MD: Hello, I’m Thannos Dimopoulos from the University of Athens, Athens, Greece, and we are here in Stockholm for the 23rd Congress of EHA. In this activity, supported by ecancer, we will be discussing the role of maintenance therapy in newly diagnosed patients with multiple myeloma. I am here with esteemed colleagues.
SK: Shaji Kumar from Mayo Clinic, Rochester, Minnesota.
MB: Meral Beksaç from Ankara University.
WJC: Wee Joo Chng from The National University Cancer Institute, Singapore.
MD: Thank you. So, Shaji, are there data to support continuous therapy for patients with myeloma versus fixed duration treatment? In the past we had several regimens that were administered for nine months or one year and then patients were followed without any treatment. However, in recent years we have several trials that involved treatments until disease progression. What is the current status?
SK: Yes, it’s interesting how the treatment paradigm for myeloma has changed over the past decade. We moved away from transplant eligible patients getting 4-6 months of therapy and transplant then stop and the transplant ineligible patients getting 9-12 months of therapy and then stop. Now, fast forward to current era, everybody stays on therapy for much longer and often until progression and there’s a lot of data to back up that. From a biology perspective we know that the myeloma cells undergo continuous clonal evolution and so it makes sense to keep patients on therapy after getting more intense therapy to the maximum suppression of the clone and then maintaining treatment. From a clinical standpoint multiple trials have shown that there is benefit to continuous therapy. In the transplant eligible patient population there are meta-analyses with various drugs showing that there is an improved progression free survival and also overall survival for some drugs when used as maintenance therapy post-transplant. Similarly, in the non-transplant eligible patient population there have been large studies, retrospective studies, which have combined the data from multiple trials and demonstrated that even for those patients a continuous therapy has a better PFS and overall survival compared to a fixed duration therapy.
MD: Thank you very much. Meral, thalidomide has been now with us for more than 17 years. It was introduced in 1999 and even from the early days of thalidomide it was used as maintenance therapy. Could you please summarise for us the data and the status of thalidomide today?
MB: Yes, of course. You’re right, in the beginning the aim was to improve the response rate. So some groups initiated the trials or treatments extending to 18 months versus those which were shorter such as a year or so. By time we saw a character which is now also valid for other IMiDs, that it takes more time for having a deeper response. So the more the treatment duration was, the better the response. So from that experience it was seen that there was a significant PFS advantage but the overall survival advantage was not so great. So there was a meta-analysis performed on the MT versus MPT trials which was able to show there is an overall survival advantage. The French group performed a study comparing thalidomide versus panobinostat. Such trials, which were also in favour of a long-term treatment but, however, we have to note that thalidomide is a drug which has significant neurotoxicity and for this extra haematological discomfort and toxicities patients usually do not tolerate long-term treatment.
MD: Wee Joo, how about bortezomib? Bortezomib also has been around now for many, many years and it has been a very active drug to induce a response in myeloma. It has helped a lot our patients. What is the experience with bortezomib as maintenance therapy?
WJC: Thannos, as you quite rightly pointed out, bortezomib is a very active agent so clearly it may have a potential role as maintenance. But really, unlike the IMiDs, the study of bortezomib in the maintenance setting has been somewhat limited and also in the few studies where it has been used in that setting it hasn’t been studied in a placebo-controlled or randomised fashion to answer specifically whether the use of bortezomib as a maintenance agent benefits patients or not. It has some theoretical potential advantage because it is active in certain high risk populations like the (4;14) myeloma so it is attractive to use it there. But it also has some disadvantages that actually make it less good as a maintenance agent, most important of which was the fact that it’s an injectable form so the patients may have to go back to the hospital for injection for long periods of time. Also it does cause neurotoxicity and it took the community quite a long time before we knew how to best optimise the dosing and the schedule to minimise this side effect. So for a variety of reasons it hasn’t been studied as much but for some trials in Europe they have incorporated Velcade as a maintenance agent.
MD: Thank you very much. And finally we have the success story of lenalidomide, Shaji. So what is the current status of lenalidomide as maintenance or continuous therapy in myeloma?
