New Treatment Regimens for Previously Treated Myeloma - Episode 7

EU Approval of Ixazomib for Relapsed/Refractory Myeloma

Transcript:Heinz Ludwig, MD: The European approval of NINLARO (ixazomib) by the European Medical Agency was announced on November 24, 2016 and has been approved for treatment of all patients who relapse after frontline therapy. So, it’s a relatively wide indication—and it’s the widest indication we’ve been thinking about because all patients who will relapse after frontline therapy can be treated with NINLARO.

Shaji Kumar, MD: Ixazomib is our first oral protease inhibitor to be introduced in the clinic. It has been studied in a variety of different combinations, and also as a single agent. It was approved in the United States for treatment of a patient with relapsed myeloma with 1 to 3 prior lines of therapy, based on data from a large phase III trial where ixazomib was combined with lenalidomide and dexamethasone.

So, the combination of ixazomib, lenalidomide, and dexamethasone was compared to lenalidomide and dexamethasone in patients with relapsed myeloma who are not refractory to bortezomib and who have had 1 to 3 prior lines of therapy. What was seen, in these phase III trials, was that there was about a 6-month improvement in the progression-free survival when ixazomib was added to lenalidomide and dexamethasone. There was no significant increase in the toxicity that was seen with the triplet compared to the doublet of lenalidomide/dexamethasone. The trial told us 2 things: 1) the addition of ixazomib increases the efficacy of the combination, improves the progression-free survival, and increases the depth of response. It also told us that the third drug can be added to lenalidomide/dexamethasone without any significant change in the toxicity profile. And 2) these patients could continue in therapy for a long period of time with this combination; again, suggesting the favorable toxicity profile of the combination.

Maria-Victoria Mateos, MD, PhD: The quality of the response is really relevant in myeloma. The better the quality of the response, the longer the progression-free survival. However, the kinetics of the response has not been evaluated in depth in the large phase III randomized trials conducted in relapsed and refractory myeloma. In the TOURMALINE-MM1 study, this concept has been evaluated, and we know that patients included in this trial responded very rapidly. The median time to first response was approximately 1 month and the median time to best response was 2.3 to 2.6 months. However, there was a significant subgroup of patients where approximately 25% to 30% of the patients achieved the best quality of the response beyond the cycle number 6. And these patients who achieved this quality of the response beyond the cycle number 6 have a significantly longer progression-free survival in comparison with patients in which the best response was achieved earlier. This means that the duration of the treatment is important because if we are able to maintain patients on therapy for a prolonged period of time, they can achieve better responses. They can improve the quality of the response, and this is going to be associated with significantly longer outcome.

Shaji Kumar, MD: One of the advantages of protease inhibitors in patients with myeloma with renal insufficiency is that we don’t really have to make many dose modifications, as we have learned with the bortezomib experience. In patients getting ixazomib, our experience so far has been that the same thing holds true. Patients can receive ixazomib without dose modification, particularly patients with mild to moderate renal insufficiency, without having any difference in the toxicity profile. In patients with mild hepatic impairment, there’s no significant dose modifications that are needed for use of ixazomib. Again, the one drug it gets compared with in this different setting depends on the metabolic profile of the particular drug, whether it’s lenalidomide, which we dose-modify in the setting of renal failure, or cyclophosphamide, which does not need any modification in the setting of renal failure. So, the good thing of having so many different drugs is we can actually choose a partner drug for ixazomib based on the particular clinical setting.

Maria-Victoria Mateos, MD, PhD: The c-MYC is a protein involved within many functions of the cells, and we know that there is a relationship between proteasome inhibitor sensitivity and c-MYC. And, in fact, we know that c-MYC is usually overexpressed in poor-risk patients. In addition, the presence of genetic abnormalities like del17, del17p, or 4;14 translocation are also associated with poor prognosis. In the TOURMALINE-MM1 study, some subanalyses were done according to the expression of c-MYC and also according to the presence of high-risk cytogenetic abnormalities. Starting by the role of ixazomib/lenalidomide/dexamethasone in a high-risk cytogenetic abnormalities subgroup of patients, I have to say that IRD is able to completely overcome the poor prognosis of the presence of 4;14 or del17. Why? Because the median progression-free survival was exactly the same in the whole series of patients, in the standard risk patients, than in higher risk patients.

In addition, a subanalysis was done according to the percentage of positive plasma cells for del17p, and the percentage of abnormal plasma cells doesn’t matter in the efficacy of IRD in this specific subgroup of patients. So, the conclusion would be that ixazomib in combination with lenalidomide and dexamethasone represents an optimal choice for this high-risk subgroup of patients. In addition, if we evaluated the role of c-MYC, the subanalysis showed that patients with high levels of c-MYC responded very well to ixazomib in combination with lenalidomide and dexamethasone. This was in patients who had high levels of c-MYC, patients who had been included in the trial after 2 or 3 prior lines of therapy.

And, in addition, if we focus on the group of patients—including after just 1 prior line of therapy—that were non-transplant candidates, they had high levels of c-MYC and they responded very well to IRD. By contrast, I probably would not choose IRD for patients receiving just 1 prior line of therapy, including autologous stem cell transplantation, because autologous stem cell transplantation induces more in mature plasma cells, resulting in low levels of c-MYC. And this can explain the low efficacy of this combination in this group of patients.

Transcript Edited for Clarity