Continuous treatment versus fixed duration therapy: Using real-world evidence to guide treatment paradigms for multiple myeloma

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Published: 23 Sep 2019
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Prof Evangelos Terpos, Prof Andrew Spencer and Dr Robert Rifkin

Prof Evangelos Terpos (University of Athens, Athens, Greece), Prof Andrew Spencer (Monash University, Melbourne, Australia) and Dr Robert Rifkin (Rocky Mountain Cancer Centers, Denver, USA) discuss the importance of different treatment paradigms for patients with multiple myeloma at the International Myeloma Workshop 2019.

The panel firstly discuss the need for real-world data, with reference to the INSIGHT MM study. Prof Spencer emphasises that patient outcomes in the real-world do not recapitulate those achieved in clinical trials, and this is especially seen in elderly patients. Dr Rifkin highlights this type of evidence may also be beneficial in identifying high-risk patients and could guide patient management.

Further differences between real-world evidence and clinical trial data are also examined, including discontinuation rates, age and co-morbidities of patients.

The panel conclude by evaluating the need for continuous treatment versus fixed duration therapy, and how this should be tailored to the patient.

This programme has been supported by an unrestricted educational grant from Takeda.

ET: Hello, I am Evangelos Terpos, Professor of Haematology of the University of Athens, Greece and I’m here in Boston for the 17th International Myeloma Workshop. With me I have Professor Andrew Spencer from Melbourne, Australia and Dr Rob Rifkin from the US today. We are going to discuss some of the interesting abstracts of the International Myeloma Workshop. One of the abstracts that was presented today as an oral presentation had to do with the real world data, a very big database, the INSIGHT database, which includes more than 4,000 patients. So one of the most important questions is do we need real world data and does it make any difference from the clinical trials that have given licence to the drugs that we use in multiple myeloma? Andrew

AS: I’ve been involved in registry activities for a number of years so I’m a big fan of real world evidence. We have an Australia and New Zealand registry which is somewhat more mature than the INSIGHT registry; it has 3,000 incident cases of data now over six years. What is very evident is that the outcomes for patients in the real world do not recapitulate that that is demonstrated in the registration trials that everyone refers to. This is particularly evident in elderly patients where the deliverability of the approved drugs and drug combinations outside of a clinical trial can really be brought into question. So I think that registries such as the INSIGHT registry will enable us to identify problems and areas of unmet need which might inform perhaps less exciting but potentially far more important clinical trials about how to use our current drugs better, particularly in certain subgroups of patients such as elderly patients.

ET: Rob, you represent one of the biggest, if not the biggest, community doctors’ society here in the US. I want to know your opinion about the real world data and the differences between the clinical trials and the real world. I’ve read very recently a paper in Leukaemia published by the Danish registry which showed that the overall survival, for example, for patients who are not eligible to participate in a clinical trial is much poorer compared to those who participate in a clinical trial. This is mainly because of the inclusion criteria of a clinical trial that cannot include more than 50% of the patients in the myeloma community. As you represent community doctors what is your opinion?

RR: Like Andrew it’s interesting, I’ve been involved in registries now for over ten years. The oldest registry in the United States is the Connect Registry which interestingly had 3,000 patients, just like yours did. What we’ve learned, it’s now become a very mature registry and what we’ve found, actually, in one study looking back is that only 42% of our patients in the registry would have been eligible for clinical trials. So we’re clearly missing out on what’s going on in the community. As Andrew pointed out, the outcomes from the registries are often quite different than the published clinical trials. In routine clinical practice in our network, and we do well, we get about 5% of myeloma patients on clinical trials. So we’re doing things that are great for the labels that are very, very specific but oftentimes don’t apply to the frail elderly, as you pointed out. Or maybe people with very, very high risk disease that we tend to fail on repetitively and those are the groups where the registries will help us, especially when you become resistant to the newer agents. That’s where we’ll really make a big gain because we’ll have all that data sitting out there. One of the most important things we can do which we’re already starting to do in INSIGHT and in the other registries is to start to really merge our data so that if we all put our data together in this room with the registries we do we might have 8,000 patients but imagine what you could do with a 25,000 patient dataset. So that will be the value of INSIGHT and the other registries.

ET: I’ve seen from the data of the real world that there are big differences, mainly in the discontinuation rate of some of the drugs that are used very often in the community. I was surprised, for example, for carfilzomib administration that the difference between the real world and what has been published in the two major studies, the ENDEAVOR and the ASPIRE, it’s much different. We’ve seen also that some oral drugs like pomalidomide or lenalidomide also the median duration during second and third line in the real world is much, much lower compared to the registrational studies. Do you have any explanation on that?

