Relapse and retreatment of multiple myeloma

Bookmark and Share
Published: 3 Apr 2013
Views: 6705
Prof Heinz Ludwig, Dr Sergio Giralt

Prof Heinz Ludwig and Dr Sergio Giralt talk to ecancertv at IMW 2013.

The approach to managing relapse in multiple myeloma (MM) has changed dramatically in the last 10-15 years. The choice of therapy has expanded to include novel therapies, but will still depend on the patient group, whether they are healthy elderly, elderly frail or relapsing after a transplant, and whether they are symptomatic or asymptomatic. The present of comorbidities, renal failure and previous experience of toxicities, such as peripheral neuropathy, will also influence treatment choice.

In patients who experience long remissions after initial autologous stem cell transplant (ASCT) a second ASCT can be considered. In these patients, where an induction, consolidation and maintenance strategy has been used, the same should be offered again. This decision is based on the outcomes seen in the European trial of bortezomib, thalidomide and dexamethasone versus thalidomide and dexamethasone in relapsed patients, which demonstrated superior outcomes in the bortezomib group.

In the elderly, frail or those that do not want to go through aggressive therapy, or those that have comorbidities, renal failure or peripheral neuropathy, treatment will be tailored to the patient's requirements. In the US, a carfilzomib based regimen can be used in a patient with peripheral neuropathy, in which a proteasome inhibitor is warranted. In patients with renal failure, lenalidomide can be used according to current guidelines, or pomalidomide can be considered. In elderly patients who are symptomatic, a treatment regimen should be considered that the patient can tolerate and that will improve outcomes. In asymptomatic patients, observation only may be warranted. In Europe, the approach would be similar, except that carfilzomib and pomalidomide are not yet approved for use.
In younger patients, where relapse has occurred within 12 months, treatment can be a particular challenge. A second ASCT has not been found to be effective in this group of patients. These patients are ideal candidates for clinical trials. Allogeneic transplant may be one option. New conditioning regimens for ASCT and innovative post-transplant combinations can also be considered.

Cereblon has been shown to predict the response to immunomodulatory drugs. It could become an important predictor of response for MM in the future. Its expression has been shown to correlate to response to lenalidomide and dexamethasone therapy. However, it did not correlate with progression free survival (PFS) or overall survival (OS). However, these initial data need to be confirmed with further studies. A good antibody is needed to detect cereblon expression with immunophenotyping. ELISA could also be used to detect cereblon in serum.

In the US lenalidomide maintenance after lenalidomide induction is commonly used. In Europe, lenalidomide maintenance is not approved. It is hoped that more data will be available soon to support the use of lenalidomide as maintenance in Europe, as it has been shown to be particularly beneficial in low risk patients.

In patients who relapse on lenalidomide maintenance, the treatment choices are less clear. The choice would depend on the initial induction therapy. The preferred choice would be to switch drug class. However, if the induction regimen included a proteasome inhibitor, this is more challenging. In Europe, a conventional drug regimen is sometimes considered in patients with aggressive and early relapsed disease. The response can be significant in these patients, but is limited in duration.

Around 20% of patients experience asymptomatic or biochemical relapse. However, with the advent of maintenance therapy in the US, patients are monitored more frequently (once a month versus once every 3 months). As a result the detection rate of asymptomatic disease has risen to almost 40-50%. A full radiological examination is needed in these patients to identify new lytic lesions or signs of bone disease progression. If these are present, early intervention is warranted. In patients with no radiological progression, inclusion in clinical trials can be considered. Gene signatures may help to distinguish those patients who have indolent disease versus those with aggressive disease, and so guide appropriate treatment.

