations,” Dr. Ailawadhi said. “The biggest issue we have to keep working toward is equal and increased access.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

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