AS: When we saw the poor outcome in elderly patients we had to ask questions as to why. So the median overall survival for patients over 70 in Australia is only 44 months, so less than 4 years median survival, significantly shorter than the VISTA trial and the FIRST trial which are oft quoted as to how things should be. So we went back and we looked at what factors might be responsible for this and the healthcare system in Australia is a universal healthcare system, the government pays for healthcare, pays for all the drugs. In newly diagnosed elderly patients the government will pay for 13 cycles of Velcade, data drawn from the VISTA trial. The median number of cycles that are used in the real world is only six. There’s very early discontinuation and it’s almost exclusively driven by toxicity. This is because we’ve never really done studies to define how best to use some of these backbone drugs in elderly patients, particularly frail elderly patients.

ET: Is the age and frailty and comorbidities one of the major reasons that we have this discrepancy between real world data and clinical trials? Because if I can remember from the last year of clinical trials in the relapsed refractory setting the median age of the patients who participate is between 64-65 and I’m talking about the ASPIRE, the TOURMALINE, the POLLUX. But this is not what we’ve seen in our clinical practice. I think even in the United States the median age of the relapsed refractory myeloma is much higher than what we’ve seen in the clinical trials.

RR: Well, we see it a little bit differently when we start to look even at just one of the first papers here was duration of therapy. What we’ve tended to see, even in average risk myeloma patients, not the frail, not the elderly, is they get a few rounds of triplet therapy, fortunately I think we’ve switched to that, and then you get a terrific response and the patient says, ‘Well my M-spike is gone, I can quit.’ So we see a lot of early discontinuation or the patients don’t want to carry on. What we have made good strides with is convenience. So all of us remember when Velcade was intravenous and quite a bit more toxic than subcutaneous. You’ll see a change in the carfilzomib dosing schedule to weekly to make it more convenient for patients. A lot of it has to do with education and we’ll probably discuss this in a bit as to whether myeloma should be a continuous therapy disease. So if you come into my office and I tell you, ‘Evangelos, you have myeloma,’ and you go, ‘How much therapy do you think I’ll need?’ I’m going to say, ‘For quite a long time.’

ET: This comes to my next question which is continuous treatment, fixed duration treatment for all the agents, for some agents that we use? I think that this is an extremely important question because, as you mentioned, you have a patient with myeloma in front of you and the patient asks, ‘For how long do I have to receive this treatment?’ Possibly many doctors may say either for a long period of time, others may say for life, according to the licence of the drugs that have been licensed until disease progression and the next one also until disease progression. So what is the message for the community doctors, continuous treatment or fixed duration for our patients?

AS: There are good biological reasons to support the use of continuous therapy but one has to be very cognisant of potential issues associated with that in that there is a subset of patients whose disease biology will not be responsive to continuous therapy and they’ll relapse early. So it’s not applicable to a subset of patients. But also that one needs to really balance, particularly in older patients, the quality of life issues related to continuous therapy. So we can look at publications which say very few grade 3/4 toxicities, this is a well-tolerated drug, but on a day to day basis patients who have got grade 1 and 2 toxicities, particularly GI toxicities, it can impact very significantly on their quality of life. One has to be really aware of that and, in fact, in some instances it may be better for those patients not to be on those drugs. Conversely, if you’ve got a patient who is tolerating something remarkably well, and there are patients like that, then there’s a good rationale for them to stay on therapy. So what I’m saying is I think it has to be individualised based on probably disease factors which will declare themselves anyway, but then patient factors and tolerability factors.

ET: So, Rob, from the US data that I have seen in different abstracts and different presentations I have realised that many community oncologists stop treatment even in patients that can tolerate the drug easily. They don’t like so much the continuous therapy. Is it a matter of education? Do you believe that they do what the patients want, for example? What is your opinion on that?

RR: I think with the registries we’re going to learn some valuable information. Right now we have a lot of choices for therapy but it’s clearly important in patients’ quality of life. So it may be something as trivial as they’re just experiencing fatigue, they might be doing fantastic, they don’t have neuropathy, they don’t have diarrhoea, they’re just tired of therapy. They’d rather sit at home or go do something else. So a lot of it clearly has to do with education, not only of the patients but also of the providers because, unlike those of us sitting here who are myeloma experts, if you only have a very few myeloma patients in your practice you may not be up to speed on all of these things. But I generally would try to keep people on therapy as long as possible. Fixed duration of therapy, as you know, one of the original trials, I think VISTA, had a fixed duration of therapy for 52-53 weeks. I had two people make it all the way, they just got tired. Now we have all of these tremendous new agents which are targeted and have, for the most part, considerably less toxicity. So I think it’s a matter of education and I think the registry data is going to help us a whole lot. Just with the simple observation that you said when you look at US data that we quit too early with treatment, for a while we were just giving doublets because people weren’t really educated as to the benefit of triplet therapy. Andrew is right, we have a tremendous number of treatments, we can tailor make therapy, you might give people a rest, a brief one, and you might even switch from an IMiD to a proteasome inhibitor or maybe one of the all-oral regimens that was presented today.

