Amrita Krishnan, MD, FACP: The goals of therapy for myeloma have changed. It used to be sort of a question of controlling disease. Really, now we’re moving into a question of…curing disease is our ultimate goal. We recognize that there is a subset of patients in whom we’re able to do that. That’s still a small subset, and, unfortunately, we’re not able to identify who those patients are going to be. But having said that, what we do know is that multiple drugs in different classes used in combination early in the course of therapy can lead to deep responses. Now we’re seeing MRD-negative responses, and, ultimately, I think that is our goal of treatment, because now we know that MRD-negative states correlate with progression-free survival. The other thing that we do know about is a backbone therapy regimen that includes a proteasome inhibitor—and you can argue which proteasome inhibitor—and that varies patient to patient. In combination with an IMiD, generally, lenalidomide is still a frontline IMiD in the United States. In Europe, it tends to be thalidomide, steroids. Unfortunately, patients don’t like steroids. We don’t really like them, but they still form a backbone of therapy given their synergy with the other drugs. And more and more, the issue of antibody therapy also in the frontline setting is what we use and to get, again, deep response.
We also want to minimize toxicity, so I think getting neuropathies is not acceptable for us any longer in terms of patient quality of life. And we’re quick to either adjust therapy or change therapy if we see that as an issue. Fortunately, the other drugs seem to be quite well tolerated. Hematologic toxicity is something we also monitor and adjust as we need to. I still plan for transplant, too, so I use that as part of my frontline package for the majority of patients I see.
Patients with comorbidities do present a challenge, but they’re the reality of myeloma, as the median age of diagnosis of myeloma is 72. So, most patients, by the time they reach that age, come along with a burden of other comorbidities. The most common one is said to be hypertension and diabetes. But having said that, those are the things that some of our treatments also exacerbate. So, if you have diabetes, you may have underlying neuropathy, for example. Obviously, the steroids are not helping your diabetes. We need to do a couple of things for patients who are older, patients with comorbidities. First of all, we need to assess them better, and there have been a lot of data from ASCO that show geriatric assessment needs to be more focused and more codified—and so, this idea of a frailty index, a comorbidity score, geriatric score—and we’ve been using that more and more in our clinics. And we’re surprised sometimes—just the eyeball test for a patient is not enough. And some of these geriatrics assessments can be really helpful in terms of picking out what is the best treatment for patients, because they also do not just encompass the physical characteristics; we’re also taking into account social characteristics, activities of daily living, independent activities of daily living, and social support, which, when you’re talking about some therapies, are very important considerations.
The other thing I think that has been important to us is being able to use these drugs but sometimes adjust the dosing. For example, RVd-lite—so somewhat of a lower dose of lenalidomide and a lower dose of bortezomib, so less neuropathy in a patient. Older patients tend to get more neuropathy. Lower dose of steroids, we recognize now to use in patients over the age of 75. We automatically will start with half the dose of dexamethasone that we do in older patients.
MRD has been very exciting to us in myeloma because we can now achieve MRD. Having said that, there are multiple, multiple challenges with it. First of all, we still don’t have complete agreement on the best method to assess MRD. The second part of that is that MRD is a narrow-based test, so that you can sometimes be MRD-negative but still be PET scan—positive, for example. You can’t use just 1 MRD test alone as your true end point and stop therapy. So, what we can say about MRD is that clearly, it’s prognostic in terms of progression-free survival, whichever way you measure it, be that by next-generation flow or by PCR-based testing. But are we able to use it to change therapy yet? And I would say the answer is no, but it is the future.
For example, we are going to be opening a huge trial that we’re very excited about through SWOG that is going to perform autologous transplant on our patients. Patients are going to get maintenance therapy. One arm will be lenalidomide/daratumumab. One arm will be lenalidomide, and then at 2 years, patients will have MRD reassessed. And patients who are MRD-negative will undergo a second randomization to either stopping therapy or continuing maintenance therapy. So, I’m very excited about that trial because it will answer for us, in a randomized prospective fashion, can you use MRD to guide therapy?