Treatment Landscape of Multiple Myeloma Expands With Supportive QOL Data

Nina Shah, MD

The BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel; BB2121) induced clinically meaningful improvements in the quality of life (QOL) of triple-class exposed patients with relapsed/refractory multiple myeloma, according to secondary QOL data from the phase 2 KarMMA study(NCT03361748). These findings highlight the clinical benefit of ide-cel as treatment of these patients, supporting the FDA’s previous decision to grant this therapy a Priority Review designation in September 2020.

The news of these promising data, which were presented in early December 2020 during the American Society of Hematology (ASH) Annual Meeting, followed several new approvals from the FDA throughout the year. Isatuximab (Sarclisa) was granted FDA approval in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who received at least 2 prior therapies in March 2020, and daratumumab (Darzalex) plus hyaluronidase-fihj (Darzalex Faspro) followed suit with an approval in May 2020 for the treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma, which allowed for subcutaneous dosing of daratumumab.

In August 2020, the combination of daratumumab plus carfilzomib (Kyprolis) was approved for the treatment of adult patients with relapsed/refractory multiple myeloma who received 1 to 3 prior lines of therapy, and earlier the same month, belantamab mafodotin-blmf (GSK2857916; Blenrep) was approved for the treatment of adult patients with relapsed/refractory multiple myeloma who received at least 4 prior therapies, which should include an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. 

As the year came to a close, physicians welcome 1 more FDA approval; selinexor received approval from the FDA in late December 2020 for use in combination with bortezomib (name) and dexamethasone) for the treatment of adult patients with multiple myeloma who received at least 1 prior line of therapy. These approvals provide an array of new treatment options for patients with relapsed/refractory disease, along with the promising new data for ide-cel.

In an interview with Targeted Oncology, Nina Shah, MD, an associate professor of Medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discussed the findings from the KarMMA study supporting the use of ide-cel as treatment of patients with multiple myeloma. She highlighted other treatment options in the paradigm as well.

TARGETED ONCOLOGY: What QOL factors are of concern right now for patients with relapsed/refractory multiple myeloma?

Shah: I think that anybody who has had to suffer or endure the marathon, as I call it, of multiple myeloma can recognize that it's treatment after treatment after treatment. It's not only the pain of having a disease but also the difficulty in life planning that you have to do because you have to go to chemotherapy, make appointments, get blood draws, and all of that. Then there's the actual toxicity of the chemotherapy, so there are drugs that make people fatigued, they make people not feel themselves, they make people feel foggy. There's always something, there's always a bad that comes with the good, so these are important things to look at. They're hard to put into granular defined data fields, and so that's what these QOL instruments try to do. They ask about different physical functioning and social functioning. This particular abstract was looking at the secondary domains.

TARGETED ONCOLOGY: What was the risk-benefit of ide-cel seen in the primary analysis?

Shah: Ide-cel itself is the BB2121 product, a BCMA-directed CAR T cell. The original data for the KarMMAstudy showed a 73% overall response rate, but this was higher in the 450 dose, which is the dose that's going to go forward. We know, with that dose, people had a progression-free survival of approximately 1 year, so we know that it works. We know that in these heavily pretreated patients, this CAR T-cell therapy works and that some people can go a year without actually having any other treatment.

We know that there's efficacy, so what is the risk? The risk is the acute risk, and then there's the long-term stuff that happens. Acutely, there's cytokine release syndrome, which happens in most people. That's not disputed, but it's low grade, usually grade 1 or 2. In addition, there's a risk of neurotoxicity, and this was fairly low in the study in general. All of these were things that people generally could recover from and are well managed. I would also say that they're the things that we've gotten better at managing, so I feel okay with that toxicity profile. However, there's the other toxicities, and that's what we were talking about before, what are the QOL toxicities? That's 1 of the things that was being looked at in this analysis.

TARGETED ONCOLOGY: What were the findings from this analysis?

Shah: This looked at both a group level analysis and an individual analysis, and it used different tools to do that. It used questionnaires that we are familiar with; for example, the EORTC QLQ-C30, and that's the generic cancer-validated instrument that has different domains in it. There are some primary domains, and then there's some secondary domains. These were the secondary domains that were looked at, and then there's a myeloma specific question. There's the QLQ-MY20, so that addresses more of the myeloma-related symptoms that patients tend to have. There was an EQ-5D assessment used as a generic instrument, and what that does is it assesses Health Index on a 1 to 5 scale, as well as a global health analysis or assessment, so there were a couple of things that we were looking at here.

