Evolving Treatment Paradigms for Hematologic Malignancies in Community Oncology Settings

The treatment landscape for hematologic malignancies like multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) is rapidly evolving, bringing new targeted therapies to the community setting. In an interview with The American Journal of Managed Care^®(AJMC^®)that took place during the 67th American Society of Hematology Annual Meeting and Exposition, Ira Zackon, MD, senior medical director, Ontada, discussed findings from 2 major analyses that explored the real-world adoption, patient characteristics, and treatment paradigms associated with these novel agents.^1,2

One study reviewed the rapid uptake of bispecific antibodies for relapsed/refractory MM, noting that real-world patients tend to be older than those in clinical trials.¹ The other analysis highlighted significant real-world discontinuation rates for covalent Bruton tyrosine kinase (BTK) inhibitors in CLL, primarily due to adverse effects (AEs), suggesting advantages for time-limited therapy approaches.² These essential insights into community-based oncology care were drawn from electronic health record data sourced across The US Oncology Network.

AJMC: Can you provide a brief overview of your investigation into bispecific antibodies in relapsed/refractory MM? What did your findings reveal about real-world uptake since their approval?

Zackon: We did a retrospective, observational cohort study using the electronic health record used across The US Oncology Network and some other practices. These are data from community-based oncology treatment of patients with MM. We looked for patients between October 2022 and July 2025, all since the first approval of bispecific antibodies, of which there are now several to treat patients with myelomas. We identified 751 patients, and 405 of those patients received a bispecific antibody during that time frame; 346 patients at least clinically qualified, meaning they had at least 5 lines of therapy. We could have potentially used a bispecific antibody, because that’s the current FDA indication. The important question we wanted to answer was, what’s happening with the adoption and use of bispecific antibodies for myeloma in the community oncology setting, specifically? What we did see, encouragingly, was there was a very steady and rapid uptake in increasing year-over-year use of the different bispecific antibodies.

For example, in 2022 only 5% of these potential patients received a bispecific; in 2023, that was already up to 39%; in 2024, it was up to 61%; and in 2025, which is only kind of halfway through the year, based on the data, it was already 73% of potentially eligible patients who were receiving a bispecific. Again, it’s very encouraging to see that steady growth year over year in the community setting, because we know that for patients to have the full benefits, they need to have access to this therapy, and that to achieve that broadly, we need to be able to deliver this in the community setting to complement that which is delivered in the academic and other hospital-based settings.

AJMC: How do patient characteristics, such as age and performance status, influence the selection of bispecific antibody therapy in community oncology settings?

Zackon: That is a good question. First, I would say that we saw patients in this real-world setting to be somewhat older than you would see in the clinical trials, and that’s the importance of real-world research outside of the academic settings: Generally, these are more reflective of the patients we see in the real world, at the community level. Within our study, in terms of how patients were selected, patients who received bispecifics tended to be younger—72 years on average vs 74 years—whereas in clinical trials, the median age was often younger than 70. We also saw that more patients who received bispecifics tended to have better performance status.

Approximately 20% of our patients had an Eastern Cooperative Oncology Group score of 2 or greater, which means a significantly compromised day-to-day function level, whereas 30% treated without bispecifics had that. We do see this influence still of some selection of patients going on, but we should also note that receiving a bispecific in the outpatient setting also requires some logistical support to be able to do that for patients. Often, they need a caregiver alongside them. They need to be able to have transportation to and from the sites of service, or there are other social determinants that could potentially influence their ability to go on these therapies. I think we have more to learn about that aspect as well.

AJMC: Within the CLL17 study (NCT04608318),³ you found that real-world discontinuation probabilities for even second-generation BTK inhibitors were higher at 24 months than in clinical trials, largely due to AEs. Does this suggest that taking these agents indefinitely is unrealistic for many patients?

Zackon: This was a retrospective observational cohort study, again sourced in the electronic health record used across The US Oncology Network, so reflective of community-based care of patients who have CLL. We identified 584 patients who were receiving a first-line covalent BTK inhibitor. That’s ibrutinib, acalabrutinib, or zanubrutinib. This was between November 2019 and July 2023, the era of the second-generation covalent BTK inhibitors. That’s acalabrutinib and zanubrutinib. Whereas ibrutinib has been around for a decade, with more accumulated experience. The median age of our patients was 73 [years], so typical of CLL, and the median follow-up was over 3 years for ibrutinib and acalabrutinib; less so, 16 months or so, with zanubrutinib, because that’s the most recent. That’s the patient population and the study period we were looking at.

We did see a significant discontinuation rate of all of the covalent BTK inhibitors. About two-thirds of patients during the study period discontinued their treatment, and that was still significant, even in the second generation. These drugs, acalabrutinib and zanubrutinib, had become preferred first-line choices of BTK inhibitors because prospective trials have generally shown they have an improved AE profile—in particular, lower cardiovascular AEs like atrial fibrillation or hypertension—and they have equivalent or better efficacy.

