Continuous therapy in multiple myeloma; updates from MM4 and MM6 including China perspective

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Published: 8 Dec 2020
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Dr Shaji Kumar and Dr Wenming Chen

In this expert discussion Dr Kumar and Dr Chen look at updated in the TOURMALINE-MM4 and TOURMALINE-MM6 studies on ixazomib for multiple myeloma.

Dr Kumar begins the discussion by talking about some of the recent updates on the MM4 studies from this year’s ASH virtual conference.

He talks about the success of lenalidomide and post stem cell transplant in treating multiple myeloma.

Dr Kumar further sheds light on recent studies regarding oral proteasome inhibitor therapy, and both Prof Chen and Prof Kumar move on to discuss real world evidence on multiple myeloma continuous therapy focusing on the latest published data on ASH 2020.

After that, Prof Kumar speaks about the MM6 and MM4 studies as well as real world evidence studies regarding multiple myeloma continuous therapy. Prof Chen further discusses proteasome inhibitor in-class switching in multiple myeloma and the latest MM6-PLUS data with relation to China.

Dr Kumar concludes with what we should be looking for in the future in terms of multiple myeloma treatment with Prof Chen giving his perspective.

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

Dr Shaji Kumar – Mayo Clinic, Rochester, USA
Prof Wenming Chen – Beijing Chaoyang Hospital, Beijing, China


SK: Hi. Welcome to the ecancer coverage of the virtual ASH 2020. My name is Shaji Kumar, I’m a consultant in haematology at Mayo Clinic in Rochester, Minnesota. It is my pleasure to have with me today Dr Wenming Chen and the two of us will be discussing the results from some of the studies that are being presented at ASH this year. As you all know, the role of maintenance therapy has really expanded in the treatment paradigm in multiple myeloma with more than one drug being tested in the setting of maintenance therapy, not only for patients undergoing an autologous stem cell transplant but also the transplant ineligible patients who are getting three or four drug induction therapy.

As well all know, lenalidomide has been studied in the setting of post-stem cell transplant maintenance in multiple myeloma and the studies have shown that there is an improved progression free survival and overall survival in patients with multiple myeloma. Similarly, lenalidomide has been continued until disease progression in the first trial in a non-transplant eligible patient population where the continuous therapy has been shown to be associated with a better progression free survival compared to the limited or 18 months of lenalidomide therapy, suggesting that continuous therapy may have a major role in the current treatment paradigm of multiple myeloma.

Now, more recently there are trials that have looked at the concept of using an oral proteasome inhibitor in the setting of maintenance therapy. Now, in the past there have been a limited number of studies that have considered using bortezomib injections as continued therapy until disease progression, however, this has been limited by some of the toxicities, particularly the peripheral neuropathy associated with bortezomib with long-term administration. It is in that context that ixazomib, which is an oral proteasome inhibitor, is being studied in the context of maintenance therapy.

There have been two large trials that have been done, both of which have been reported. The first one looked at the role of ixazomib maintenance in the post-transplant setting and that trial randomised patients after a single transplant to getting ixazomib maintenance versus no maintenance. That trial showed that there was a significant improvement in the progression free survival of about six months with ixazomib maintenance compared to no maintenance.

It is important to note that the ixazomib maintenance was continued for a limited duration in this particular trial. Another important trial, the results of which and the subgroup analysis of some of which are being presented at ASH this year, looked at ixazomib maintenance after non-transplant therapies. So patients who had 9-12 months of induction therapy with any regimen could then go on to get ixazomib maintenance versus placebo and patients were randomised in a 3:2 fashion. This trial showed that there was a significant improvement in the progression free survival with the use of ixazomib maintenance compared to placebo.

In some of the additional data that is being presented at ASH they also looked at the kinetics of minimal residual disease negativity in patients who were on this particular trial. What they were able to show was that the patients who were MRD positive at the time of randomisation to ixazomib maintenance or placebo who subsequently became MRD negative had the best outcome, closely followed by people who were already MRD negative and continued to be MRD negative. In contrast, those patients who were MRD positive at randomisation and stayed on being MRD positive, those patients had the least benefit in terms of progression free survival.

There is another subgroup analysis of the same study that looked at the impact of frailty on the outcomes of this phase III trial. That study particularly looked at how the fit, the unfit and the frail patients did with the placebo versus ixazomib. What was clear was when patients received ixazomib maintenance they all did quite similarly, irrespective of their frailty status whereas in the placebo arm patients who were frail did not do well at all and patients who were unfit or fit did slightly better compared to the frail patients.

So these studies clearly show that there is a role for proteasome inhibitor maintenance, both in the post-transplant and in the transplant ineligible patients after induction therapy. Obviously none of these trials are looking at one drug versus the other drug so they are not comparative trials but the results are just an oral proteasome inhibitor, like ixazomib, could be one way to approach this concept of continuous therapy in patients with myeloma.