SK: Yes, so we have a whole bunch of trials from both the transplant eligible and ineligible patients demonstrating a benefit for lenalidomide. So the phase III trials with lenalidomide, the one that was done by the French group showed that there was a progression free survival advantage but no overall survival advantage when used post-autologous stem cell transplant. The CALGB trial clearly showed an improved overall survival and a progression free survival and so did the Italian trial. So a meta-analysis of these three trials that were done showed that there was a significant improvement in the progression free survival, also a 2½ year improvement in the overall survival when patients were placed on lenalidomide maintenance post-transplant. There are some differences between these trials in terms of the duration of maintenance and there is still some debate as to how long the maintenance with lenalidomide needs to be continued for these patients.
For the transplant ineligible patients, if you look at the first trial, there was clearly a progression free survival advantage for patients who stayed on continuous lenalidomide until progression whereas no significant overall survival difference was noticed between the people who stopped lenalidomide after 18 cycles versus continued on lenalidomide until disease progression. Nevertheless, the sum data shows that there is a clinical benefit, certainly in all studies, of delaying the disease progression and definitely an improved overall survival post-stem cell transplant. Clearly there are some disadvantages to lenalidomide maintenance. One is there can be some cumulative haematological toxicity over time but, most importantly, some increase in the second malignancies that you can see in these patients. So that also factors into the concerns around how long the maintenance needs to be kept on.
MD: So, outside the clinical trial in your practice, in your everyday practice, when you have a young patient with myeloma after high dose therapy and you decide to prescribe lenalidomide maintenance, could you tell us for how long you advise the patient to remain on lenalidomide?
SK: I typically do two years of maintenance and it is a discussion with the patient at the end of the two years about the pros and cons. Some patients feel uncomfortable going off and they stay on it and some other patients might weigh the risk of second cancers or rank them much higher and stop after two years of maintenance.
MD: I think it’s a very reasonable approach. Meral, lenalidomide has shown a significant improvement of PFS and overall survival, especially in younger patients after high dose therapy. However, clearly these studies and the meta-analysis have identified a subset of patients that do not appear to benefit, the hazard ratio is essentially 1. What are these subsets?
MB: High risk patients are among those number one in the list. So for those proteasome inhibitors are the best drugs of choice because we know from the front-line studies that proteasome inhibitors are more effective on high risk patients. So, for this reason, if a maintenance treatment is to be chosen a PI based regimen is the one to be recommended. Currently we have bortezomib sub-cu which can be given every two weeks for two years. Or one of the newer agents are also possible for this reason. We have emerging data with ixazomib but we have no data with carfilzomib, so these are the drugs that are to be thought of. Regarding renal impairment, this is another issue because lenalidomide is detrimental for patients who have renal impairment, those should be reduced. Pomalidomide is another agent but we don’t have any pomalidomide maintenance study or reference to give. So this is what we can think about.
MD: Wee Joo, for older patients who respond to lenalidomide are there any data that will make you decide either to continue, let’s say after one or two years, or to discontinue? For example, do you take into consideration the depth of response of the patient in this decision?
WJC: So far, based on the data available and the best data for elderly populations is really the FIRST study, we will actually take a practical approach, like what Shaji does, is two years minimal and then discuss with the patients about continuing on, bearing in mind that there’s no survival benefit with the continuous treatment. But I do think that this debate about continuous or fixed duration, in the future we may get a better handle on this when we start to look at the depth of response and maybe we can use the depth of response, meaning minimal residual disease, as a guide to when we can actually stop treatment or for how long we may need to continue. But, as of now, we only have two extremes, which is one a fixed duration usually of about 18 months to two years duration and then one that is continuous. We usually have a discussion with the patient to see how long they want to continue.
MD: Yes, that’s an excellent point that we hope in the future that evaluation of minimal residual disease, either by next generation flow or next generation sequencing will help us guide our treatment decisions. Of course, there are large prospective trials that need to be conducted so that we can decide whether we can stop in a patient who has achieved MRD negativity or continue in a patient who is MRD positive thinking that we can suppress the clone that Shaji mentioned. Shaji, Meral alluded to new proteasome inhibitors and we have an oral proteasome inhibitor. You have done a lot of work in establishing this drug in the relapsed setting, along with lenalidomide and dexamethasone this is the approved indication. But there are ongoing trials that evaluate ixazomib as a maintenance drug, can you describe these trials for us?
