Research has shown that Black American patients with multiple myeloma experience significant disparities in treatment patterns and outcomes compared with White patients. In this interview, Oncology Data Advisor editorial board member Dr. Rahul Banerjee speaks with Dr. Samer Al Hadidi, Assistant Professor at the University of Arkansas Medical School and a leading researcher in the field of multiple myeloma treatment disparities. Dr. Al Hadidi explains the differences in disease biology and treatment outcomes experienced by Black patients and shares solutions for closing this gap and ensuring equal access to care for all patients with multiple myeloma.
Rahul Banerjee, MD: Welcome to Oncology Data Advisor, a digital resource for the multidisciplinary cancer team. My name is Dr. Rahul Banerjee. I'm one of the editorial board members. Today, it is my honor to be joined by Dr. Samer Al Hadidi, who is an Assistant Professor of Medicine at the University of Arkansas Medical School. Dr. Al Hadidi is both an exceptional clinician as well as a prolific researcher.
What I'll be speaking to him about today is some of his research regarding disparities—socioeconomic, racial, and otherwise—in the treatment of multiple myeloma. Dr. Al Hadidi, Samer, if I may, it's a pleasure to have you today.
Samer Al Hadidi, MD, MS, FACP: Yes, thank you. The pleasure is mine. Thank you for having me.
Dr. Banerjee: Of course. Conceptually, it might be nice for our audience to kind of go through this thematically, throughout the journey of a patient with myeloma. That often starts with pre-myeloma lesions, monoclonal gammopathy of undetermined significance (MGUS), and I'd love to pick your brain on some of the disparities that you're aware of and are researching in the pre-myeloma space for MGUS or smoldering myeloma. Then we'll talk about the newly diagnosed setting and access to trials, access to transplant, disease, biology, and so forth. Then at the end, we'll talk about relapsed/refractory multiple myeloma. I know that you've done some work with racial disparities, with chimeric antigen receptor (CAR) T therapy, for example, in the relapsed/refractory setting. I'd love to talk about that.
Maybe we can start with MGUS. Most people learn in medical school that MGUS happens more commonly in patients of African American descent. That's kind of all that most clinicians, I feel, understand about MGUS. What should a clinician who is practicing, caring for patients with myeloma, know about MGUS and disparities or MGUS in particular in the Black patient population?
Dr. Al Hadidi: Yes, thank you. Now, multiple myeloma is thought to come from MGUS. I think this is very important to know that monoclonal gammopathy of undetermined significance or MGUS is something that comes before myeloma. Multiple studies looked into if the prevalence of MGUS is different between African Americans and other ethnic/racial groups. Since myeloma is twice as common in African Americans compared with non-Hispanic Whites, MGUS was looked at, and actually, this difference is also noted in the MGUS level.
There is a study, for example, that looked into a younger age group, 10 to 49 years, from the National Health and Nutritional Examination Survey (NHANES). That was reported back in 2017. They included more than 12,000 individuals and screened them for possible MGUS, which was identified in 63 of them, at a rate of around 0.3%. So, MGUS was higher in Blacks in this study; it was almost 0.8% compared with 0.2%. Specifically in this study, it was almost four times higher.
They believe it's anywhere from two to three times more common across all studies. If you look at the prevalence of MGUS, which is the precursor disease for myeloma, it seems to be more common in African Americans and also happens at a younger age compared with the other racial or ethnic groups.
Dr. Banerjee: You bring up an excellent point, which I also should add, that we all know that myeloma is often more common in the African American community. Based on this, do you think it's kind of a rising tide of MGUS that means more cases of myeloma? Or do you think that something with the disease biology about MGUS means that it is not only more common in Black patients, but often more likely to progress to active myeloma? Or is it a little bit of both, or unknown?
Dr. Al Hadidi: Well, I think part of it is unknown. The belief is that it's mostly related to the higher incidence of MGUS. There are some studies that support each claim. For example, we just said that MGUS is more common in Blacks compared with Whites, in general, and also that it is more pronounced in a specific age group. If you look at the age group of 40 to around 50, there is actually a higher amount of MGUS compared with myeloma, in this specific age group, between Blacks and Whites. It seems that when you start with MGUS in African Americans, it seems to be progressing more quickly to myeloma. The reason why, if you look at myeloma incidence, is it usually happens around five years younger in Blacks compared with Whites.
