Professor Philip McCarthy – Roswell Park Cancer Institute, New York, USA
Professor Guillermo Ruiz-Argüelles – Centro de Hematologia y Medicina Interna, Mexico

PM: Good morning, my name is Dr Philip McCarthy and I’m here today at the European Haematology Association in Madrid, Spain in June of 2017. I’m here today with Dr Guillermo Ruiz and there have been several new developments in the treatment of multiple myeloma. Today we’re going to talk about how do we maintain initial response after induction therapy with or without transplant. Dr Ruiz, what’s the standard in Mexico after initial therapy?

GRA: Most centres in Mexico would go ahead with thalidomide and dexamethasone until the patient becomes intolerant to thalidomide and then they are switched into lenalidomide. The reason for this being that thalidomide is substantially more cheap than lenalidomide, at least in Mexico, and for us it is very critical, the cost of an item, and not only for us but for all people living in developing countries which, in this moment, represent more than 50% of all the inhabitants in the world.

PM: Did you see there’s the paper from Paul Richardson looking at ixazomib maintenance where they used an ixazomib/Len/Dex induction and then after several cycles of induction therapy went with ixazomib maintenance. This is another oral agent. Also Millennium is conducting a study looking at two years of ixazomib maintenance after stem cell transplant. Do you think this may be a reasonable alternative to, say, thalidomide or again it would depend on cost?

GRA: Yes, obviously there are better options than thalidomide to maintain duration of the patients after transplant but again we have to really carefully look at the cost to these. I strongly believe that one of the possible solutions to this is to find out different doses to deliver maintenance - instead of using them every day, twice a week or something or reduce the dose is probably enough. But what we have learned in Mexico is that the bone marrow transplant in patients with multiple myeloma is critical and should be done practically in every patient.

PM: Absolutely, for all transplant eligible patients high dose melphalan still remains an incredibly potent way of treating a myeloma patient. It’s interesting because in the States we often don’t have as many patients who are transplant eligible going onto transplant. I think it’s because there are so many drugs available and we just don’t yet know how to sequence them all and how to position them in terms of therapy. We do know for induction but more for the relapsed refractory setting. So you make a really very important point that high dose melphalan really is the backbone for the transplant eligible patient. In the US after that transplant then we’re using, right now because it was just FDA approved as well as by EMA, lenalidomide maintenance and you were talking about schedule – the British and the Italians did three weeks on, one week off whereas the French and US studies were daily until progression in the US and the French curtailed it because of concerns of second cancers.

GRA: Correct. We have done some analysis as far as the cost of the procedures is concerned and we have found that transplant in multiple myeloma is still the most cost-effective option for these patients and then after the transplant the maintenance schedules are particularly important and we have to very carefully look for novel forms to deliver this. In Mexico as a result of the economic constraints we are used to trying to cut down the doses of the drugs and probably in some drugs and in some diseases this may be successful. This is something that should be carefully pursued in patients that have been transplanted and that need some type of maintenance.

PM: Yes, again in the US because the FDA indication is for daily it’s usually prescribed on a daily basis. However, it’s usually at a dose of about 10-15mg but if the patient is intolerant to it, which can happen, there was an initial dose reduction by 5mg a day down to 5mg total dose daily which then went to 5mg three weeks on, one week off but some patients are receiving, say, 10mg three weeks on, one week off. So it remains to be determined, as you say, what may be the best dosing schedule because lenalidomide is a pretty powerful drug. It will be important, of course, to determine not only the daily versus the monthly schedule, also the length of time a patient should be on maintenance. Are there patients who don’t need maintenance until progression and we need to study that more.

GRA: That is a point and that’s another way to cut down the expense of the treatment. In the case of thalidomide which is used very frequently in Mexico as maintenance we have been able to show that a reduced dose of specifically 100mg a day are enough, probably the same as recommended options for lenalidomide and, as I said, the costs are totally different. So for us this cost problem is very critical but to overcome this problem we are in the way of designing protocols that could produce good results, probably cutting down expenses by cutting down the doses or the way to deliver them.

PM: Yes, in some countries drug availability can be based on the patients participating in a clinical trial. For example in the UK a large number of patients go on clinical trial and thus have access to novel drugs that allow for better treatment responses. So the Myeloma XI study was presented at this EHA demonstrating that lenalidomide maintenance also is beneficial and it was in a large number of both transplant eligible and transplant ineligible patients. So I think we’re going to have to see how we can best get those drugs to patients to optimise their responses and then maybe later on we’ll be doing the same thing with other drugs because still many patients relapse or progress even on maintenance therapy and we have to then decide what do we do next

GRA: Correct. What you have said is very important; having access to multicentre trials in developing countries is critical because you not only benefit the creation of new knowledge but you also benefit patients, you expose them to drugs that they would never be able to afford. So that is very important for us and this is one of the reasons why drug companies are interested in making these multinational studies which I find very adequate, a lot of people get benefit from this type of trials.

PM: Yes, we also, actually because of our access to all these drugs, sometimes we don’t have as much clinical trial participation which is a shame. A lot of our trials are more for relapsed refractory disease and that’s fine but we really need to better study, for example, the induction therapies. So we have a large Eastern Co-operative Oncology Group is looking at carfilzomib/lenalidomide/Dex versus bortezomib/lenalidomide/Dex but it’s for patients who aren’t going on to transplant. So that, again, points at a study design where the patients were actually not offered transplant; they could have their stem cells collected but then they would have transplant at first progression. That’s another big issue is that not all patients who delay transplant are able to get transplant later on because they have a comorbidity or some other problem occurs. Then it brings up the whole idea, as we talked about earlier, of giving high dose melphalan as part of the initial therapy and then maintaining response.

GRA: Yes, along the line of cutting down expenses in the case, for example, of bortezomib we have found that bortezomib can be delivered once a week instead of twice a week and that half of the vial of bortezomib can be used for one week and then you can keep the rest of the vial and not discard it until four weeks so one vial is enough for two weeks of treatment of bortezomib. So these types of observations in our countries are critical and the generation of new knowledge will eventually result in benefiting a substantial number of patients.

PM: I can’t imagine that dexamethasone is too expensive.

GRA: No, it is very affordable as well as thalidomide in Mexico. The problem is with the novel drugs and, as I said, we have found that transplanting those patients is substantially cheaper than keeping them in the novel drugs, especially after transplant.

PM: What schedule do you use for dexamethasone as part of induction?

GRA: 40mg once a week orally.

PM: And if they don’t tolerate it do you dose reduce?

GRA: Correct, to 50%, 20mg. This is in the Mexican guidelines of treatment of multiple myeloma and thalidomide 100mg a day together with aspirin, dexamethasone and bortezomib subcutaneous if the patient can tolerate it.

PM: This is Philip McCarthy here with Dr Guillermo Ruiz at EHA, or European Haematology Association, in Madrid, Spain. Thank you very much for listening.