There are a three of trials ongoing to determine if novel therapy could obviate the need for transplant in the future. In the meantime, ASCT is the standard of care in younger patients.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

14th International Myeloma Workshop

Relapse and treatment of multiple myeloma

Professor Heinz Ludwig – Wilhelminenspital Center for Oncology and Hematology, Vienna, Austria
Dr Sergio Giralt – Mayo Clinic, Scottsdale, Arizona, USA

Welcome to the audience of ecancer. My name is Heinz Ludwig, I am a medical oncologist haematologist working in Vienna, Austria and we are here at the International Myeloma Workshop in Kyoto, Japan. We are discussing here with my colleague, Professor Sergio Giralt, Professor of Medicine of Cornell University and head of the Bone Marrow Transplantation Unit of Memorial Sloan-Kettering Institute. The question: how do we manage patients who present with relapse? May I ask, Professor Giralt, what is your approach if a patient comes in with relapse?

Heinz, I think we’ve all seen over the last 5 – 10 years how myeloma has changed and the way we approach relapse today is totally different from the way we approached it fifteen years ago because we have new drugs and new agents, although the principles are the same. A lot of it depends on whether we’re talking about the elderly frail, the healthy elderly or people who are relapsing after a transplant; I’ll just answer your question with the transplant patient who is now relapsing. A lot of it depends on whether they are on lenalidomide maintenance and whether it’s an asymptomatic relapse or it’s a symptomatic relapse. I don’t know, have you felt that the patterns of relapse for you have changed in the modern era, now with maintenance therapy?

I don’t think the patterns have changed so much but we are not only dealing with patients after transplant, we are dealing with elderly patients as well. So first it’s important to see whether it’s a fit patient, whether his performance status is OK, whether he has multi-morbidities or, for instance, neuropathy or renal failure, so that has an impact on the selection of drugs which we would choose. I would like to ask you, Sergio, how important is the quality of the response and the response duration for your decision making?

Actually it is very important, particularly because we now, based on the data coming out from the CIBMTR, from the BMT, we strongly feel that patients who have long remissions after initial transplant should be considered for a second autologous transplant if they have cells available and, even now, we know that it is possible to collect them a second time with either [?? 2:35] or with chemomobilisation. So what you say is true, I think as we approach the people who are relapsing we need to think the type of relapse – is it asymptomatic or not; the type of patient – are they available, are they able to be able to tolerate intensive therapy? And finally the duration of remission and what drugs or toxicities these patients have had to previous drug therapies.

So if your patient comes in with a very long duration of remission would you consider retreatment with the induction regimen?

I think initially I was one of those who actually thought about just starting slow. The paper from Garderet et al that was published last year in the Journal of Clinical Oncology, which was a European trial in which patients relapsing after auto-transplant were randomised to thalidomide-dex versus bortezomib-thalidomide-dex actually has changed my point of view. In that trial, actually, patients who got bortezomib-thalidomide-dexamethasone did much better than those who got thalidomide-dexamethasone. So I think in patients who have had long remissions with an induction consolidation and maintenance strategy we should do the same; if it worked well the first time it should work well the second time. We think these patients obviously should all be encouraged to participate in clinical trials.

I think the Garderet et al paper is a very important one because it has changed a little bit the scenario because it’s clear when it comes to induction treatment before transplant we now use this three drug regimen. In relapse it was not so clear whether a three drug regimen is significantly superior to a two drug regimen but now this paper has clearly shown that three drugs are better than two. So what we do in relapse treatment is we repeat what we have done in induction and we select a very active regimen which contains three drugs but not in every patient probably. In an elderly patient what would be your approach then?

I think the elderly or the frail or even patients who do not want to go through aggressive therapy, I think it’s important to, as you’ve discussed, look at the whole patient and particularly look at comorbidities. So the way we approach a patient with renal failure is different to the way we approach a patient who already has peripheral neuropathy. In North America we have the advantage that we now have both carfilzomib and pomalidomide available so in a patient who has peripheral neuropathy who we want to use a proteasome inhibitor we can use a carfilzomib-based regimen. In a patient who has renal failure, although we have guidelines on how to use lenalidomide, we can also use pomalidomide in which there is less of a chance of having severe cytopenia, although you still have to be careful with severe cytopenia after pomalidomide. So I think with the elderly patient it depends on what your goals of treatment are. If that patient has a symptomatic relapse I think you should treat, trying to obtain a good response with a combination of drugs that that patient can tolerate. If, on the other hand, the patient has an asymptomatic relapse you may be better off observing.

