Practice-Changing Research in Myeloma: Expert Insights From ASH 2021

Clinicians gathered recently for the premier global event in malignant and nonmalignant hematology: the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, held virtually and in person in Atlanta, Georgia, from December 11th to 14th, 2021. Ground-breaking research was presented, including immunotherapy in myeloid malignancies, advances in gene editing, and emerging diagnostic tools and techniques. The 2021 meeting also included a compelling program focused on multiple myeloma (MM).
 
Samer A. Al Hadidi, MD, MS (CRDSA), FACP, is a hematologist/oncologist at the Myeloma Center at the Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences (UAMS) in Little Rock. Dr Al Hadidi is also an assistant professor in the UAMS College of Medicine’s Department of Hematology and Oncology. He shared his insight and key takeaways based on MM research presented at ASH 2021.

Several poster presentations and sessions focused on MM at ASH this year. Which ones were the most interesting or have the greatest clinical impact?

There were several exciting presentations on MM this year, but 1 of the most clinically important posters discussed the extended follow-up on preliminary phase 1b/2 data from the CARTITUDE-1 trial (ClinicalTrials.gov Identifier: NCT03548207).¹ This trial assessed the role of a single low-dose infusion of the chimeric antigen receptor (CAR) T-cell product ciltacabtagene autoleucel directed against B-cell maturation antigen (BCMA) in patients with MM who were heavily pretreated. Progression-free survival was observed in 66% of patients with an overall survival of 81% after an 18-month follow-up period. The CARTITUDE-1 trial revealed early, deep, and durable responses in a clinically challenging population of patients with MM and provided clinicians with longer follow-up data that are useful for understating treatment response in various patient populations with MM.
 
An insightful presentation by Kaufman and colleagues concerned the introduction of quadruplet-based induction therapy for transplant-eligible patients with newly diagnosed MM (NDMM).² The investigators presented updated efficacy data from the primary analysis of the phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) in this population that assessed the addition of daratumumab, a CD38-specific recombinant monoclonal antibody, to the backbone treatment regimen of lenalidomide, bortezomib, and dexamethasone (RVd). After a median of 27.4 months of follow-up, it was clear that the addition of daratumumab to RVd induction and consolidation had resulted in better disease control than RVd alone, as reflected by higher rates of minimal residual disease negativity.

CAR T-cell therapy is a relatively new treatment for hematologic malignancies and has proven to be a significant advancement in the management of lymphoma, leukemia, and myeloma. Can you comment further on why CAR T-cell therapy has shown such promise and share any interesting or noteworthy observations you have made during your own research?

CAR T-cell therapy is effective against various hematologic malignancies. It is approved not only for MM but also for acute lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. Use of CAR T-cell therapy has also been assessed during first relapse in certain hematologic malignancies with promising results. Administration of CAR T-cell therapy earlier in the course of treatment may result in better outcomes given that the immune system’s response might be more robust with reduced cytotoxic chemotherapy. Employment of CAR T-cell therapy in the treatment of hematologic malignancies has resulted in long-term control of difficult-to-treat diseases for which treatment options are otherwise limited.
 
The most noteworthy observation I have made occurred during my research on ethnic disparities. By analyzing the CAR T-cell therapies currently approved in the United States, we found that, unfortunately, these effective therapies were rarely administered to Black patients. This was even the case for patients diagnosed with hematologic malignancies such as MM, which are known to be more common among Black patients.³
 
My research has shown that Black Americans are under-represented in clinical trials that test CAR T-cell therapies for various hematologic malignancies, especially MM. Since clinical use of and research into these products occur across the United States, lack of access to these novel therapies may result in further widening of existing established healthcare disparities. It is imperative that clinicians work together toward elimination of these disparities.
 
Further, the US Food and Drug Administration needs to mandate that registrational trials include a specific number of patients from minority groups to reflect the frequency of the disease among specific minority groups. In this way, we can ensure that the results are applicable to the studied populations and that those products are used in a timely manner for patients who are hard to treat. The solution would be to develop patient-centered approaches such as training healthcare professionals in the use of high-quality, patient-centered communication; implementing patient navigation models that provide educational and facilitative services; increasing community involvement; incentivizing collaboration among different research groups; and involving community hospitals in the recruitment of patients to clinical trials. We also need to conduct clinical trials in centers that serve a majority Black patient population and not limit clinical trials of these newer therapies to centers that are located farther away from where people in these populations reside.
 