So, why this five-year gap? It could be because MGUS is more common. It could be because MGUS is developing to myeloma more quickly. That's possible. Now, if you look into other data that may not support this claim, for example, the Veterans Affairs (VA) data where they looked at more than four million patients, they found that the increment in myeloma is likely related to the higher incidence of MGUS, just because there is more MGUS than there is more myeloma in the patients if you follow them up in the future. When they looked at 10-year follow-up, they didn't find differences in the incidence of myeloma in their subset. It seems MGUS was higher, and this higher incidence turned into higher myeloma—but without, let's say, a relationship to a biological factor, at least by suggestion. There is very limited data in the field, if any, on biological components of MGUS to myeloma in African Americans, to be honest.
Dr. Banerjee: Absolutely. This is interesting. I'd be curious to see whether the rate of MGUS in the VA population was higher than in that National Institutes of Health (NIH) study. I'm sure VA patients have their own unique exposures, whether it be to Agent Orange in Vietnam or other things going on that might explain or change how MGUS behaves in the VA population versus the general population. Is there any truth to that, do you think? Or do you think that it's a pretty homogenous population between the VA and this other cohort that was done?
Dr. Al Hadidi: I think the VA study is quite a lot larger in number, and the good thing about it is that they followed patients all across the US, so it's more representative. They have a relatively higher number of African Americans in their data set, which is more relevant, so I think their numbers are a better estimate. There was a report in Blood saying that if you provide African American patients with equal access to care, they do better, and also saying that deletion 17p, which is an adverse feature, is less common in Black Americans.
I think this is very important to highlight since they have data, but there are lots of missing data on that subset. Whatever they reported, they reported on the actual data they have, out of their very big proportion of patients. When I looked at it, up to 85% of their data was missing on the fluorescence in situ hybridization (FISH) level, on the genetics level. Whatever you have is 15% out of all the myeloma patients. In this 15% you have, there is less deletion(17p) comparing African Americans with Whites. But with the caveat of this big missing data, I think, this is important.
The thing that I'm trying to work at, to be honest with you, is looking into our gene expression profiling here at the University of Arkansas—looking at data from the beginning and at the time of relapse, to see if at any point there are actually differences in the biology of multiple myeloma across different ethnic and racial groups. This has not been reported before, at least on our data set, and we're working on it right now. But this is, interestingly, now being reported from the VA group, and there was previously also some talk about higher incidence of translocation t(11;14) in African Americans compared with Whites, which is associated with a better prognosis in myeloma.
Dr. Banerjee: Absolutely. This is all fascinating. I think it's a good segue; you've kind of already moved from MGUS into the setting of newly diagnosed myeloma. Certainly, there are biologic differences, as you said. There are absolutely socioeconomic differences in how myeloma presents and how patients are treated. Can you speak to some of those variations—what we know, what we don't know, and what we're working on to fix disparities?
Dr. Al Hadidi: Yes, and I think one thing is, should we really screen for MGUS? We say that MGUS is more common in Black Americans. Should we just screen them for it? There are some things to come into screening whenever we talk about any screening. First of all, how much of a risk is there? If you find somebody with MGUS, how much of risk is there for it to turn into myeloma? That's important. Usually, we define low-risk MGUS as having no risk factors out of three suggested risk factors—M-protein above or equal to 1.5 g/dL; the non–immunoglobulin G (IgG) subtypes like IgA, IgM, IgD; and abnormal free light chain ratio of more than 1.65 or less than 0.26. Low risk, which is absence of any of those risk factors, tell us that the patient likely is having 5% risk of progression over 20 years. If you develop MGUS at an age of 70 years old or 65 years old, there's a risk of 5% over 20 years, which is very important to know.
The other thing, as we're getting better and better, is trying to identify proteins at a much lower threshold and better sensitivity. Now we're really able to catch proteins in a better way. How much of a significance this is, is still in question? Black Americans are more common to have MGUS; should we screen them? I personally think no. But I think we should be more self-educated that if they come to us with signs and symptoms of myeloma or something to suggest that they may have it, to try to catch it early and start treatment early, because it's more common for them. I think it's just a piece of effort that we need to do.
Now there is, as you know, that big Iceland study. This is a big study to look into the benefit of screening for MGUS in general. I think the only downside relevant to our talk is that the number of Black patients there will be minimal, if any, given the structure of the country that's been studied. To be honest to you, I'm not sure how applicable this is to the US, because around 20% of all our patients with myeloma are Black Americans. This is not a trivial amount by any means. It's approximately one fourth; it's very common.
Dr. Banerjee: Absolutely. It's an excellent point that you bring up, because the proportion of African Americans differ between parts of the country or between countries. Iceland or the Olmsted County Mayo Clinic data might not be as representative of Arkansas or Philadelphia, where I trained before, or San Francisco. That makes it tough, but I think it's good to see that researchers like you are leading the field to get at some of this.
