Oncology Data Advisor: Welcome to Oncology Data Advisor, I'm Keira Smith. Today I'm joined by Dr. Shaji Kumar, Professor of Hematological Malignancies at the Mayo Clinic Cancer Center. Dr. Kumar, thank you so much for joining me today. Since the ASH Annual Meeting just happened recently, would you like to tell us about the abstracts that you presented there?

Shaji Kumar, MD: One of the abstracts that we have presented was on the long-term follow-up of the MAIA study. That is a phase 3 trial looking at the impact of adding daratumumab to lenalidomide and dexamethasone (len-dex) for patients who are not eligible to undergo stem cell transplant. We had longer follow-up, a little over five years now, that shows consistent benefit in terms of overall survival and progression-free survival.

The addition of daratumumab with the longer-term follow-up does not seem to show any new risks. There's clearly increased risk of infections with the three-drug combination compared with the two, particularly pneumonia. In terms of efficacy, we do see a higher response rate. We also see deeper responses with minimal residual disease (MRD) rates, about three times what we see in the len-dex group, which has translated to a median progression-free survival (PFS) of more than five years. This is one of the longest we have seen in the setting of a transplant-ineligible patient population.

There was data from the ASCENT trial, which is a phase 2 trial looking at the impact of intense limited-duration therapy in patients with high-risk smoldering myeloma. The existing data support the use of lenalidomide only and lenalidomide/dexamethasone as treatment for high-risk smoldering based on data from phase 3 trials. This is one of the series of trials done by different investigators that are trying to ask the question, can we give more intense therapy but for a shorter duration to try and cure some of these patients, or at least provide long-term control of the clone in patients with high-risk smoldering myeloma?

The ASCENT trial treated patients with high-risk smoldering, as defined by the International Myeloma Working Group criteria, with carfilzomib, lenalidomide, daratumumab and dexamethasone. The four drugs were given for 12 cycles and then maintenance for one year with two drugs, lenalidomide and daratumumab. What we found with the ASCENT trial was that this is a very effective combination. We get a complete response or better in two-thirds of the patients. The majority of those patients end up being bone marrow MRD–negative, as well. We have seen very few progressions so far, only four out of the 87 patients. Most of the progressions, three out of the four progressions, are biochemical alone.

The regimen was well tolerated. There were hematologic and non-hematologic toxicities, but they could all be managed with dose modifications. There were a few patients who went off-study for a variety of different reasons, including patient preference and adverse events. But overall, given that very few patients have progressed so far, and the minimal residual disease negativity rates are pretty high with the three-drug combination and seem to be persistent, it certainly seems promising. Obviously, longer-term follow-up is needed before we know, but we are truly curing patients with this approach.

There was data looking at one of the arms from the MyDRUG trial. The MyDRUG trial is a genomically guided study that is being conducted through the Myeloma Research Foundation in patients with functional high-risk multiple myeloma. You have myeloma that is progressed within a year, year and a half, or three years if you have maintenance treatment, and those patients are considered functionally high-risk. Those patients were then subjected to a sequencing of their bone marrow plasma cells to identify predominant mutations. People with specific mutations were then assigned to individual arms of the study using targeted agents specific for that mutation.

But we also had an arm that looked at that enrolled patients who did not fit into any of the others by virtue of not having an actionable mutation. What we found in the study was that people with functionally high-risk multiple myeloma who were treated with the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone had a good overall response rate, and there were also deep responses in a significant number of patients. We don't have longer-term data in terms of median PFS or overall survival, but that's certainly something we will be looking forward to in the year to come.

Oncology Data Advisor: Great, thank you. As far as other abstracts that were presented, are there any that you think are the most significant or the most practice-changing?

Dr. Kumar: I don't think there's any one abstract that's practice-changing necessarily, but there are a lot of data that were presented across the spectrum of multiple myeloma that will all have incremental effect on the field. A lot of the questions were related to disease biology, specifically looking at single-cell approaches to understand the mechanisms of disease progression from precursor conditions to active myeloma.

There were some clinically relevant questions, like in which patients do we need to do bone marrow sampling if they have a diagnosis of monoclonal gammopathy of undetermined significance? This was data presented by the Iceland group, and they actually have a tool online that you can use to decide whether you want to do a bone marrow sampling for your monoclonal gammopathy of undetermined significance (MGUS) patient whom you're seeing.

Otherwise, there was a lot of focus on high-risk multiple myeloma. There were data from retrospective studies as well as prospective clinical trial data looking at next-generation proteasome inhibitors combined with monoclonal antibodies, five-drug combinations for injection therapy, followed by prolonged maintenance with two drugs. For all these approaches, again, we don't have a clear comparison for superiority of any one approach. But in comparison to what we have seen with these high-risk patients in the past, these treatment approaches certainly appear to be of benefit.

There are some studies that are being done in the transplant-ineligible patient population, particularly a study that sought to decrease or eliminate the need for a significant amount of steroids. They looked at daratumumab/lenalidomide, comparing it with lenalidomide and dexamethasone, again showing that this steroid-free approach is still quite effective. We also saw data asking the question about autologous stem cell transplant in the older patient population using a reduced dose of melphalan. That trial did not show any significant benefit for transplant in any of these groups, bringing up the question whether we should be transplanting the older patients with multiple myeloma.

We also saw data from some of the newer therapies, particularly the bispecific antibodies, targeting both BCMA as well as other antigens like GPRC5D and FcRH5. We also saw data from CAR T cells, particularly with respect to understanding the mechanisms of resistance and relapse in those patients after CAR T. Data from a trial in China looking at dual targeted CAR T, targeting CD19 and BCMA in patients with newly diagnosed high-risk multiple myeloma, was, I think, quite informative. Obviously, it was a small sample size, and we need longer follow-up, but it's certainly something that we will be looking out for.

Then, finally, there was also data from the European Myeloma Network looking at using daratumumab as a single agent in patients with light-chain amyloidosis with stage IIIB disease. If you recollect, stage IIIB patients were excluded from the ANDROMEDA trial. This trial gives us a sense of how much daratumumab can do for these really frail, advanced light-chain amyloidosis patients. I think the data is quite interesting in comparison to what we have seen with historical data. We are seeing good hematological responses as well as some organ response, all of which should translate to better outcomes for these patients.

Oncology Data Advisor: Awesome, thank you so much for sharing all these really exciting updates today.

Visit https://i3health.com/relapsed-refractory-multiple-myeloma to book a live or virtual meeting at your own institution and hear more expert perspectives from Dr. Kumar or other esteemed multiple myeloma faculty!

About Dr. Kumar

Shaji Kumar, MD, is a Professor of Hematological Malignancies at the Mayo Clinic Cancer Center in Rochester, Minnesota, where he is also a Consultant in the Department of Hematology. Dr. Kumar specializes in the treatment of patients with hematologic malignancies, with particular expertise in amyloidosis and multiple myeloma. His research focuses on the development of novel therapeutic agents and combinations for these diseases.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.