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Naresh Bumma, MD, discusses the focus of each presentation on frontline therapy, early and late relapse, and CAR T-cell therapy in multiple myeloma.
Novel CD38-directed monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR T-cell therapy have found their roles in the paradigms of early relapsed and triple-class refractory multiple myeloma, explained Naresh Bumma, MD, who added that what has been particularly exciting is the signal of benefit that has been seen with isatuximab-irfc (Sarclisa) in patients with comorbidities and high-risk disease––a population deserving of further study.
“There’s a lot of other questions we don’t have answers to. There’s a lot of areas of need in multiple myeloma that still need to be addressed, such as patients who have kidney dysfunction, or patients who have cardiac issues, patients from racial or ethnic minorities, frail patients, and patients who would otherwise not have made it on a lot of the clinical trials that are being reported or have been reported,” Bumma said in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on multiple myeloma, which he chaired.
“There is a lot of room to grow, and we still are chasing that cure within myeloma, which we are hoping is just around the corner,” Bumma added.
In the interview, Bumma, an assistant professor in the Division of Hematology at Ohio State and a hematologist at The Ohio State University Comprehensive Cancer Center (OSUCCC)-James, discussed the focus of each presentation on frontline therapy, early and late relapse, and CAR T-cell therapy in multiple myeloma.
Bumma: We were really excited to be able to have this meeting and share insights with everybody around us, including our cooperatives in the community. The main highlight was the audience interest and the audience interaction. It is an exciting time for those of us who are invested in myeloma to be in myeloma, but it was great to see that providers in the community have and share this interest with us. Also, it gives us very interesting insight as to what the challenges are that providers in the community face while they’re treating this very complex disease and the gaps in knowledge and the gaps in practice that we can help bridge.
It is a very exciting time to be in multiple myeloma. There are all these new approvals for new therapies that we have. There’s much more coming down the pipeline, and although we are blessed with so many options, there are still some challenges.
The biggest challenges are: How do you pick a specific therapy and which treatment line should you go down? Sometimes it becomes complicated and difficult to be able to piece out every piece of clinical trial data and pick out which one is the best option available. That’s why collaboration is important between different centers, and between people in academia and people in the community.
In this era of personalized medicine, we need to be cognizant of all the features that are involved in patient care. I like to think of [these features] in separate baskets. The first [basket] is the patient and their baseline characteristics. The age of the patient plays a role in [our treatment decisions]. We now have much more data about racial disparities and how myeloma behaves in different racial or ethnic subgroups. The patient’s performance status is also very important [as is] their organ function, such as their kidney function and their cardiac function. The socioeconomics of the patient, for example, their access to health care, the ability to afford medication, where they live, their access to transplant and access to a center that focuses on myeloma, those are also very important [elements] to keep in mind.
The second basket is the disease-specific characteristics. ISS [International Staging System] or Revised ISS staging at diagnosis, cytogenetics of the disease, the aggressiveness of the disease, the pace at which the disease is progressing, and the presence of extramedullary disease is associated with worse outcomes. All of those [elements] also need to be paid [attention to].
Thirdly is the availability of clinical trials. That’s how we advance the field and whether that is available to the patient and whether they’re willing to participate in it [is important to understand]. Also, what are the barriers to increasing participation and access to clinical trials for patients across America and not just across academic centers?
Finally, in the era that we live in [we have to consider] ongoing issues such as access to health care, disparities, financial issues, and the impact of COVID-19 may have on the patient and their ability to get to treatment and take treatment. Therefore, it ends up being much more than just what regimen you pick. You really have to sit down and get to know your patient and truly [create] a plan for them.
ICARIA-MM was a phase 3 study looking at the combination of isatuximab with pomalidomide [Pomalyst] and dexamethasone [Pd] vs Pd alone. The primary end point was progression-free survival [PFS], and survival was improved with addition of the new anti-CD38 antibody. It also led to improvement in time to next treatment and PFS2, which is the time that patient had with the next line of treatment compared with Pd. There was also an improvement in overall survival [OS] of 7 months, which didn’t hit statistical significance. The addition of [isatuximab] did not lead to any significant safety signals, which is very encouraging. This gives us an added treatment regimen for patients that meet the criteria. In the subgroup analysis, they had a fair number of patients who had renal dysfunction, which is a subgroup that was not always involved in other studies.
IKEMA was a phase 3 study that looked at adding isatuximab to carfilzomib [Kyprolis] and dexamethasone [Kd] vs Kd alone. The primary end point was PFS, which was improved in the 3-drug arm, with a hazard ratio of 0.31. Patients had to have had 1 to 3 prior lines of therapy. What was interesting to me in this study, other than the improvement in PFS, OS, response rates, and MRD [minimal residual disease] negativity was also the fact that there was some interesting data about high-risk patients.