Once myeloma is diagnosed, whether it be through augmented screening or through that first chronic kidney disease (CKD) workup or a fracture or so forth, are there differences that you're aware of in terms of the racial or socioeconomic disparities, as well as in in terms of how myeloma is treated, access to treatment, time to treatment, availability of transplant, and so forth?
Dr. Al Hadidi: Yes, that's an excellent question. I think this is extremely relevant. First of all, the testing for an established patient with myeloma is done less in African Americans. There was an American Society of Hematology (ASH) abstract for last year that actually presented data from Surveillance, Epidemiology, and End Results (SEER). Even doing complete blood counts for patients with established myeloma is less common to be done in Black Americans compared with Whites. Those differences should not exist.
Dr. Banerjee: I agree.
Dr. Al Hadidi: Staging information, like beta-2-microglobulin, lactate dehydrogenase 1 (LDH-1), marrow biopsy, positron emission tomography (PET) scan, even skeletal survey like what we used to do before, all of those diagnostic tests are done less frequently. That's one problem. Then even when you diagnose patients, the median time to start the first treatment is significantly longer in Black Americans. They're also less likely to initiate any first line of treatment. If you look at all newly diagnosed myeloma, they have lower likelihood to initiate a first-line treatment. Some of them likely present very advanced or will not get a first line of treatment before something bad happens, like death or worsening of their clinical condition. Also, median time from diagnosis to novel therapy is significantly longer. Novel therapy, what the studies at least reported, was an immunomodulatory drug plus proteasome inhibitors.
There are also studies to suggest lower utilization of lenalidomide in African Americans. The studies say there's 20% less lenalidomide use in African Americans as initial therapy. We know all those drugs are very effective in myeloma, and they're less frequently used. Now looking at symptoms, for example, there's also longer time from the presence of symptoms to diagnosis in Black Americans. That's another problem. That's where we talk about how Black Americans are usually younger at diagnosis, five years younger. Despite that fact, they still are diagnosed relatively delayed.
This all comes to how they're diagnosed and how they're treated. Now, if we come to more complex treatments—let's say, transplants, for example—they're receiving fewer transplants. They're receiving fewer triplets. If you look at bortezomib/lenalidomide/dexamethasone, they received less in multiple SEER analyses. Some work I did last year looked into other factors in a national sample of inpatient hospitalization, where there are fewer inpatient transplants for non-Hispanic Blacks in general. There are more blood product transfusions and more intensive care unit (ICU) care cases, so all the patients are sicker. Despite being sicker, they're receiving fewer palliative care consultations and less inpatient chemotherapy. They're dying more, compared with all other groups. Even if you look at the rates currently, in 2022, Black American patients still die more frequently than other races or ethnic groups.
Now, I need to draw attention to one thing. We believe that there are also lots of disparities affecting Hispanics, for example. They do better compared with Whites, and their outcomes are better. For example, they receive fewer transplants, but they still do better. But the other piece of info that Black Americans generally do worse, despite all those disparities, is heartbreaking. Now, as we just talked about the differences in genetics and the higher amount of translocation t(11;14) in African Americans, which as important, there was some thought about less high-risk cytogenetics and less deletion 17p. There was an excellent study looking at RNA sequencing of more than 700 patients, looking at differences between European-origin patients and Black-origin patients. They actually found some differences in some mutations; they're not very significant, but there is no major difference to report. What I am trying to work at now with the longer data that we have, specifically the gene expression profiling data, is to look into those differences and their significance on very long follow-up. I think that is where the interest comes in, and I'm working on that as we speak.
Dr. Banerjee: Agreed. The University of Arkansas Medical Sciences (UAMS) is a leader in this field. I'm excited to see where that goes. I think it's a good segue to gene expression profiling, not just at diagnosis, but now for relapsed/refractory disease. Moving into the final part of our discussion, does clonal evolution happen differently? Do the dynamics of the myeloma biology behave differently? There are obviously the same socioeconomic disparities that apply to the newly diagnosed setting. How do they apply to the relapsed/refractory setting? I know that you've published about disparities with regards to access to CAR T-cell therapy, for example.
