Over the past two decades, the U.S. Food and Drug Administration (FDA) has approved a number of new treatments for patients with myeloma – most recently the anti-CD38 monoclonal antibodies – and new ways to measure disease response. This innovation has given clinicians the opportunity to redefine the goals of disease treatment and the value of specific endpoints, milestones, and biomarkers.
In this edition of Drawing First Blood, ASH Clinical News invited Sagar Lonial, MD, of the Winship Cancer Institute at Emory University in Atlanta, and Paul Richardson MD, of the Dana-Farber Cancer Institute in Boston, to debate whether these new treatments and tools should change the goals of myeloma treatment. Dr. Lonial will be arguing that functional cure should be the treatment intent for patients with myeloma, and Dr. Richardson will be arguing that complete remission and other efficacy endpoints should be the goals of treatment.
Paul Richardson, MD: In myeloma, there has been a remarkable team effort to improve patient outcomes at all stages of disease. The past 20 years or so have seen a paradigm of bench-to-bedside translation, with cooperation among research, pharmaceutical companies, and clinicians.
And this has had an extremely positive impact on the field: We've had more than 20 FDA approvals, and there are, obviously, more to come. It's an exciting time for our patients.
There is an important caveat to note, though. While we are striving for a functional cure for our patients with myeloma, we fully recognize that certain subgroups – those who have what would be defined as high-risk disease – still have a terrible prognosis.
However, we have evidence that long-term maintenance after hematopoietic cell transplantation leads to phenomenal outcomes: A paper recently published by Sarah Holstein, MD, PhD, and colleagues showed that median survival among patients who received lenalidomide maintenance therapy after receiving an autologous hematopoietic cell transplantation is now 10 years.1 The critical questions, then, are, "How do other new therapies affect our clinical decisions, and what role does transplant play in this decision? How much treatment is enough – who needs more and who needs less?"
Sagar Lonial, MD: As we begin this discussion, remember that some patients with myeloma can do exceedingly well with available therapies. A Spanish study found that there are 15 percent of patients who are in continuous complete remission (CR) over 10 years after initial induction and transplant.2 In this context, it is also important to realize that while we talk about "replacing transplant," transplant clearly improves outcomes for patients treated with every therapy we have used so far. While subsets of patients can be considered for delayed transplant or no transplant at all, we cannot easily identify them at this time. So we should continue to use transplant.
When we discuss the "cure-vs.-control" question in myeloma, we should identify the goal of therapy and what clinical indication would prompt us to change therapy.
And by that, I mean that I see many patients who achieve a very good partial response (VGPR) with induction therapy, but, because they are not in a CR, a physician made the decision to change their therapy to provoke a deeper response.
Switching therapy in pursuit of a deeper response may be a good idea, but there are no data that suggest that switching to achieve a deeper response leads to better patient outcome.
"We should identify the goal of therapy and what clinical indication would prompt us to change therapy."
â€”Sagar Lonial, MD
To me, if your goal is to try to get a patient to hematopoietic cell transplantation, achieving a VGPR is a perfectly reasonable endpoint. After a patient reaches VGPR, we can offer him or her the next step – transplant, which we know from available data does improve outcomes – as opposed to changing therapy and running the risk that the patient may not benefit and get to transplant.
Endpoints such as VGPR, CR, or minimal residual disease (MRD)–negativity are important endpoints because they tell us whether patients have achieved certain benchmarks of response but, in many ways, these endpoints do not represent the goal of every treatment regimen.
We want to administer a treatment that gives a patient the highest likelihood of achieving a CR, but if a patient doesn't achieve a CR, that doesn't mean that he or she needs to change treatment. That's a subtle point that is often lost in these discussions. I find value in those endpoints; they are prognostic endpoints more than anything else and are laudable goals. However, I think sometimes people – both patients and doctors – get too hung up on achieving a certain number, without realizing what that number may or may not mean.
Also, many trials demonstrating the benefit of achieving MRD negativity did so in the context of limited or no maintenance; we may get different results if we extrapolate those results to patients to whom we give risk-adapted maintenance therapy or continuous maintenance therapy.
Dr. Richardson: Keep in mind, though – these endpoints are valid tools for regulatory approval, which is a different issue. The important question is whether achieving these endpoints should change our clinical practice. I don't think we can answer that yet. We don't know enough about exactly what these endpoints mean clinically in terms of treatment choices. But are they helpful from a regulatory point of view? Yes, I believe they are.
Dr. Lonial: The randomized, phase III CASTOR and POLLUX trials, which served as the basis for the approval of daratumumab, demonstrated early improvement in progression-free survival (PFS) with the combinations of daratumumab and either lenalidomide and dexamethasone or bortezomib and dexamethasone.3,4 The data also suggested improvement in overall survival (OS), although those have not yet been reported as clearly statistically significantly different.