That’s why we wanted to study this era of the second-generation BTK inhibitors. And yet we found that almost 40% of patients discontinued acalabrutinib, about 50% discontinued zanubrutinib, and I think it was 56% for ibrutinib. That’s pretty significant, half the patients discontinuing their drug. Our data show this was primarily for toxicity or AE reasons. Only a small minority were for progression, although about a third of the patients we didn’t have documentation of the reason for discontinuation. That’s somewhat of a limitation on the data.

As to continuous therapy vs time-limited therapy, I think it is suggesting that in the real world, among patients who tend to have more variation in their health status and performance status, there is a tendency to not be on therapy continuously. That’s a potential limitation, at least, of that paradigm of continuous therapy, which is the method with data that has the most mature follow-up and is still reasonably indicated to use. There is an argument that time-limited therapy may have some advantages that way, and certainly that’s a direction that CLL treatment paradigms are moving both in clinical practice and in ongoing clinical trials.

I should also mention that the shorter time to discontinuation was associated with lower performance status, more comorbidities, and certain AEs. So again, some specific factors that may be more common in the real-world setting.

AJMC:With these findings, do you think this means we need more time-limited therapies and combinations?

Zackon: As far as time-limited therapies, we currently have that choice with our patients to either go with a continuous covalent BTK inhibitor or a time-limited, fixed-duration approach. For example, venetoclax, a BCL-2 inhibitor, with obinutuzumab, an anti-CD20 monoclonal antibody. The National Comprehensive Cancer Network even supports combinations, such as acalabrutinib and venetoclax. There’s a good rationale, or potential advantages, to time-limited approaches. The patients will be on therapy for a shorter time overall; that means they’re going to achieve, hopefully, some treatment-free interval, which is valuable in terms of quality of life. Also, from a cost perspective, it’s going to be a lower cost burden on patients to be able to come off therapy, as well as for payers who are paying for expensive drugs, so that the overall cost of care can be lower with a fixed-duration treatment.

I think this is already a paradigm that exists. As we mentioned, combinations are becoming more common. We’ll also continue to learn, because clinical trials are studying these combinations. Also, we need to learn how to best use what’s called minimal residual disease [MRD] measurements, so that studies are looking at informing how MRD can be used, if you achieve a very deep MRD—meaning patients have minimally measurable residual disease, and there are different levels of sensitivity. Patients may be able to then stop therapy based on that, or perhaps continue therapy if they happen to achieve that optimal goal, because it can be associated with these longer-term outcomes of duration of remission and potentially overall survival. We still have a lot to learn about how to use MRD, but [those] data are being studied well in prospective trials that are ongoing, and it won’t be too long before we’ll hopefully have some of those answers to guide us more clearly in the management of these patients.

AJMC:Different AEs were more pronounced with each of the BTK inhibitors, but were the various AEs seen at some level across the 3 drugs, just at different levels?

Zackon: That’s generally true. As a class, covalent BTK inhibitors do have a spectrum of AEs that overlap between the drugs, but they can vary. As I mentioned, the second-generation covalent BTK inhibitors have become preferred—acalabrutinib with zanubrutinib—not only based on equivalent or superior efficacy in the first-line treatment of CLL but because of some improvements in their AE profile. Again, in particular cardiovascular events, reduced atrial fibrillation and less hypertension. In our data, we did see that ibrutinib tended to have more hypertension, more atrial fibrillation, but I’d say gaps are not as prominent in the real world [as] in the clinical trials. They’re closer together, although we still see those same trends.

Other important AEs of a more serious nature associated with these BTK inhibitors include risk for bleeding, spontaneously or with invasive procedures, but we didn’t see any significant difference of more significant bleeding between the 3 covalent BTK inhibitors. It was about 8% or so in each group. Then, we know that these drugs are immune-suppressive and so can increase the risk for infections. In fact, BTK inhibitors are finding uses as immune suppressants in nonmalignant diseases, such as autoimmune diseases. We generally found minor differences in infection rates of significance between the 3 BTK inhibitors; a little bit more with acalabrutinib, but not significantly so, and generally less than 20% or in the range of 10% to 20%.

In some ways, there are some that are similar and some that a little more or a little less, on these agents, and that allows us to choose drugs in a more precise way to tailor to our patients as we understand their age, their health status, if they have complicating comorbid health issues, especially if they have established cardiovascular disease or other bleeding issues, and choosing an agent that we think may be most appropriate for that particular patient.

References

1. Whitesell M, Su Z, Herms L, Espirito J, Paulus J, Zackon I. Evolving real-world uptake and patient characteristics of bispecific antibodies in relapsed/refractory multiple myeloma: insights from a US community oncology network. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL. Abstract 15172.
2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: results from the randomized CLL17 trial. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL. Abstract 2071.
3. Ibrutinib monotherapy versus fixed-duration venetoclax plus obinutuzumab versus fixed-duration ibrutinib plus venetoclax in patients with previously untreated chronic lymphocytic leukaemia (CLL) (CLL17). ClinicalTrials.gov. Updated December 31, 2024. Accessed December 17, 2025. https://clinicaltrials.gov/study/NCT04608318