Now the situation in Europe is different because you may not have the availability of all these drugs. How do you approach first the elderly frail patient and, second, that young patient who’s had young… like you and me, for example, who has had a three year remission with induction consolidation and maintenance?

So the elderly, I think, depends again on the quality of the response, so if the response was complete, the duration of response was long, then we still are inclined to use retreatment in many patients if the patient tolerated first line treatment very well. So if there are problems with tolerance or if the first line treatment was not effective as intended, if there was only partial response, we of course would switch drug classes. But in Europe we have the problem that both drugs which you mentioned, carfilzomib and pomalidomide, are not approved as yet, they will be approved later, hopefully later during the year, so we have to work around and to use the other drugs.

In young patients it’s easy because if the duration of remission was short after transplant I don’t think a second transplant makes sense here so we have to use an aggressive second line regimen. Also we know that those patients have a poor prognosis who have relapsed, let’s say, within twelve months after transplant. So this is a really difficult to treat patient population. What is your approach in those patients?

That’s a very interesting and unfortunate group of patients because I agree with you that in those patients the idea of a second autologous transplant generally has not been effective. We consider these are ideal candidates for clinical trials and particularly the younger the patient. We have clinical trials for allogeneic transplantation, we think they’re an appropriate group to explore the role of allogeneic transplant. We also think they’re an appropriate group to explore new conditioning regimens for autologous transplants and new innovative post-transplant therapies like combinations for maintenance. But, as you say, they remain a very challenging group.

I was going to ask you, we’ve heard a lot about cereblon in this meeting and how it may predict the response to a variety of immunomodulatory drugs. Do you get the feeling that this will be something we will use in the future to be able to guide which patients should get an IMiD or not?

I think cereblon, of course, could become an important target or important predictor of response. We’ve also just published a series of patients where we have showed that the cereblon expression correlates with response to lenalidomide-dexamethasone. In our series we couldn’t correlate it with progression free survival and overall survival but still. So there’s a good correlation but probably if you want to use it in the future, first of all you have to confirm the data, the initial data which are there, and, secondly, it would be much easier to have, let’s say, either to have an assay available where you detect cereblon expression using immunophenotyping but the problem is to have a good antibody against cereblon. People are working on ELISA and the question is is cereblon measurable in serum in significant quantities, concentrations, so that that could also be a marker of lenalidomide for IMiD responsiveness. But I think it’s a little bit too early, but for the first time we have a molecule which seems to be correlated with response to IMiDs and that’s interesting.

I think the other thing is, when we talk about relapse and it will be interesting to compare and contrast what happens in Europe versus what happens in America, in North America with the publication of the two randomised trials, lenalidomide maintenance, lenalidomide maintenance actually is happening in more than 50% of patients undergoing autografts and prolonged lenalidomide therapy is very common in older patients who were induced with lenalidomide-dexamethasone. What’s happening in Europe?

That’s different in Europe because lenalidomide maintenance is not approved in Europe so we have to stay within the label more or less. Of course we have the option to discuss this situation with the patient and so there are patients who opt for treatment and then in many countries in Europe it then will be possible to provide lenalidomide for those patients. But I think these are not more than 10-20%, depending on the country. I think when you have this very interesting CLGB study which showed the significant survival advantage and if the second study, the IFM study, really becomes positive, and there is hope that it may become positive with longer follow-up because maintenance treatment is most effective in good risk patients. So with longer follow-up there should be a better discrimination between the maintained patients and the control patients. So there is hope that the figures will diverge also in the European study and if you have two studies which show a survival benefit, then I think the regulatory authorities in Europe would also be motivated to be more flexible here.

I don’t mean to put you on the spot, I actually would very much, and I think the audience of ecancer would also like to hear your opinion. So you have patients on lenalidomide maintenance who relapse, what would you think would be your preferred re-induction treatment in those patients? Would you go to a carfilzomib-based or if you had access to pomalidomide would you think about pomalidomide? We’re struggling with this question currently at this time.

