We sat down with Professor Andrew Spencer, head of the malignant haematology and stem cell transplantation service at The Alfred Hospital, Melbourne, to ask his thoughts on the impact of MRD negativity analysis on future trial design and clinical decision-making. He also offered his perspective on the importance of moving to a more personalised treatment approach for multiple myeloma.
Q: MRD seems to be causing a lot of excitement across a range of blood cancers. Why is this?
A: There are a number of reasons. The most obvious is that there are now more effective therapeutic agents that are leading to deeper levels of response. In turn, this may lead to more prolonged duration of disease control (although there is still more follow-up required to confirm this).
There’s still uncertainty about whether this deeper level of response will mean that patients are cured, or whether they will simply remain in remission for longer.
This focus on MRD is a natural evolution in the history of multiple myeloma treatment. If you look back, there have been certain times where the definition of response has needed to be redefined. In fact, at one point there wasn’t even an entity known as ‘Complete Response’. As the therapeutic armamentarium is refined, we are seeing better responses and tools for MRD are exquisitely sensitive and can detect very low levels of disease.
Q: Is there evidence to show that MRD negativity is a strong predictor of clinical outcomes?
A: Yes there is. There are multicenter trial data from the IFM Group in France, PETHEMA in Spain, and recent trials undertaken (albeit not all using the same assays) that show that MRD negativity is achieved in a substantial proportion of patients. Patients with MRD negativity have been shown to have longer progression free survival (PFS). Whether that translates into Overall Survival or Functional Cure is still unknown and requires longer follow-up data.
Q: Where does MRD negativity sit as an end-point for drug approval by regulatory agencies such as the EMA and FDA?
A: As recently as in this past week, the FDA has approved the next-generation sequencing platform that can be used for MRD detection. This is a big step forward in recognising that this is a valid way of measuring the disease, and should give the pharmaceutical industry confidence in using MRD negativity as an endpoint in clinical trials. There is a view that MRD negativity could be an early surrogate of overall outcome. This may help accelerate drug development and potential drug approvals.
Due to the remitting relapsing nature of myeloma, the ultimate outcome is confounded by the subsequent treatments patients receive and the decisions made at first relapse. Particularly with younger patients, it’s very difficult to determine the impact of early treatments on overall survival because they will go on to receive other therapies. It’s less of a problem in the elderly who will usually receive fewer lines of therapy. If we can use these MRD approaches to broadly define a group who will get long-term benefit from treatment, then this is what we should be doing. The issue that complicates matters is that the disease is so heterogenous: MRD negativity in one subset of patients may not necessarily mean that MRD negativity will be achieved in another subset.
The available data at the moment looks at treatments as ‘one size fits all’, rather than in individual patient subgroups. Post hoc analyses have looked at high-risk versus standard-risk patients and found that MRD negativity seems to be predictive of outcomes in both groups. However, I think the definitions for these groups is somewhat lacking.
Q: Will MRD have any relevance outside of clinical trials?
A: This may take some time. The cost of the MRD sequencing platform is somewhat prohibitive and unlikely to be used in a universal healthcare system such as in Australia. I think it would be very difficult to justify the cost unless you could offset it by savings gained by avoiding ongoing drug treatment in patients with MRD negativity. The trials evaluating cessation of treatment based on MRD negativity have not yet been performed. These trials have been planned, but it will be several years before we have any findings.
Q: Where is MRD best placed as an endpoint in MM trials?
I still don’t believe the disease is curable, so I think it’s very important to be able to explore new therapeutics in a more rational fashion. For this reason, I’m keen to see MRD negativity as a surrogate endpoint in clinical trials to allow for more rapid answers.
Another area where MRD analysis may be very useful in clinical trials is in determining when a patient should move to the next sequence of therapy or whether a patient can cease costly maintenance therapy based on MRD negativity.
Q: MM is a very heterogenous disease. If we strive for MRD do we run the risk of over-treating some patients, patients who may live in a stable VGPR (very good partial response) for years?
A: There is a paradigm whereby a subset of patients will never achieve a complete response and their disease behaves in a more indolent fashion (such as in patients with monoclonal gammopathy of undetermined significance – MGUS). Clearly in this subset of patients, MRD analysis is irrelevant.
Q: Where do you feel patients have benefited the most in recent years?
A: Clearly, the younger patients have benefited the most because more effective drugs are now available. There are many elderly and frail patients who cannot tolerate these drugs. There is data that if you need to stop therapy in an elderly patient, it’s an independent predictor for very short survival. So we need to define how to use these drugs in very elderly patients. In fact, we have just received a grant to conduct a large multicenter trial to investigate standard of care in elderly patients and determine the best scheduling and dosing for these drugs in this population.
The proteasome inhibitors are very effective agents that result in rapid responses. Now that we deliver bortezomib differently to the original IV route and schedule, it’s tolerated well, even in a subset of fit older patients. Carfilzomib (Kyprolis) is very effective (even in patients who have failed bortezomib), but needs to be given intravenously twice a week, which some patients find challenging. Ixazomib is a once-weekly oral medication and well-tolerated, but the response data hasn’t been as compelling as that for carfilzomib.
Q: Lastly, what is your ‘holy grail’ for the Multiple Myeloma field?
A: There needs to be some personalisation of treatment for this variable disease. The approach of a proteasome inhibitor backbone is valid – as the agent directed against the plasma cells. But agents on top of this: there needs to be some level of personalisation to take into account the mutational spectrum and other features that vary widely. It’s not a ‘one-size-fits-all’ disease.