Now, another interesting concept that has come up is what if patients were started on a different proteasome inhibitor like bortezomib as part of their induction therapy – can we switch them to an oral proteasome inhibitor to make the regimen more convenient? Those studies have been done and, Dr Chen, maybe you want to talk about those before we come back to a discussion of these studies?

WC: Usually in my centre the patients are from everywhere else in China. You know Beijing is in the centre of China and also the patients want to go to the bigger hospitals for treatment. Usually the first cycles of treatment are severe - anaemia and bone pain and also renal impairment. We usually use a bortezomib-containing regimen for three or four cycles until maintenance then the patient is into recovery and then the patients must come back to their home town. Because then you know that bigger hospitals come back to their home town. So I have decided that for the treatment regimen the first four cycles of bortezomib-containing treatment and then the patients are usually oral ixazomib-containing regimen; to come back by oral is very effective. The patients must stay at hospital because there is a severe syndrome. Then after some cycles of treatment the patient is in recovery and no pain and then it is okay and so they can come back to an oral treatment.

So I have decided that the MM6-PLUS regimen, at least a partial response, and then in-class regimen for more than four cycles and the oral also maybe for the purpose of disease progression. I have in this ASH meeting I have reported from China results where there are 97 patients from seven hospitals, patients who received that transition due to the pandemic. These are the patients that received at least seven cycles of the ixazomib-containing treatment. You know that patients first received bortezomib-containing treatment and in the real world patients received bortezomib-containing treatment for 2-3 cycles and then the maintenance is seven cycles of bortezomib-containing treatment and they are then transferred to ixazomib-containing treatment for another seven cycles. But proteasome inhibitor containing treatment for fourteen cycles and then the patients achieved around 35% CR and also the sCR. So the alternative for patients is a necessity for the proteasome inhibitor containing treatment so that patients receiving more than seven cycles of ixazomib-containing treatment is a very, very possibility and also is acceptable for that study and also is very, very satisfying for the patients that received so longer of treatment.

SK: I think it’s an important concept, especially in the setting of the pandemic, when patients are not able to come to the clinic very often. Many people have considered using an oral drug – changing to an all-oral regimen can sometimes be much more convenient for the patient. So the data from the MM6 trial particularly with the use of ixazomib len-dex is an interesting way of examining that question.

So in terms of the proteasome inhibitor maintenance approaches, Dr Chen, what have you been using in your own practice and is that a common practice in China in terms of using proteasome inhibitors as maintenance?

WC: Yes, sure. Normally we use lenalidomide for the maintenance because that is a generic drug that’s under-utilised and very cheap so usually we use lenalidomide for maintenance. But for some patients with renal impairment we usually change lenalidomide to bortezomib but that’s all you can do there – usually bortezomib or also maybe ixazomib. But bortezomib for the patients with neuropathy it can’t be used, bortezomib, and usually we change to using ixazomib. And also for the patients it’s not very convenient for them to go to the hospital. Usually you use it for the patients if they’re in a rural area and it’s not very common to go to the hospital for use. In China there is a policy for patients for using lenalidomide or also proteasome inhibitors – you must be in the grade 3 hospitals. Usually for the country and also for the rural areas hospitals are not grade 3. So usually the patients must go to the bigger hospital for accepting lenalidomide and also the proteasome inhibitors. So if the patients need also the IV bortezomib it’s not very common. So usually we change bortezomib to ixazomib for the maintenance.

SK: Yes, absolutely. I think the combination with ixazomib lenalidomide again is quite valuable because our approach right now for the high risk patients is to use a bortezomib plus lenalidomide combination for maintenance. Especially if someone has peripheral neuropathy or if they cannot come back every other week for the bortezomib injection then substituting that with ixazomib is an approach that many of us have taken. Again in the context of that combination setting for high risk patients, as you said Dr Chen, we don’t also use ixazomib as maintenance routinely, the lenalidomide is the more commonly used maintenance therapy. The patients where ixazomib tends to get used is mostly in combination with lenalidomide in the high risk patients and in those patients who clearly cannot tolerate an IMiD based maintenance, if they have significant skin issues with lenalidomide and so forth.

Obviously there is more data coming with monoclonal antibodies in the maintenance setting too and I’m sure that will also change how we approach this particular paradigm in the years to come. Anything else you would like to add, Dr Chen?

WC: Usually we use lenalidomide and also ixazomib for the maintenance of the high risk patients. Usually there is a trial for daratumumab for the maintenance but in China the drug is so expensive and the patients cannot accept the price. So we cannot use daratumumab for the maintenance.

SK: Thank you very much and for joining us and also sharing your thoughts on this topic. Again, thank you for watching this coverage of the virtual ASH 2020 on ecancer. Thank you.

WC: Thank you.