The reason there are a lot of tools is because these are validated. Once you start using these tools in 1 [study], you can use them across different studies. We could see what the trends were with this, and we looked at both the group level changes and the individual changes. What we found out was that for these secondary domains, which include a role functioning, emotional functioning, social functioning, so those are the good, and how well do you function, then the symptoms of nausea, constipation, diarrhea, insomnia, dyspnea, appetite loss, and financial difficulties in general. Once the patient has started on study, or at the time of start on study, those patients tend to be lower or in the worst functioning category versus the general population. What was found out is that as you follow these patients throughout their course, even like, for example, following through month 9, there tended to be definitely not a worsening but also an improvement in certain domains. All the functioning secondary subsets that I mentioned improved. Particularly, we looked at role functioning, emotional functioning, social functioning, and these are important to patients. They're what make you human, being emotionally functional, and feeling like what you're doing in your role in life is something that remains functional. Social functioning is what makes us human, and all of those actually statistically improve over time, which was really nice to see. The symptoms for constipation, nausea, vomiting, and diarrhea also did better over time. Particularly, they looked at going from month 0 to 9, and generally, those scores were better.

Looking generally at other secondary substances, there seemed to be improvement from month 1 to month 9 in general for the population, so that was something that we were looking for. One of the interesting things that we looked at was future perspectives, I think that's an interesting outcome to look at because that's what is this treatment doing for doing for you for the future? Those were some outcomes. And then the other the EQ-5D-5L also showed improvement as well.

TARGETED ONCOLOGY: What do these results imply about the future of these new CAR T cells?

Shah: The one thing that these analyses do is confirm what we as the physicians have been feeling, so I was really excited to be a part of this project. I love telling patients, you're going to get 1 treatment, then you're going to go home. Generally, you don't have to come back for more treatments until this doesn't work anymore, and people love hearing that. To put it into a quantitative that you can even tell the patient, we actually measured this, and people did better from a QOL perspective, this helps the patient to make a decision. Ultimately, I think the value of these data is not so much to tell patients they should get this CAR, but it's going to tell patients, you should get a CAR versus another type of treatment. For example, an antibody-drug conjugate or a BCMA bispecific or another traditional chemotherapy, so the more data we acquire and accumulate about these particular treatment modalities, from what we can compare them between modalities and less so within product to product, I think that's going to be less useful.

TARGETED ONCOLOGY: Could you share your thoughts on the 4 new approvals granted by the FDA in 2020 for the treatment of multiple myeloma?

Shah: Having approvals from the FDA is always very helpful because it gives us more latitude as physicians, and it helps the patients to also have more options. Much of these approvals, with the exception of belantamab, had to do with anti-CD30 antibody, and the approvals, in general, were in the relapsed setting. The one that I think changed the QOL the most is the approval of the subcutaneous daratumumab because of course, people don't like to have IVs, and they are okay with having shots so that from, again thinking about QOL perspective, that's great. What I think that the daratumumab, for example, combined with the carfilzomib, or the isatuximab combined with pomalidomide, those offer more variety in options for the early relapse space, so that patients who are in the first-, second-, or third-line setting, those people now have these options, which is great, and particularly combining the daratumumab with carfilzomib is something that has not been done. Traditionally, it's new as far as a combination, and right on the tails of this, we know that the IKEMA data was presented earlier this year and was represented for the depth of response also. That looks like it's very similar to daratumumab/carfilzomib, so we know that anti-CD38 plus carfilzomib is a good option for these people [who have received] the 1 to 3 prior lines.

Belantamab is the first BCMA-targeting agent that had FDA approval and the first ADC that has had approval. What it is is something beyond those daratumumab combinations that we already talked about because all the patients that were in that study had been exposed to daratumumab, and so this gives us an option for the later lines of treatment. It's also off-the-shelf, and it allows us to give an option with a new mechanism of action and a new target that patients won't have seen before. It's great that we have these new FDA approvals, and I really think that we're always looking for the next thing and to try to line them up in the sequence that we think is best. We still haven't answered those questions, but luckily, the FDA helps us by giving us labels and telling us what people had to be exposed to before. That helps, but I think we also have to do some of our own sort of medical artistry.

TARGETED ONCOLOGY: What message would you like to share with your fellow oncologists about the advances we've seen over the last year as we look ahead to what’s to come in 2021?

Shah: 2020 was a challenging year for everybody, and most definitely for cancer patients. The uncertainty of knowing when they can go to the doctor, when they should go to the doctor, or how sick they are going to be, but 1 of the good things that have come out of this is that our research machine has continued. There was a little bit of a blip, but the research and discovery machine has gone through this and has continued to enroll patients and to get results. We're so excited that because of this and because of all our partnerships, in community and industry, even with the FDA, all of these things have come together to continue to get more answers to our patients and get them more options. These 4 approvals are only possible because all of these oncologists, whether they're in academics or community who referred these patients for clinical trials, and that hasn't stopped. We know that our myeloma patients are doing okay with COVID-19, and I would encourage everybody, anybody who has a myeloma patient in the practice, that I would be so happy to talk to them, just so that person can see somebody who only sees myeloma. There are many myeloma specialists throughout the country who love to talk to any practitioner who wants to talk about myeloma, and maybe we can get them enrolled in a clinical trial that would benefit them and also help us to get more answers for the myeloma community in general.