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Patient Selection for Ixazomib in Myeloma

Panelists: Shaji Kumar, MD, Mayo Clinic; Heinz Ludwig, MD, Wilhelminen Cancer Research Institute; Maria Victoria Mateos, MD, PhD, University Hospital of Salamanca
Published Online: Monday, Jun 12, 2017



Transcript:

Shaji Kumar, MD:
The combination of ixazomib, lenalidomide, and dexamethasone is a highly effective combination that has been studied in the relapsed setting, but less in the newly diagnosed setting. The combination of ixazomib, lenalidomide, and dexamethasone is currently approved for patients with relapsed myeloma who have received 1 to 3 prior lines of therapy. It is an effective combination, which also has the added advantage of being a completely oral combination. We know that the combination of a proteasome inhibitor with an immunomodulator drug is one of the most effective combinations we have currently available for treating patients with myeloma.

For the first time, we actually have the ability to provide this combination in a completely oral fashion, and I think that is the distinct advantage of ixazomib compared to the other proteasome inhibitors that we currently have in the clinic. The combination has been shown to be effective across all age groups. In all patients with relapsed disease who are not refractory to bortezomib, the combination has clearly been shown to improve progression-free survival and should be a choice when you think about the different options that we currently have for treating patients with relapsed myeloma.

This is particularly relevant for patients who have responded favorably to the initial combinations that may have included a proteasome inhibitor and an immunomodulatory drug, many of whom may have received the combination for a short duration of time, prior to going to a stem cell transplant. So, we know in those patients that particular combinations are highly effective, and now we have the ability to deliver that in a much more convenient fashion.

Now, there is no reason not to choose that regimen, particularly in the more fit patients or less fit patients. We know from the phase III trial that it’s very well tolerated across the board. It is particularly relevant for the older patients because it is more difficult for those patients to come to the clinic to get injections on a weekly basis. So, in those settings, the all-oral combinations certainly have a distinct advantage.

The key thing that one needs to keep in mind when using the ixazomib/lenalidomide/dexamethasone combination is obviously the management of the toxicity. Understanding which of the toxicities can be related to which of the drugs will allow practitioners to better dose modify, so that we can actually decrease the risk of toxicity. The second part is monitoring for efficacy. It’s a quite efficacious regimen, so careful monitoring of the disease response is important, because obviously there are some patients who don’t respond or respond suboptimally. In those patients, it would be important to change treatment.

One of the advantages of the all-oral regimen is the fact that it’s convenient for patients to not have to come back very often. But at the same time, it also brings up the question of adherence to therapy, and that is something physicians have to keep in mind to ensure that patients are taking their medications as they are expected to. It sometimes can be more challenging when a drug is taken once a week instead of every day, because when it’s every day, it’s easier to remember. When it’s once a week, there are more chances of either missing a dose or taking more than what is prescribed on a given week.

So, it’s important for the nursing staff and other health staff who support the practice to proactively reach out to patients and make sure they’re taking the drug the way it was prescribed. There are several tools and reminder mechanisms that are being thought about or have been implemented, which can also make sure the patients actually stay on schedule.

Heinz Ludwig, MD: The question is how to select patients for treatment with ixazomib/lenalidomide/ dexamethasone. I think that’s an easy question because you can actually enroll patients who are very fit, patients with cytogenetic high-risk features, patients with neuropathy, or patients with renal impairment. Patients also show good hematological tolerance to this combination. There is little risk for infections, and you can enroll younger and elderly patients. So, I think the indication, it’s a combination for every season. But I will carefully consider what the previous treatment was and what the response to the previous treatment was. What was the patient’s tolerance to the previous treatment? That is important to make your best choice.

I always say these are the 4 pillars. Number 1: the patient condition. Is he fit? Is he frail? Has he or she comorbidities? Number 2: how did he react to the previous treatment? Did he achieve an excellent response? Did he tolerate the response? And was the treatment response maintained for long? Of course, another important question, number 3, is which options are available in your center, in your private practice? What choices are available for you? And then number 4: patients’ preferences. Many patients opt, of course, for oral therapy and don’t want to come to the hospital or the private office too often. So, those are the determinants, where you base your decision in cooperation with your patient. Now it’s easier to find a good solution for each individual patient.