SK: Sure. Ixazomib is an oral proteasome inhibitor, it’s typically given once a week, three weeks on, one week off. As you mentioned, it’s currently approved in combination with lenalidomide dexamethasone for relapsed disease. But there has been a lot of experience using it in the newly diagnosed patients as well. There was a large phase II trial which looked at ixazomib len-dex followed by ixazomib maintenance in newly diagnosed patients. There are other newly diagnosed patient trials using ixazomib in combination with cyclophosphamide and dexamethasone. When you look at the cumulative data from these trials, as we have done, what is clear is that we can keep these patients on ixazomib for fairly long periods of time. There is some deepening of responses that you see as patients continue on therapy and there is very little that we have seen in terms of cumulative toxicity, either hematologic or any significant worsening of peripheral neuropathy as these patients continue on ixazomib. So that is one of the critical advantages that ixazomib has over bortezomib. As was previously mentioned, one of the problems with keeping bortezomib on for long-term is the peripheral neuropathy and that does not seem to be as much of a problem with ixazomib. So this has led to at least two large phase III trials, one of them in the post-transplant setting, randomising patients to ixazomib maintenance or a placebo maintenance. Hopefully we should hear some results from that trial soon. In another trial patients who were not eligible for stem cell transplant once they finished initial therapy they were randomised to, again, ixazomib maintenance versus no maintenance. That trial, hopefully, will give us a better handle on how the patients who are not transplant eligible do. Obviously there is going to be a lot of interesting data here, especially are there subgroups of patients who benefit more with ixazomib, especially the patients with high risk disease.
MD: Yes, I would like also to mention my experience by participating with a large number of patients in these two prospective randomised trials which are placebo-controlled that usually we cannot tell whether the patient is taking the drug or the placebo. This is the best test that a regimen is very well tolerated when you cannot differentiate between the active drug and the placebo. Meral, do you think the role of combination therapy for prolonged periods of time or maintenance therapy now, that hopefully we will have on top of lenalidomide, ixazomib and also we know that we have monoclonal antibodies that we can administer them on a monthly basis for prolonged periods of time?
MB: Yes, I think this is the best approach for myeloma treatment. We all know that myeloma is not a homogeneous disease, it consists of different types of myeloma within the myeloma overall. Also within an individual patient there might be multiple clones which are susceptible to different drugs. So if you put all your money on one drug it’s the potential risk that you might have a resistant disease coming up, appearing, which is even more difficult to control. We all know also that a PI and an IMiD combination has multiple synergistic features so this is an ideal combination to have as a maintenance or a consolidation approach. So this is something which has been planned and ongoing. On the other hand, molecular antibodies are different because they attach to the surface of the malignant cells and they also have off-target effects on the immune system. So PI plus a monoclonal antibody is an effective regimen, especially for high risk patients and this has been proven already with bortezomib. So there’s a potential that ixazomib could also be such a partner for a monoclonal antibody for continuous treatment and since it’s tolerable it can be achieved.
MD: Wee Joo, today with the regimens that we have we essentially have bortezomib, we have lenalidomide, how would you approach, let’s say, a patient with newly diagnosed myeloma who has responded to treatment, a young patient with 17p deletion after high dose therapy? How will you prevent recurrence of the disease?
WJC: So this is a very challenging group, as we know, and 17p deleted patients probably amongst the highest risk patient outcome has not been very good, even with the advent of all these new agents that we have. So in the current setting, based on data that is available, what we would do is besides induction treatment and the transplant these are the patients that we probably will explore a second stem cell transplant goal with a tandem transplant and then we will maintain them with proteasome inhibitor based maintenance therapy, maybe in combination with an IMiD as well. Then T them up, if they’re young, for an allotransplant at the point of first relapse, particularly if the initial PFS is very short. So that would be our current approach but, again, with all the new drugs there may be better options in the future.
MD: I think that at this point we would like to conclude our discussion. It is obvious that continuous therapy is advantageous for most of the patients with multiple myeloma. We have great improvements with the use of lenalidomide. We would like to be able to use a proteasome inhibitor and we believe that ixazomib, which is an oral and potent proteasome inhibitor with an excellent safety profile, would be the best partner, the best representative of proteasome inhibitors. We are waiting to see the readout of the trials but on top of this there are great hopes that with monoclonal antibodies that we have, anti-CD38, anti-SLAMF7, we will have a third agent that could be given as maintenance therapy in myeloma. Thank you very much.