In both trials, more patients in the daratumumab-treated groups achieved MRD-negativity than in the comparator arms. In POLLUX, 22.4 percent of daratumumab-treated patients met criteria for MRD-negativity, at a threshold of 10-5, compared with 4.6 percent in the control group (p<0.001). In CASTOR, 18.3 percent, 10.4 percent, and 4.4 percent of daratumumab-treated patients achieved MRD-negativity at thresholds of 10-4, 10-5, and 10-6, respectively. What is often lost when people look at these data, though, is the difference in the methods for assessing MRD. Those are three different benchmarks for MRD-negativity, and not all levels of negativity are the same. When thinking about MRD as a pathway to cure or to achieving the longest-possible PFS and OS, we want to use the most stringent response (10-6) as an important endpoint. People need to read these data critically and understand that every MRD – and every study – is not the same.
Dr. Richardson: I completely agree with Dr. Lonial, and I would add the following: What's so interesting in these trials is that, in comparisons of MRD-negativity rates between the control groups and the triplet groups, the outcomes for both groups correlated with each other, which is an important validation. Having said that, what's even more clinically interesting to me is that patients who are MRD-positive, regardless of duration, did better with the triplet regimen than the two-drug regimen. You may think, "Well, that's obvious." But, I would argue that this information gives us clues for combining various therapeutic modalities. For example, we may not need as much for MRD-negative patients, but we absolutely need more treatment for MRD-positive patients.
Newer treatments have offered us the opportunity to add more therapy when we need to, without an adverse effect on quality of life. They offer novel, entirely non–cross-resistant mechanisms of action – be they antibodies, immunomodulators, proteasome inhibitors, other small molecules, or a part of this whole emerging platform of cellular therapy or immune therapies.
"[Myeloma] is remarkably plastic, even within one patient over time.
… We have to be particularly cautious to avoid a â€˜one-size-fits-all' treatment model."
â€”Paul Richardson MD
Dr. Lonial: Yes, the availability of new drugs and new targets has given us the opportunity to talk about cure vs. control in a much different way than we did before.
In plasma-cell disorders, we have settled on a paradigm of continuous maintenance. The new tools we have, though, mean that it may be time for us to think about how we can give treatment for a defined period of time. We need to ask ourselves whether we are potentially increasing the cure fraction, as opposed to just keeping people on continuous therapy and adding one drug, two drugs, and three drugs to their maintenance approach.
Perhaps there is a growing subset of patients in whom we have either eliminated disease or caused remission long enough that PFS and OS will be outstanding.
Dr. Richardson: I agree with that, but our challenge is to just remain cognizant of the fact that maintenance is a standard of care. Every patient probably will have an absolute need for some form of continuous therapy to achieve the goals that we have discussed. We may need a backbone of specific drugs, to which we can rationally add additional agents according to specific patient needs, to achieve those goals. In other words, we will be able to tailor therapy to optimize outcome.
Myeloma is a complex disease. It's not one disease; it varies enormously between patients. But it is remarkably plastic, even within one patient over time. For clinicians making treatment-sequencing decisions, that's an important factor to understand because it means we have to be particularly cautious to avoid a "one-size-fits-all" treatment model.
Conversely, the best evidence we have for length of treatment is that it should continue until disease progression and/or treatment intolerance. However, monitoring MRD, for example, may provide us with the opportunity to offer patients a "drug holiday" at certain times. Personally, I am very cautious about that because, at the end of the day, the disease may recur.
Dr. Lonial: That seems to be where our current level of evidence stands, but I do think we need to challenge ourselves to think beyond that model. I have patients, as I'm sure you do, who have been on continuous maintenance for seven, eight, or nine years. There does come a point when the patient and the clinician start to ask, "Are we really doing any good here? Have we already achieved the maximum benefit that we're going to get?" And we don't know the answer to that.
Yes, the present paradigm is treatment until progression. The newly available tools and drugs haven't been fully incorporated into the treatment model, though, so maybe we can start to think about how to define when a patient can stop therapy. Ultimately, that is a sustainable model, while the continuous-treatment model involving one-, two-, three-, or four-drug regimens until progression becomes unsustainable over time.
Dr. Richardson: Another factor to be aware of – and it is a point that is relevant to all discussions about treatment sequencing – is that, at the end of the day, we have to face the reality of costs.
There's an important distinction between value of therapy and actual price, so we also need to treat patients in a financially responsible fashion. Going forward, we need to consider costs, because we must be able to provide our patients with sustainable therapeutic approaches. What I fear is a model where clinicians are constrained, not by clinical evidence and good science, but by overzealous regulatory authorities worried about price alone.
As members of our academic and research community, it behooves us to study real-world combinations and strategies to provide cost-effective options, because they increasingly matter. We can, and need to, conduct elegant studies with the best-available agents, but we also must evaluate the most rational and least financially toxic combinations. By doing so, such real-world clinical research can be of particular value to our community colleagues and our patients.
- Holstein SA, Suman VJ, McCarthy P. Update on the role of lenalidomide in patients with multiple myeloma. Ther Adv Hematol. 2018;9:175-90.
- Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118:529-34.
- Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31.
- Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-66.