My personal experience with ixazomib/lenalidomide/dexamethasone is that we participated in the TOURMALINE-MM1 study, of course, and we were surprised because we couldn’t figure out who was in the control group and who was in the treatment group because it’s so well tolerated. We are now on the trial with ixazomib/thalidomide/dexamethasone, and when I look at the toxicity data, I’m surprised that there is so little toxicity. The only toxicity in a few patients comes a little bit from thalidomide, but it’s also well tolerated and sometimes one wonders if a proteasome inhibitor negates or mitigates the neuropathic activity of thalidomide—but I don’t know that. But there is very little toxicity.

So, it’s very well tolerated. Sometimes you feel that you want to increase the dose, but we have to stick to the label. But I think that is worth following in further studies because of its excellent tolerance. You can go with this treatment for a very long period. We also participated in the TOURMALINE-MM3 study using ixazomib as maintenance therapy after stem cell transplantation and, again, there’s nothing. There’s practically no side effect.

My colleagues working in private practice are very interested in, of course, maintaining the quality of life of patients and also providing the patients treatment that is well tolerated, because it makes a patient’s life easier, but also a physician’s life easier. You don’t have to intervene so often. So, for both parts, that is an excellent choice, and I think clinical experience will confirm it. I haven’t heard of any negative data or any unusual toxicities up until now. But we have to be careful because sometimes you see toxicities only after a very long time—but that’s very unlikely, in my opinion.

Maria Victoria Mateos, MD, PhD: My personal experience with ixazomib in combination with lenalidomide and dexamethasone is good. First, my experience was coming from the clinical trials in which I have included some patients who were relapsed and refractory, and the experience was good. And now I am using ixazomib in combination with lenalidomide and dexamethasone in some patients outside of clinical trials.

The efficacy is good, and I would say that almost all patients responded to IRD (ixazomib/lenalidomide/dexamethasone). The overall response rate is over 85% to 90%. In addition, approximately 12% to 15% of the patients are able to achieve a complete response. But what is important is that the administration of this 3-drug–based combination is able to prolong progression-free survival in comparison with the conventional standard of care that we used in the past: lenalidomide and dexamethasone.

And what is much more relevant is that the addition of the third drug—in this case, ixazomib—is not associated with a high toxicity; the toxicity profile is excellent. And we have to be careful at the beginning of treatment to evaluate the toxicity profile in terms of hematological toxicity: neutropenia, thrombocytopenia, fatigue, or even a skin rash that is present in some patients. But if we are careful at the beginning—during the first 2 or 3 cycles—I would say that patients can continue on therapy for prolonged period of times without any problems. In addition, as the combination is of oral administration, the convenience is great and patients have to come to the hospital just once per month.

Transcript Edited for Clarity
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Transcript:

Shaji Kumar, MD:
The combination of ixazomib, lenalidomide, and dexamethasone is a highly effective combination that has been studied in the relapsed setting, but less in the newly diagnosed setting. The combination of ixazomib, lenalidomide, and dexamethasone is currently approved for patients with relapsed myeloma who have received 1 to 3 prior lines of therapy. It is an effective combination, which also has the added advantage of being a completely oral combination. We know that the combination of a proteasome inhibitor with an immunomodulator drug is one of the most effective combinations we have currently available for treating patients with myeloma.

For the first time, we actually have the ability to provide this combination in a completely oral fashion, and I think that is the distinct advantage of ixazomib compared to the other proteasome inhibitors that we currently have in the clinic. The combination has been shown to be effective across all age groups. In all patients with relapsed disease who are not refractory to bortezomib, the combination has clearly been shown to improve progression-free survival and should be a choice when you think about the different options that we currently have for treating patients with relapsed myeloma.

This is particularly relevant for patients who have responded favorably to the initial combinations that may have included a proteasome inhibitor and an immunomodulatory drug, many of whom may have received the combination for a short duration of time, prior to going to a stem cell transplant. So, we know in those patients that particular combinations are highly effective, and now we have the ability to deliver that in a much more convenient fashion.

Now, there is no reason not to choose that regimen, particularly in the more fit patients or less fit patients. We know from the phase III trial that it’s very well tolerated across the board. It is particularly relevant for the older patients because it is more difficult for those patients to come to the clinic to get injections on a weekly basis. So, in those settings, the all-oral combinations certainly have a distinct advantage.

The key thing that one needs to keep in mind when using the ixazomib/lenalidomide/dexamethasone combination is obviously the management of the toxicity. Understanding which of the toxicities can be related to which of the drugs will allow practitioners to better dose modify, so that we can actually decrease the risk of toxicity. The second part is monitoring for efficacy. It’s a quite efficacious regimen, so careful monitoring of the disease response is important, because obviously there are some patients who don’t respond or respond suboptimally. In those patients, it would be important to change treatment.