With amyloid light-chain (AL) amyloidosis, which can be related to MM, there are limited data on disparities that affect Black Americans. To circumvent this, we accessed the Nationwide Inpatient Sample, which allowed us to study AL amyloidosis-related hospitalizations from 2016 to 2018. Our main observation was lower utilization of palliative care services by Black patients compared with non-Hispanic (NH) White patients but higher utilization of the intensive care unit (ICU). Despite their higher utilization of ICU care, however, our data suggest possible superior outcomes of AL amyloidosis among Black patients compared with NH White patients.⁴ This indicates that outcomes in Black patients are potentially better when they are provided equal access to care, with the avoidance of delays in diagnosis and/or treatment.

Mouhieddine and colleagues presented an investigation of bispecific antibodies (BiAbs) as a treatment option for relapsed/refractory multiple myeloma (RRMM).⁵ How do BiAbs compare with CAR T-cell therapy in terms of MM outcomes?

These researchers reported an approximately 60% overall response rate to BiAbs in patients with RRMM. Their study showed that patients who were heavily pretreated and predominantly triple-class refractory and who experience relapse after BiAbs therapy may still have good outcomes when they are sequentially treated with other immunologic or T-cell-directed therapeutics, such as BiAbs and CAR T-cells.
 
A reason BiAbs have emerged as an important treatment option in MM patients is that compared with CAR T-cell therapy, BiAbs are administered at multiple intervals with various dosing intervals that are specific to the product. BiAbs are a continuous therapy whereas CAR T-cell therapy requires time for T-cell collection, modification, production, and lymphodepleting chemotherapy.
 
On the other hand, CAR T-cell therapy has its advantages: it is a single treatment that allows for the possibility of treatment-free intervals while yielding significant efficacy in a difficult-to-treat patient population. The drawback is that CAR T-cell production in the setting of MM is slow because we are still in the process of improving the procedure. This limits the availability of CAR T-cell therapy for many patients who are in immediate need of the treatment.
 
Although CAR T-cell therapy and BiAbs have both been shown to be effective in MM, they share a similar peculiar side-effect profile that includes cytokine release syndrome and neurotoxicity. The research presented by Mouhieddine and colleagues provided evidence that in a real-world situation, some patients with MM whose disease had progressed were able to gain access to various other therapies after they had been treated with BiAbs. These are “proof-of-concept” findings that may allow us to study the sequence of therapy in a manner that could enable provision of effective MM treatment in a timely fashion.

Mailankody and colleagues described the safety and efficacy of MCARH109, a G protein-coupled receptor class-C group-5 member-D (GPRC5D)-targeted CAR T-cell therapy.⁶ In their phase 1, first-in-class trial, they observed promising efficacy with MCARH109 in patients with RRMM who were heavily pretreated, including response in 6 patients who had previously experienced relapse after BCMA CAR T-cell therapy. What are your thoughts on the use of BCMA- and GPRC5D-targeted CAR T-cell therapy as dual treatment for MM?

Mailankody and colleagues evaluated the first CAR T-cell therapy targeting GPRC5D, which is different from BCMA, the original target of CAR T-cell therapy studied in MM. Their presentation, which provided preliminary results of an ongoing first-in-human, dose-escalation trial, demonstrated initial efficacy with GPRC5D, especially in patients with MM who had previously received a BCMA-based CAR T-cell product; 2 of 6 patients achieved a stringent complete response to therapy. This may be a promising avenue of treatment for patients who exhibit disease progression following BCMA-based CAR T-cell therapy, which is normally a challenging clinical situation with limited effective treatment options.

For many diseases, personalized medicine is the ultimate goal, but it essentially relies on identification of disease-specific biomarkers. Is there a place for personalized medicine in MM?

We are now aware of the power and possibilities of personalized medicine, as well as its place in the future of medicine. Multiple myeloma, for example, is a heterogeneous disease, so a “one-size-fits-all” treatment approach does not necessarily make sense. Therefore, personalized medicine is an avenue of research that needs to be further explored. This heterogeneity was exemplified by a study presented at ASH this year in which investigators successfully used venetoclax in combination with selinexor in patients with translocation t(11;14) MM.⁷ A caveat is that venetoclax did not exhibit the same efficacy for all subtypes of MM, and it can actually have harmful clinical effects. Personalized medicine will allow us to better identify specific patient and disease characteristics that can inform selection of therapies that will improve outcomes for individual patients.

Do you have any final thoughts about the 2021 ASH Annual Meeting?

The research presented at ASH 2021 brings hope to patients and raises the bar in terms of which therapies are considered effective. We are seeing new therapeutic modalities that yield higher response rates compared with previously used treatments. There are important clinical research findings in MM that ultimately will allow us to use more efficacious products while avoiding those with marginal benefit and a higher toxicity profile.
 
Overall, the presentations this year also remind us that healthcare disparities in MM still represent a major issue that must be addressed. If these disparities remain unaddressed, they will continue to worsen, with effective therapies preferentially administered to a subset of patients only as opposed to all patients who need a certain treatment.