Panelists: Shaji Kumar, MD, Mayo Clinic; Heinz Ludwig, MD, Wilhelminen Cancer Research Institute; Maria Victoria Mateos, MD, PhD, University Hospital of Salamanca
Shaji Kumar, MD: At this point, most of the patients with myeloma are going to relapse, whether they go through a transplant or go through a known transplant type of treatment. The speed with this patient’s relapse is highly variable. When patients go through stem cell transplant off label, 20% of those patients will relapse within the first 1 to 1.5 years after their stem cell transplant. These patients have very aggressive disease and would need, right away, some kind of treatment for the relapsed disease. Now the patients who relapse very slowly—and this is particularly relevant in the post-transplant setting—there’s probably about one-third of these patients where the protein slowly starts going up over a long period of time. We know that these patients actually have a better disease biology and they generally tend to do better with all kinds of treatment that we have available.
I think it’s important for us to not overtreat some of these patients. What we are seeing in this setting is similar to what we see in the smoldering myeloma setting. So, there are patients who are at a higher risk of progression. The key thing for this group of people is to identify who are at high risk of getting some of those end-organ damage in a relatively short timeframe.
We don’t have all the answers, but right now what we can safely say, are patients who have rapidly rising monoclonal 14—patients who ordinarily present with catastrophic end-organ damage, whether it’s logical compromise or renal failure—we generally want to treat them early on after the relapse. The same thing is probably true for patients with high-risk myeloma at baseline. I think, with these patients, we also need to intervene earlier than later. Patients who have standard risk disease who are having a very slow increase in their monoclonal protein, without any other end organ damage, can be watched for some time before we intervene in those patients, because they might go for several years before they actually develop any kind of end-organ damage.
Heinz Ludwig, MD: So, if the patient progresses, the patient may present with different symptoms. He may be completely asymptomatic; he may present with what we call a biochemical relapse. The pattern of relapse usually resembles the presentation at diagnosis—a patient who is diagnosed with active, full-blown disease, various symptoms, pain in the lumbar spine, he usually relapses with aggressive disease. That is a completely different patient from one who has been diagnosed with almost asymptomatic, slowly progressing myeloma. You achieve remission in those patients, the duration of the treatment-free interval is much longer, and then they slowly will relapse into a biochemical relapse.
The treatment strategy depends a little bit on how often you can see your patients. In Europe, it’s not a problem because you can ask the patient to come in every month or every 3 months so you can watch them without any need of therapy, and then you can individualize your treatment decisions to his or her needs. But sooner or later, there will be a time to start treatment even in those patients, but we have to be careful that you don’t overlook progression of bone disease because you may have a biochemical relapse, and few patients may also have bone disease or progression of bone disease. So, you should monitor the skeleton in certain intervals in order to prevent significant bone disease before you start on therapy.
Maria-Victoria Mateos, MD, PhD: There are big differences between relapsing patients and primary refractory myeloma patients. Relapsing patients means one patient has previously received 1 or more than 1 prior line of therapy, and they have achieved at least a minor response. So, the outcome has decreased at least 25%, and after at least minor response, the disease is coming again. By contrast of the primary refractory is one patient that has never achieved at least a minor response to any prior line of therapy. So, the situation is completely different, and the primary refractory myeloma patient is a patient at high risk. For this group of patients, we have to select combinations of agents completely different to try to achieve any response. The outcome for this group of patients is usually very poor. By contrast, for relapsing patients, we can consider different combinations; even re-treatment with prior lines of therapy, prior drug classes to which the patient has been previously sensitive. But the primary refractory myeloma patient is, I would say, an ultra-high-risk group of patients, and, fortunately, the number of patients with primary refractory disease is very reduced, I would say that it’s not superior to 3% or 5%.
Heinz Ludwig, MD: The goals of therapy change over time because, at the beginning, you want to achieve the best possible outcome. Initially, you want to achieve minimal residual disease negativity and you want to prolong this. These may be feasible in a few patients, but then sooner or later, most patients relapse. And then, after first relapse, you want to achieve a very good remission and MRD negativity. But when it comes to the third or fourth relapse, you want to maintain best possible quality of life. You might want to get your patient going. You are satisfied with, let’s say, not complete remission but very good partial remission. You want to control the disease, and that is important. You want to improve his symptoms and get him going; have him enjoy, as much as possible, the days that are provided to him.