Dr. Al Hadidi: Yes, I think that's a great question. We could even think about the relapsed/refractory setting to be more of a need for us, because those patients usually do worse than the newly diagnosed. They live shorter. We consider their disease biology to be aggressive just by definition, because they relapsed already. I think it's a very important disease population to look at. It's more troublesome for relapsed/refractory in general, given their disease. Patients are usually older, as you know; they may have more other comorbidities. Heart disease is common, diabetes, you name it. We know that clinical trials for relapsed/refractory patients, and even newly diagnosed, enroll very low numbers of African Americans.
Looking at all cancer and specifically in myeloma, as you know, many myeloma clinical trials are run worldwide, globally. You may not have enough Black patients to enroll worldwide. But looking at CAR T, for example, CAR T is a very recent development. We knew about disparities before we established CAR T studies. We now have approved products for patients who previously had very minimal effective treatments. This is very relevant. When I looked at the FDA approvals for CAR Ts for lymphomas and myeloma, we have now two approvals for myeloma, and the number of Black patients enrolled in those clinical trials is extremely limited. They're less than two digits. If you adjust it to how common multiple myeloma is, for example in Black Americans, this adjustment—what we call participation-to-prevalence ratio—is extremely low. If you look at how many patients are there, you are kind of selecting some of them, but not all of them.
This is a problem because, first of all, patients miss opportunities to receive effective drugs. Second of all, our results may be not accurate. Because you're doing some sampling errors there, you're studying a subset of patients. There is some sampling error for how you are selectively choosing some of the patients. That's why we don't know much about biology, to be honest. We never have this proper data to really look into differences, because we don't enroll many of those patients there. The sad part is that most of those CAR T pivotal trials were done in the US using US patients for the vast majority of those patients. It's not a global trial, it's here, where we're not enrolling patients enough.
I think this is very complex and can probably speak for itself. But it has to do with many things; it also has to do also with us as physicians maybe not telling patients about those opportunities as we're supposed to. It has to do with socioeconomic problems, financial constraints, availabilities. Access to those trials is a very big problem. You cannot open those trials in Olmsted County, Minnesota, and hope for the best, for example. You need to open them where African Americans are available. Where are they? In the different states and different counties where they live. That they have access to this, I think, is very important.
Dr. Banerjee: That's actually an excellent segue to my final question. I think step one in this process is calling these problems by their name, identifying the disparities that exist, and trying to figure out why they're happening and how pronounced they are. The next step is trying to mitigate them, trying to erase them, or trying to give everyone equal access to the care opportunities that they need. Are there any strategies or tools on the horizon that you think people are using or could be using—people meaning us as myeloma physicians—to help address and mitigate these disparities, both in standard of care and in clinical trials?
Dr. Al Hadidi: Yes, thank you. I think that's the core, and that's what we really care about—getting better. I think there are some improvements, and I need to call good things when I see it. There are some pharmaceutical companies that keep trials open for longer to recruit more Black patients. That's a positive thing, I think that's good, because you want to try to fix the problem by allowing more time for those patients to get enrolled, to search for them and get them.
I think we need to put more effort into including more centers where they serve those patients. Give them access to those clinical trials so we can enroll those patients. Also, personalized medicine—you need to look at what prevents patients from enrolling. If a patient loses their job, they will not be able to support their family. We need to financially support those patients, maybe give them the transportation costs that they may end up paying out of their pocket. We need to educate them about clinical trials better. There were lots of issues in the clinical trial effects in the past that we need to overcome by explaining and teaching, and reexplaining and reteaching. I think this is very important.
I'm a big believer of regulations. I think we should have a regulation to ensure a certain number of patients enrolled in registrational trials. If you want to really use a drug for the population, you want to make sure it works for the population you want to use that in. The FDA, I believe, should have those hard stops of the clinical trials, to make sure that a certain amount of patients should be enrolled. This can be a gradual process, something that will get better over a few years. But at least we can show this improvement and make sure that pharma works with us to improve this.
Believe it or not—and I'm looking into this, hopefully we'll get it out soon—most of the clinical trials for bispecifics and CAR T are sponsored by pharma, 98%. Even if you have regulations by the government to say that you need to enroll minority patients, those studies cannot follow up those regulations. Those regulations are for National Cancer Institute (NCI)–supported research, for example. I think pharma wants to help and they want to enroll more patients, but we need to work with them on good regulations to enforce this and make sure that we do it the right way.
Dr. Banerjee: Agreed. You brought us some excellent solutions, and as you said, it'll be a gradual process. Allowing more time for clinical trial enrollment is an excellent point, because you're right. Even anecdotally for us, Black patients take longer to present. They may not know about CAR T therapy or aren't referred to the academic center earlier. I think that's important. I know that there are definitely some trials out there, both in the newly diagnosed setting and the relapsed/refractory setting, that have a Black cohort or something along those lines. They're specifically trying to enrich for this patient population, and that's very commendable. Dr. Al Hadidi, this has been very, very, very illuminating. Thank you again for your time. Any parting words or anything else you want to say as we wrap up?