About 23% of patients had high-risk cytogenetics defined as translocation 4;14, deletion 17p, translocation 4;16, and Gain 1q, and patients who had at least 1 high-risk cytogenetic feature had better responses with the triplet. Unfortunately, the study wasn’t powered to show statistical significance, but there was a clear trend there. Another subgroup analysis of patients with Gain 1q was done, which included patients with isolated Gain and Gain combined with other high-risk features, and that [subgroup] derived PFS benefit [with the triplet] as well. But again, the study was not fully powered to address that question.
Whenever we think about adding another drug to a regimen, we always wonder whether we’re going to add toxicity. Looking at the safety profile, grade 3 or more treatment-emergent adverse effects [AEs] while slightly more common in the triplet arm, the incidence of fatal or serious AEs was similar in both arms. Now we have another new regimen that is potent and that can be used in patients if your patients meet, what would be the inclusion criteria for that study.
Triple-class refractory multiple myeloma is defined as multiple myeloma that would be considered refractory to an immunomodulatory drug, a proteasome inhibitor, and a monoclonal antibody. Now that we’re started to use these agents much earlier within the disease course, we’re starting to see a higher incidence of these patients that are available to us in clinic. Over the past few years, there has been an increase in the number of drugs that have shown activity within this subset.
There is the ADC, belantamab mafodotin-blmf [Blenrep], which was approved very recently by the FDA. It’s just a single drug infusion with dexamethasone for patients who have received more than 4 lines of therapy. One of the most worrisome AEs is the visual toxicity or the ocular toxicity. There is a REMS [Risk Evaluation and Mitigation Strategy] program that is mandated by the FDA to further mitigate these AEs which include an exam by an ophthalmology specialist as well as the use of eyedrops. Corneal AEs are newer compared with other AEs we’ve seen with other therapies in myeloma. This is something we have to be very vigilant of and intervene earlier if these AEs start to affect patients.
Another drug that we have in that subgroup is selinexor [Xpovio], which is a SINE [selective inhibitor of nuclear export] inhibitor, and it has been studied in combination with bortezomib [Velcade] or with carfilzomib. With selinexor, the biggest AE that we have seen has been gastrointestinal [GI] issues, such as nausea, vomiting, and diarrhea. It is very important to be aware of these AEs because they can be significant and impact patients’ quality of life. A very aggressive antiemetic regimen is usually recommended with olanzapine [Zyprexa], ondansetron [Zuplenz], and prochlorperazine [Compazine] as needed for nausea to help mitigate these GI AEs. Hydration [is important] as well. Cytopenias have also been seen with thrombocytopenia, and we have used TPO [thrombopoietin] mimetics to help with that, as well as growth factor support to help with neutropenia in these situations.
The other agent that we also use in this class is panobinostat [Farydak], which is an HDAC inhibitor that can be combined with bortezomib or carfilzomib. The biggest AEs that we see is cytopenia, neutropenia, anemia, and thrombocytopenia, so close monitoring of blood counts is very essential. Prompt intervention with red cell transfusions or platelet transfusions is [recommended] and also appropriate prophylaxis with antiviral and antibiotic and anti-bacterial [agents] is also recommended to prevent any complications from these specific agents.
CAR T cells are the new kids on the block, and everybody’s super excited about CAR T cells. We are also very excited to have been part of the trials and have them here.
The phase 2 KarMMa study [NCT03361748] looked at idecabtagene vicleucel [ide-cel; Abecma]. In that trial, patients with relapsed/refractory multiple myeloma who had received a median of 6 prior lines of therapy had a good response rate with this agent. Within about 24.8 months of follow-up, the median OS was 24.8 months. The overall response rate was 73% out of 128 patients, which was impressive, and the median PFS was 8.6 months, and that was with the initial target dose. With the target dose of 450 million cells, the median PFS was improved to 12.2 months. However, the FDA label for ide-cel is for patients with more than 4 prior lines of therapy, whereas the trial only required 3 prior lines of therapy.
In a subset of the study that looked at patients who had received 3 prior lines vs 4 or more, there was no significant difference between those 2 groups in outcomes. Ide-cel is an option for patients who have had multiple lines of therapy.
The other trial that has looked at CAR T-cell therapy in multiple myeloma is CARTITUDE-1 [NCT03548207], which is a phase 1b/2 trial looking at cilta-cel. In that study, we saw an initial impressive response rate of 97.9% and then with additional follow-up, we that the response had depended. The median duration of response was 21.8 months, which was impressive, and the median PFS was 22.8 months. More than 80% of patients had a complete response [CR], with 67% having a stringent CR, which was also sustained across the long-term follow-up, which was exciting. We’re looking forward to the approval for this CAR T-cell therapy in multiple myeloma to further add to the armamentarium that we have now.
Editor’s Note: This interview was conducted prior to the 2021 ASH Annual Meeting.