ET: So one important issue is the education of both the providers, the doctors I mean, and the patients, but on the other hand do you believe the route of administration of a drug makes a difference in the continuous versus the fixed duration? For example, an oral triplet may be more tolerable or more easy for the patients to continue on that for more cycles compared to a drug that is given intravenously, 3-4 hours of intravenous duration every week, for example?

AS: Undoubtedly. We’re obviously a very active clinical trials centre where I work so we’ve been involved in various antibody studies over the years. We’ve had patients who have had very robust complete remissions on antibody therapies but have withdrawn consent and gone off the trials because of the inconvenience of requiring regular IV treatment. So this is not an easy decision for these patients because their disease has responded brilliantly but they’re just fatigued and they’ve had enough of coming back and forth to the hospital for therapy. So it’s a very strong factor, probably, in compliance and acceptance if a therapy is oral rather than given intravenously or even subcutaneously in a hospital setting.

ET: We’ve seen from the INSIGHT study that in the frontline setting probably the combination of Velcade with either lenalidomide, cyclophosphamide or thalidomide with dexamethasone seems to be the standard of care. We’ve seen that approximately one-third of the patients receive one of the three combinations. But when we go to the second or third line of therapy we’ve seen in Katja Weisel’s presentation, oral presentation, today that there are so many combinations there is not even one standard of care, for example, for second line or third line therapy. So what is your comment on that? From Rob?

AS: Rob should comment on that because of the Connect Registry data.

RR: Right, the Connect Registry. So I think the thing people don’t realise is at some point they are going to need a second line of therapy. The most common scenario we see now are people who get RVD and they have a great response, it gets mellowed out. They’re usually on some kind of an oral maintenance therapy because they’ve had enough visits and then they relapse and they relapse when they’re on IMiDs and then it’s really difficult, there is no standard. So in Connect we actually publish these rather colourful plots that you will remember where we looked at each colour represented a different line of therapy in our 3,000 patient population. We ran out of colours and the thing looks so confusing it should be in the New York Museum of Modern Art. So that was a very telling thing, actually, when we looked at it that way. Then we looked at it for length of therapy and, as you correctly point out, people get shorter lengths of therapy as the lines progress. They’re tired, they might have accumulated a toxicity or so, but an all-oral regimen is great. A lot of our patients drive a great distance to come to clinic and it seems difficult to come to clinic for a 15 second shot.

ET: Andrew, do you have the same experience in your registry?

AS: We have huge geographical challenges. I have patients who fly to Melbourne to be seen. So the concept of getting injectable therapy is simply not feasible. So some of these patients have to make a decision really that’s not based on medical merit but on the feasibility of obtaining therapy. So oral therapies really do counteract some of the tyranny of distance that our patients face.

RR: I think you’re in good countries because you have a lot more socialised medicine than we do. What we’re actually seeing now is a significant hit with financial toxicity. So if you get on a triplet some of them could easily cost in excess of $20,000 per month.

ET: Which is a real problem.

RR: So that’s not sustainable.

ET: So can we summarise, saying that continuous treatment yes, probably, for the majority of the patients but not for all of them? That possibly the oral triplet seems to be more easy to be given in the patients, more tolerable with a better safety profile and that, for example, the INSIGHT study and other registries are needed in order to confirm in the real world what the clinical trials have shown?

AS: I absolutely agree, particularly with the last point. I think we need to bring to bear real world evidence to really demonstrate whether these drugs are making an impact and ask questions about how to use them better.

ET: And one last word from you, Rob, about the continuous or fixed duration treatment?

RR: I think I’m still a fan of continuous but the frail and the elderly are the difficult ones. Professor Palumbo has done a great job, and some others, with frailty, frailty indexes. But there are now tables of drugs published where it’s very easy if you’re not a regular myeloma treater to know that you might need a triplet and then it would tell you how to dose reduce things so that patients can tolerate it and stay on therapy. We have a lot of drugs and a lot of choices. I guess you could say in a way it’s a fortunate time to have myeloma because we are making huge strides but we’re still not very good at high risk folks and the elderly and the frail. Those are big holes that the registries will help fill in.

ET: Thank you, both of you, for this important data that we discussed today. I hope that in the near future we have even more drugs for our patients.

AS: Thank you.

RR: Thank you.