At IMS 2024 we were privileged to have the opportunity to present some of the results from a phase II investigator initiated study which is known as the MILESTONE trial. What it is looking to do is essentially use MRD as a means to make a decision regarding patients going forward with transplant or deferring that strategy. So MILESTONE essentially stands for minimal residual disease adapted deferral of transplant in dysproteinemia.

Essentially, minimal residual disease, or measurable residual disease or MRD, is a very important prognostic marker for progression free as well as overall survival. Recently the FDA has received a favourable recommendation from the ODAC for its use as an early clinical endpoint for accelerated approval of novel therapies. Autologous stem cell transplant has been a prime consolidative strategy for patients with newly diagnosed multiple myeloma and is very helpful in improving the rates of MRD negativity and depth and duration of response. However, the strategy is full of both short-term as well as long-term toxicities and there’s an importance in understanding who are the patients who are best served by this approach.

So, with that in mind, we designed the study to treat patients with six cycles of quadruplet induction that included daratumumab, lenalidomide, bortezomib and steroids. We gave that for six cycles of therapy. This was essentially followed by evaluation of a post-induction MRD assessment. We used next generation sequencing technology via the ClonoSEQ platform and essentially we used that information to make a decision regarding transplant. So patients who were MRD less than 10-5 we deferred transplant and they proceeded with additional consolidation with the quadruplet for three additional cycles followed by maintenance. Whereas those patients who remained MRD greater than 10-5 had the opportunity to proceed with stem cell transplantation followed by maintenance which on both arms of the study was daratumumab with lenalidomide, so doublet maintenance.

Our primary endpoint was to evaluate the proportion of patients who were able to defer transplant based on achievement of MRD negativity and looking at their outcomes in the long term. We also had several other secondary endpoints, including PFS, OS, determination of change in MRD burden with transplant as well as outcomes of patients who reach sustained MRD negativity and go on to a phase of active surveillance.

Overall, 20 patients were treated. These were really patients who were more reflective of the real world with half of the patients being more than 70. We had 45% minorities, we had 50% males, 15% were high risk and 40% were high risk if you include [gain of 1Q].

What we saw is we had NGS was trackable in every single patient and all datapoints were obtained. We were able to defer autologous stem cell transplant in a quarter of the patients. After induction the MRD less than 10-5 rate was 25% which increased to 55% following consolidation. The best overall MRD negativity on the study was 65%.

In terms of traditional responses we see that the IMWG overall response rate was 100% and so far none of the patients on the study have progressed. The CR rates after induction were 35%, after consolidation were 75% and after best response were 85% for the whole study. So overall patients are doing really well and it will be important to follow their long-term outcomes to see how sustainable these MRD negative responses are in the absence of transplant.

What is the clinical significance of these results?

Essentially autologous stem cell transplant has been a prime consolidative strategy for patients with myeloma. However, it is associated with several short-term toxicities such as cytopenias, infection risk, mucositis, hair loss, hospitalisation. This period of debility that can take anywhere from 6 weeks to 6 months to improve, so those are the short-term toxicities; we know about the risk of second cancers as well as several long-term clinical toxicities of high-dose melphalan and stem-cell transplant. What’s important is while we know that autologous transplant helps increase the rate of MRD negativity, it’s unclear in terms of the benefit that autologous transplant adds to patients who are already MRD negative with quadruplet inductions. Really, for the first time we have an opportunity, because so many of our patients are achieving these landmark milestones, to ask the question about do those MRD negative patients still benefit from transplant and how they do and can we spare a proportion of patients this toxic procedure and have identical outcomes.

So really in our study I think the single most important thing we saw is that the MRD negativity across the study is very similar to the GRIFFIN and the PERSEUS studies and we are seeing almost identical MRD negativity responses with up to two years of study follow-up. This is while sparing a quarter of the patients the toxicity of transplant. So I think this is a step in the direction of personalising the management of myeloma and using this new available measurable residual technology to identify patients who we can spare additional toxicities.

What is next for this study?

The title of our study, MILESTONE, actually stands for measurable residual disease adapted deferral of transplant for dysproteinemia and therefore the study actually has two cohorts: cohort A looking at patients with newly diagnosed multiple myeloma and cohort B newly diagnosed AL amyloidosis.  So the cohort B required for us to obtain an investigational device exemption from the FDA and is now open for accrual and is going very well. So we anticipate using MRD to make decisions in AL amyloidosis regarding stem cell transplant. I feel this will be a very important study for these patients because right now it’s very unclear how treatment with dara-VCd intersects with transplant and there’s really no clear understanding of who those patients should be and who will most benefit from this approach. So we’re very excited about cohort B of the study.

Additionally, because we have established the feasibility of using a real-time MRD assay in making treatment decisions in the newly diagnosed myeloma space, we’re using that information and this has served as a pilot study for the now open randomised phase II MASTER-2 clinical trial which is a large randomised effort wherein we are looking to make decisions regarding deferring transplant as well as taking patients who remain MRD positive following quadruplet therapies and intensifying that treatment with a bispecific antibody.

So, overall, I think there are several clear paths forward, we’re looking forward to the MASTER-2 trial as well as looking at this approach in AL amyloidosis.