It depends what was the induction therapy. We would prefer, if possible, to switch classes because I think that makes sense, but if the patient has been pre-exposed to a proteasome inhibitor then it will become more difficult. So then we have to work around. I must say, if this is a very aggressive case, if this is a patient with rapid relapse, if the patient has been resistant to proteasome inhibitor and relapses under an IMiD then I think we still go back to an old treatment which is DCEP, which is continuous therapy with conventional drugs for four days. This is often very effective in those patients; the response rates are quite significant but the duration of response is limited in this kind of patients. So that is certainly a difficult to treat patient group. But Sergio, I want to ask you, what is your recommendation if you have asymptomatic relapse? What should be done; which laboratory tests should be ordered and how often do you want to see the patient?

That’s actually a very important question, particularly in the context of modern treatments. So when we did our first look at what was our incidence of biochemical or asymptomatic relapse, it was similar to what Adrian Alegre had reported, around 20%. But at that time we were monitoring the patients every 3 – 6 months because they were not on any maintenance therapy. Once we went to maintenance therapy, patients were being seeing once a month and actually most patients are having their myeloma checked once a month. So our incidence of asymptomatic relapse, probably because of just we’re looking for it more, has increased to almost 40-50%. Now we recently published that in patients with asymptomatic relapse it’s very important to do a full radiologic evaluation. Many of these patients, about 20-30%, will actually have new lytic lesions or sign of bone progression. So those patients really, although they might be asymptomatic by virtue of not having any symptoms, those are patients that if we do not intervene early can get into trouble. So for those patients we really do intervene early. Now the true asymptomatic relapse who has no radiologic evidence of disease progression, who is not anaemic, who is actually doing fine is a great candidate for clinical trials. We have a trial with len intensification, so we’re increasing the dose of lenalidomide. There are a significant proportion of these patients can go on 18 – 20 months before showing signs of any disease progression, so putting them on treatment early may not benefit. I think the challenge is to identify who are those who are, quote-unquote, indolent and who are those who are the aggressive asymptomatic responses. And in this meeting we’re learning that some of the gene signatures may be able to help us to distinguish those groups of people as well as their previous cytogenetic abnormalities. So my threshold of treatment in a patient with asymptomatic relapse is much lower if they had very aggressive disease starting off or if they had poorer cytogenetics. You’re facing the same problem, I imagine, now also.

I think, Sergio, this was an excellent statement because this is, I think, the recommendation which is really important. If you have a patient with asymptomatic relapse, you have to follow those patients very carefully, you have to ask him specifically certain questions in order to see whether he has still, because he has some minor symptoms which he is not willing to disclose when he comes in, and you have to check for signs of progressive disease because you may have, as you mentioned, you may have a disconnection between the paraprotein increase and the symptoms elsewhere in the body like an indolent skeleton or increasing anaemia or renal impairment. So if you know, if you have all this instrumentarium available and if you have the experience, I think you can follow those patients for quite a while but you have to follow them carefully. I think this is very similar in your institution and in my institution and I wonder whether we should, with this statement…

Before we close I have one last question. The role of allogeneic transplant, you know where I stand, I’d like you, before we… for the audience, where do you think allogeneic transplant has a role in myeloma or does it have a role at all?

That is difficult, if you ask me Sergio. I believe that the role of transplant will be limited, even of auto-transplant. Transplant was an excellent treatment and is still the standard of care at the time being but you know there are three trials on-going trying to figure out whether novel drugs can overcome the need for transplant. And it’s my vision that sooner or later, I don’t know whether these three trials will show already that you can obviate the need for transplant, but sooner or later we will have drugs available which will obviate the need for autologous transplant and, in my view, also for allogeneic transplant. But at the time being I would reiterate auto is standard of care for younger patients.

Thank you very much, Heinz, this was a very good conversation.

I enjoyed talking to you, thank you very much Sergio.