What is maintenance therapy and how does it differ from consolidation and induction?

What is maintenance therapy and how does it differ from consolidation therapy? So maintenance therapy is what we do after induction and consolidation. So for the newly diagnosed patient, the induction therapy is the more intense of a combination therapy that we do initially to bring the disease down from the initial high level, a diagnosis down to a very low level, if possible, MRD negativity. That's always what we aim for. And then we do the consolidation, which typically is the stem cell transplant. That's also being discussed. So for the maintenance, the goal of the maintenance is when we have gotten to that low level, hopefully MRD negativity, is to then keep it at that low level. The most common standard of care therapy for maintenance is linalydomide, but at a lower dose. And then we do that over a longer period of time. So the initial trials, they were done on maintenance for two years, but then updated trials with longer follow-up, we've seen that continuous maintenance until progression has been the recommendation. We've seen that for most patients, the overall outcome is that there is a progression-free survival benefit with continuing maintenance. However, there was a little bit of a difference in terms of MRD status. So for those patients that are MRD positive, yes, there is a benefit of continuing maintenance. For those that are MRD negative, so they have a sustained MRD negativity, this benefit was clear for three or four years, and after that, you don't really know. So there are actually trials ongoing with stopping maintenance for those that have sustained MRD negativity. So for those patients that are MRD negative and have a sustained MRD negativity, a cessation trial where patients that are MRD negative after three years can go off therapy and read monitored off therapy. And based on the abstract data, including 23 patients, the majority of patients are still MRD negative with a medium follow-up of 15 months. So I think we need more data, but for in general, the general recommendation is to have continuous maintenance for those, especially for those that are MRD positive, for those that are MRD negative, we'll see if there is a possibility that we can stop and monitor. So induction therapy happens first, consolidation happens second, and maintenance therapy happens third. You can think of the intensity of the therapy declining with each step. So in maintenance therapy, we have least intense treatment. That treatment is often low dose of a single drug, such as Revlimid, and we might give that daily or maybe for three weeks on and one week off, and that treatment is continued for as long as the patient can tolerate it. That treatment is generally well tolerated without as many side effects as the induction or the consolidation, but can cause neutropenia, which is low neutrophil count, after a prolonged use, in which case we might have to adjust the dose. And it can increase the risk of some bone marrow diseases. So it's important that your bone marrow is regularly assessed with a biopsy while you're on treatment. Maintenance therapy is continual therapy after induction, initial therapy, or after autologous stem cell transplant. The purpose of maintenance is to maintain that remission as long as possible. In the US, the standard is Revlimid maintenance and not fixed duration, but Revlimid continues until progression or intolerability. However, we know that people with high risk cytogenetic lesions won't do as well as those with standard risk, so we have ongoing studies looking to augment this with multi-agent maintenance. The most mature data is from the Forte study, giving Kyprolacin Revlimid as a maintenance, which really did seem to help a lot of people have better outcomes. Kyprolacin getting four times a month is somewhat cumbersome, so there's several ongoing strategies looking at doing things like Dara and Rev maintenance, where the Dara only goes to once a month, or even Ninlaro and Rev maintenance, so that you can give multi-agent something that's tolerable for potentially many years. Who should consider maintenance therapy? I think currently the idea of continuous therapy is pretty broad in pretty much every course of treatment for patients. So in my mind, everybody is going to be on some form of continuous therapy unless the side effects from that continuous therapy are so bad that they preclude continued freedom. So I think everybody. Should maintenance therapy be continuous or fixed, and what should a patient consider before making that decision? That's another great question that's, I think, still very controversial in the field without great randomized trials to guide us. If we look at the leadalidomide or reslinid maintenance trials, in the United States the trials gave continuous maintenance. In the large French trial, the leadalidomide maintenance was capped after one year. Both trials did show a benefit in terms of extending duration of remission. In the US trial, though, there was overall survival advantage for patients without leadalidomide maintenance, where this wasn't seen in the French trial. So this has led many US investigators to recommend continuous maintenance therapy, meaning you just stay on the leadalidomide maintenance as long as it's working until the myeloid comes back unless significant toxicity develops. I think this is really still an unanswered question in the field, and we don't really know how long is long enough for maintenance. Fortunately, there are now some trials that are ongoing that are comparing two years of maintenance to indefinite maintenance with leadalidomide. We'll get some information about that in the next year or so. In addition, there are recent trials that have started where we'll be serially doing bone marrow biopsies and looking for what's called minimal residual disease, very low levels of myeloma that is below the level of our usual detection, but where specialized can tell if patients may have even one in five, one in 100,000 or even one in a million cells may contain a myeloma cell. And the hope is that those trials will explore if you can stop the maintenance, if you're a minimal residual disease negative, or if you maintain, if you're continuing to be minimal residual disease positive, if you should change or add something to maintenance. So we're hoping that these trials will give us a little bit more data to guide us and then allow us to guide patients about when you should stop or continue maintenance.