One of the advantages of the all-oral regimen is the fact that it’s convenient for patients to not have to come back very often. But at the same time, it also brings up the question of adherence to therapy, and that is something physicians have to keep in mind to ensure that patients are taking their medications as they are expected to. It sometimes can be more challenging when a drug is taken once a week instead of every day, because when it’s every day, it’s easier to remember. When it’s once a week, there are more chances of either missing a dose or taking more than what is prescribed on a given week.

So, it’s important for the nursing staff and other health staff who support the practice to proactively reach out to patients and make sure they’re taking the drug the way it was prescribed. There are several tools and reminder mechanisms that are being thought about or have been implemented, which can also make sure the patients actually stay on schedule.

Heinz Ludwig, MD: The question is how to select patients for treatment with ixazomib/lenalidomide/ dexamethasone. I think that’s an easy question because you can actually enroll patients who are very fit, patients with cytogenetic high-risk features, patients with neuropathy, or patients with renal impairment. Patients also show good hematological tolerance to this combination. There is little risk for infections, and you can enroll younger and elderly patients. So, I think the indication, it’s a combination for every season. But I will carefully consider what the previous treatment was and what the response to the previous treatment was. What was the patient’s tolerance to the previous treatment? That is important to make your best choice.

I always say these are the 4 pillars. Number 1: the patient condition. Is he fit? Is he frail? Has he or she comorbidities? Number 2: how did he react to the previous treatment? Did he achieve an excellent response? Did he tolerate the response? And was the treatment response maintained for long? Of course, another important question, number 3, is which options are available in your center, in your private practice? What choices are available for you? And then number 4: patients’ preferences. Many patients opt, of course, for oral therapy and don’t want to come to the hospital or the private office too often. So, those are the determinants, where you base your decision in cooperation with your patient. Now it’s easier to find a good solution for each individual patient.

My personal experience with ixazomib/lenalidomide/dexamethasone is that we participated in the TOURMALINE-MM1 study, of course, and we were surprised because we couldn’t figure out who was in the control group and who was in the treatment group because it’s so well tolerated. We are now on the trial with ixazomib/thalidomide/dexamethasone, and when I look at the toxicity data, I’m surprised that there is so little toxicity. The only toxicity in a few patients comes a little bit from thalidomide, but it’s also well tolerated and sometimes one wonders if a proteasome inhibitor negates or mitigates the neuropathic activity of thalidomide—but I don’t know that. But there is very little toxicity.

So, it’s very well tolerated. Sometimes you feel that you want to increase the dose, but we have to stick to the label. But I think that is worth following in further studies because of its excellent tolerance. You can go with this treatment for a very long period. We also participated in the TOURMALINE-MM3 study using ixazomib as maintenance therapy after stem cell transplantation and, again, there’s nothing. There’s practically no side effect.

My colleagues working in private practice are very interested in, of course, maintaining the quality of life of patients and also providing the patients treatment that is well tolerated, because it makes a patient’s life easier, but also a physician’s life easier. You don’t have to intervene so often. So, for both parts, that is an excellent choice, and I think clinical experience will confirm it. I haven’t heard of any negative data or any unusual toxicities up until now. But we have to be careful because sometimes you see toxicities only after a very long time—but that’s very unlikely, in my opinion.

Maria Victoria Mateos, MD, PhD: My personal experience with ixazomib in combination with lenalidomide and dexamethasone is good. First, my experience was coming from the clinical trials in which I have included some patients who were relapsed and refractory, and the experience was good. And now I am using ixazomib in combination with lenalidomide and dexamethasone in some patients outside of clinical trials.

The efficacy is good, and I would say that almost all patients responded to IRD (ixazomib/lenalidomide/dexamethasone). The overall response rate is over 85% to 90%. In addition, approximately 12% to 15% of the patients are able to achieve a complete response. But what is important is that the administration of this 3-drug–based combination is able to prolong progression-free survival in comparison with the conventional standard of care that we used in the past: lenalidomide and dexamethasone.

And what is much more relevant is that the addition of the third drug—in this case, ixazomib—is not associated with a high toxicity; the toxicity profile is excellent. And we have to be careful at the beginning of treatment to evaluate the toxicity profile in terms of hematological toxicity: neutropenia, thrombocytopenia, fatigue, or even a skin rash that is present in some patients. But if we are careful at the beginning—during the first 2 or 3 cycles—I would say that patients can continue on therapy for prolonged period of times without any problems. In addition, as the combination is of oral administration, the convenience is great and patients have to come to the hospital just once per month.

Transcript Edited for Clarity
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