Dr. Al Hadidi: Thank you so much. I think this is great. Pointing out those things, as you just said, is great. You're an excellent researcher and clinician to be. You're starting your new job, just starting it. If we're all hand-to-hand hoping, hopefully helping to solve this, ultimately, it'll get solved. Patients have concerns, but if you talk to them and you explain it, they'll listen. I have no patients saying "no" for research. If they understand it and they have the time to do it, they'll do it.I think we all should work together to make this better. Thank you for highlighting this. I think it's so important.
Dr. Banerjee: Thank you so much. Wonderful. Thank you again.
About Dr. Banerjee and Dr. Al Hadidi
Rahul Banerjee, MD, completed his undergraduate and medical training at Brown University, followed by an internal medicine residency and a quality improvement (QI) chief residency at the University of Pennsylvania. He then completed his hematology/oncology fellowship and advanced fellowship in bone marrow transplant (BMT)/CAR T therapy at the University of California, San Francisco (UCSF). Most recently, he has joined the multiple myeloma faculty at the University of Washington Fred Hutchinson Cancer Center in Seattle. His clinical interests are in multiple myeloma and AL amyloidosis, and his research interests are in CAR T therapy, digital health, and care delivery.
Samer Al Hadidi, MD, MS, FACP, is an Assistant Professor at the University of Arkansas Medical School, a hematologist/oncologist at UAMS Myeloma Center, and an Associate Member in the Developmental Therapeutics Research Program at UAMS Winthrop P. Rockefeller Cancer Institute. Dr. Al Hadidi's research interests include the prevention, treatment, detection, and prognosis of multiple myeloma, particularly health disparities among racial, ethnic, and socioeconomic minority groups. He has authored or coauthored numerous publications focused on improving treatment outcomes among patients with multiple myeloma.
For More Information
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Fillmore NR, Yellapragada SV, Ifeorah C, et al (2019). With equal access, African American patients have superior survival compared to white patients with multiple myeloma: a VA study. Blood, 133(24):2615-2618. DOI:10.1182/blood.2019000406
Munjuluri A, Fillmore N, Cirstea D, et al (2019). With equal access, African Americans with non-del17p multiple myeloma have superior overall survival, but del17p still carries poor prognosis across race: a VA study. Blood (ASH Annual Meeting Abstracts), 134(suppl_1). Abstract 4388. DOI:10.1182/blood-2019-131247
Badar T, Hari P, Davila O, et al (2020). African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States. Cancer, 127(1):82-92. DOI:10.1002/cncr.33208
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International Myeloma Foundation (2022). How is myeloma different in African Americans? Available at: https://www.myeloma.org/diversity/how-myeloma-different-african-americans
Notardonato LD, Langerman SS, Zhou J, et al (2021). Racial disparities in the diagnostic evaluation of multiple myeloma. 63rd Annual ASH Meeting & Exposition. Abstract 4116.
Ailawadhi S, Parikh K, Abouzaid S, et al (2019). Racial disparities in treatment patterns and outcomes among patients with multiple myeloma: a SEER-Medicare analysis. Blood Advances, 3(20):2986-2994. DOI:10.1182/bloodadvances.2019000308
Al Hadidi S, Dongarwar D, Salihu HM, et al (2021). Health disparities experienced by Black and Hispanic Americans with multiple myeloma in the United States: a population-based study. 62(13):3256-3263. DOI:10.1080/10428194.2021.1953013
Manojlovic Z, Christofferson A, Liang WS, et al (2017). Comprehensive molecular profiling of 718 multiple myelomas reveals significant differences in mutation frequencies between African and European descent cases. PLOS Genetics, 13(11):e1007087. DOI:10.1371/journal.pgen.1007087
Al Hadidi S, Schinke C, Thanendrarajan S, et al (2022). Enrollment of Black participants in pivotal clinical trials supporting US Food and Drug Administration approval of chimeric antigen receptor-T cell therapy for hematological malignant neoplasms. JAMA Netw Open, 5(4):e228161. DOI:10.1001/jamanetworkopen.2022.8161
Awidi M & Al Hadidi S (2021). Participation of Black Americans in cancer clinical trials: current challenges and proposed solutions. JCO Oncology Practice, 17(5):265-271. DOI:10.1200/OP.21.00001
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.