KRd-D Generates High MRD Negativity Rates in Smoldering Multiple Myeloma

C. Ola Landgren, MD, PhD

When given for a fixed duration of 2 years, the combination of daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd-D) induced high response rates and deep responses, including high rates of MRD negativity in patients with smoldering multiple myeloma at a high risk of progression.¹

Data from the phase 2 ASCENT trial (NCT03289299) showed that the best overall response rate was 97%, and induced a 37% stringent complete response (CR), 26% CR, 29% very good partial response (PR), 2% PR, 1% stable disease, and 2% not evaluable. A total of 73 (84%) patients became MRD-negative, and the progression-free survival rate at 3 years was 89.9% (95% CI, 82.3%-98.3%).

Regarding safety, the KRd-D regimen was well-tolerated. Any-grade toxicity was observed in 83 (97%) patients, and was possibly related to therapy. There were only a few grade 3 or 4 toxicities observed, including hematological toxicity in 13 (15%) patients and non-hematological toxicity in 44 (51%) patients.

The trial is ongoing with nearly half of the patients still receiving therapy. Therefore, the depth of response is expected to improve.

In an interview with Targeted Oncology^TM, C. Ola Landgren, MD, PhD, professor of medicine, chief, division of myeloma, Sylvester Comprehensive Cancer Center at the University of Miami, discussed the ASCENT trial and his predictions for future developments in the myeloma space.

Targeted Oncology: Can you discuss some trials and ongoing research in the myeloma space?

Landgren: The ASCENT trial, which was presented by my longtime friend and collaborator, Shaji Kumar, MD, from the Mayo Clinic [at ASH 2022], is a study that's been going on for several years. It is a multicenter study that focuses on the population of [patients with] high-risk smoldering myeloma. There have not been many studies in this population of patients, because there is no FDA-approved indication for high-risk smoldering myeloma. Most of the studies have been investigator-initiated, and there is only 1 ongoing registrational trial at this current time, and that has not yet worked out. That's why we don't have any FDA-approved drugs yet in that space.

The ASCENT trial uses a 4-drug combination of carfilzomib with lenalidomide, dexamethasone, and the addition of daratumumab. This is the exact same regimen that we published last year in the JAMA Oncology journal in the MANHATTAN trial [NCT03290950] where we used it for newly diagnosed multiple myeloma. The difference here is that it's used for the smoldering high-risk patients. What they show is that you can achieve very high rates of MRD negativity. The MRD rate in the study is around 80% to 90% after the completed number of cycles in the study. That is a very impressive number. If you look at the MANHATTAN trial in newly diagnosed patients with the same regimen, it was 71% MRD negativity. So, there is an improvement in MRD negativity if you treat it earlier.

What are the follow-up results of the ASCENT study compared with other studies?

If you look at the follow-up in this study, the progression-free follow up time or PFS shows around 80% or so. The follow-up is just a few years in the study. As I mentioned, the sample size is around 80 patients. That's a very good PFS rate with quite short follow-up if you look, for example, and compare with historical newly diagnosed patient populations.

There is some data with just the KRd regimen that was also published last year from the NCI trial that uses KRd. It's the same regimen as used in this trial, minus daratumumab. The NCI trial has 8 years of follow-up. It's a very long follow-up and that study is around 50 or 53 patients. That study showed that at 8 years of follow-up, 70% of the patients had a sustained MRD negativity, and this is again KRd without daratumumab. It will be interesting to see in this ASCENT trial, what the long-term follow-up will show and if we see further deepening of MRD over time, or if it's going to land around the same time. We will have to just follow-up. I think it's a very interesting study.

What are your predictions for future research in the myeloma space?

The prediction for the myeloma space, in my opinion, is that we will continue to see a lot of change, and the change is going to happen faster and faster. There will be a lot of improvements for all patients. I think we will probably have a lot of chemotherapy-free regimens. We will see more and more patients having no detectable disease, or what we refer to as MRD negativity, and I think probably MRD will come, eventually, into most clinics. It's going to take some time to implement it everywhere. I have worked on it for over 15 years and there are still a lot of barriers to it being implemented everywhere and to see how MRD can be used for treatment decision making.

What other areas in myeloma need to be further assessed?

I also think an important area that I focused my research on right now is to understand the biology of patients who unfortunately fail their therapy. We talk about high-risk disease, but looking at those markers that we currently have in patient cytogenetics data sets, they are very poor predictors of outcome. These are probability tests, so it is almost like telling a woman that they may be pregnant. They want to know if they are pregnant or not, and that's the same exact dilemma with high-risk disease. [We may] tell a patient, you may have high-risk disease, and then the patient doesn't have high-risk disease, that's something that you don't want to do. If that is used for decision making and finding the right therapies, [we] need to understand this in more detail.

I think a big task is to drill into the full biology. We have done discoveries with NSD2 or or 4;14 translocations, and we see that there's a subset of those patients that have additional highly proliferative genes. In cluster analysis, there are small clusters of patients that drive the poor outcome in the 4;14 translocation group. So, not every patient with 414 has a bad prognosis, but some of them have a much poorer prognosis than the average. If you study 100 patients with 4;14, those very aggressive cases are the ones that drive the 4;14 in a bad direction, so to speak. If we could identify those cases and truly understand which would be the ultimate targets, that's when we start delivering precision medicine. That is what the myeloma field needs to focus on. Those patients who don't benefit from all the new drugs are probably about 10% to 15% of patients, unfortunately, in that group, and we really need to help those patients. The only way to do that, in my opinion, is to drill into the biology and to understand how it works and start targeting those different subsets of diseases that are in that category of patients.

REFERENCE:

Kumar SK, Alsina M, Laplant B, et al. Fixed duration therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone for high risk smoldering multiple myeloma-results of the ascent trial. Blood. 2022;140(1):1830-1832. doi:10.1182/blood-2022-168930