Pre-Conference Perspectives on Hematologic Malignancies - Episode 9

Daratumumab for Smoldering Myeloma


John Leonard, MD: So, then the other drug that obviously is well known to the audience in more standard myeloma is now getting a look in smoldering myeloma: Daratumumab, the antibody-based therapy. Your thoughts on this trial from Hofmeister and colleagues?

C. Ola Landgren, MD: This is another study for smoldering myeloma. All of a sudden, there are now all these trials going for smoldering myeloma. So, it’s a randomized phase II trial.

John Leonard, MD: I didn’t even know there was smoldering myeloma years ago, now it’s more common than myeloma.

C. Ola Landgren, MD: The myeloma field is changing so rapidly. Every 6 months there are new data. There will be 5 new drugs in the coming 5 years. I do think there will be so many new things coming. So, this trial by Hofmeister is a randomized phase II trial with 123 patients. There were 41 patients in each arm. One arm has only 8 weekly doses of daratumumab, the CD38 monoclonal naked antibody. The other 2 arms go out to a total of 3 years, and they are different in terms of the intensity of the dosing. And the study has 2 primary endpoints. One endpoint is complete response rate at 6 months and the other one is progression-free survival at 12 months. According to the abstract, there is a progression-free survival difference already at 12 months of follow-up in this patient population. So, here you have it, John. Maybe we should start thinking about early treatment.

John Leonard, MD: And that leads us, obviously, to biomarkers, like in every malignancy, but particularly when you have some heterogeneity in the clinical outcomes and trying to choose therapy. We have Bustoros and colleagues. And I know this has been an area that, just like in leukemia, just like in lymphoma, there’s the molecular profiling of one sort or another to try to predict who’s going to do better and worse in treatment. Insights on that from this report?

C. Ola Landgren, MD: I think this is an interesting study. It’s from the group up in Boston. They have taken close to 200 patients, and they have conducted whole exome sequencing, and they have done whole genome sequencing on a subset of these patients, deep whole genome sequencing. And really the idea they have is to see whether you actually genetically can predict who is going to go into multiple myeloma. There is no study that so far really has done that in full resolution, and I think this study doesn’t fully answer but it provides a lot of new clues. It shows, for example, that mutational burden is higher in what we clinically refer to as high-risk smoldering myeloma. They look at the number of mutations per megabase pair and it’s 1.4, and if you look at studies that look at multiple myeloma, it’s 1.6. And then, they look at the low-risk smoldering myeloma, and in that group, it’s around 0.7. So, there’s almost a doubling.

They also look at somatic mutations in pathways that are known to be important in myeloma, and there are striking significant differences. They do different types of analysis. And they show there are differences. What they do not show here, at least in the abstract, is really how the mechanisms work, and if this is something that could be used for treatment, could we use these as targets. So, there’s more work to be done, but it’s very exciting.

John Leonard, MD: To reiterate then, as we move from smoldering, it sounds like outside of a trial, it’s really not standard to treat patients at this point.

C. Ola Leonard, MD: Yes, that is absolutely right.

John Leonard, MD: Great, but certainly it sounds like that may change before too long.

C. Ola Landgren, MD: I think so.

John Leonard, MD: Excellent.

Transcript Edited for Clarity