In 2015, four new drugs were approved for the treatment of multiple myeloma by the U.S. Food and Drug Administration: panobinostat (Farydak), daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro). Of them, the first three are drugs with unique new targets, whereas ixazomib is the third proteasome inhibitor to be approved for myeloma. In the crowded field of new drugs for myeloma, does ixazomib deserve a prominent place in therapy? Does it distinguish itself from the other two available proteasome inhibitors, bortezomib (Velcade) and carfilzomib (Kyprolis)? In my opinion, the answer is a qualified ‘yes.’
Avoiding Unreliable Comparisons
In the TOURMALINE MM-1 trial, reported by Moreau and colleagues1 and summarized in this issue of The ASCO Post, median progression-free survival was significantly longer with ixazomib/lenalidomide (Revlimid)/dexamethasone vs placebo/lenalidomide/ dexamethasone—20.6 vs 14.7 months (hazard ratio = 0.74, P = .01). Ixazomib is therefore clearly an active drug for the treatment of myeloma. But there will be a temptation to compare progression-free survival with ixazomib/lenalidomide/dexamethasone with that seen with other recently reported triplets such as carfilzomib/lenalidomide/dexamethasone, daratumumab/lenalidomide/dexamethasone, and elotuzumab/lenalidomide/dexamethasone. These comparisons across randomized trials are not reliable and must be avoided.
In the crowded field of new drugs for myeloma, does ixazomib deserve a prominent place in therapy? In my opinion, the answer is a qualified ‘yes.’— S. Vincent Rajkumar, MD
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One important factor to keep in mind is that the TOURMALINE study was a double-blind, placebo-controlled trial, whereas phase III trials with the other triplets were open-label studies. In open-label trials, patients may tend to stay on the experimental therapy arm as long as possible (based on the desire to have access to an otherwise unavailable “new” drug), whereas they may go off therapy more readily from the control arm (probably viewed with disappointment from the outset) if the perceived benefit is not adequate or side effects occur. Overall, this may result in a more pronounced progression-free survival difference in open-label trials than in double-blind trials. Thus, the progression-free survival duration seen with ixazomib cannot be compared with that derived from open-label trials.
Important Addition to the Repertoire
In my opinion, ixazomib has many desirable features that make it an important addition to the repertoire of myeloma treatment. First, as an oral agent requiring only three doses each month, it lends itself as an ideal option for long-term therapy in front-line, relapsed, and maintenance settings. Second, the rates of severe adverse events with ixazomib/lenalidomide/dexamethasone are similar to those with lenalidomide and dexamethasone, making ixazomib a particularly attractive option in the treatment of elderly, frail patients. Finally, as with bortezomib, ixazomib also seems to have excellent activity in high-risk myeloma, a setting in which new options are critically needed.
Challenges Ahead
What are some challenges to the use of ixazomib? In the near future, bortezomib is likely to become generic, greatly reducing the cost of using bortezomib/lenalidomide/dexamethasone compared with newer regimens. When bortezomib is administered once weekly subcutaneously, any concern about neuropathy is greatly minimized, and inconvenience is low. Unless the cost of ixazomib is adjusted to keep it competitive, we would need more data to determine whether it has any major advantages over bortezomib.
Next, now that we know four different triplet regimens (ixazomib/lenalidomide/dexamethasone, carfilzomib/lenalidomide/dexamethasone, daratumumab/lenalidomide/dexamethasone, and elotuzumab/lenalidomide/dexamethasone) are all superior to lenalidomide and dexamethasone in relapsed myeloma, we need to answer the more pressing question: How do they fare in comparison to the widely used combination of bortezomib/lenalidomide/dexamethasone? In a patient who is not refractory to bortezomib/lenalidomide/dexamethasone, is there any benefit to choosing a newer regimen in terms of efficacy, toxicity, or cost? If so, which regimen will be the best option? These questions need randomized trials; one such trial comparing carfilzomib/lenalidomide/dexamethasone with bortezomib/lenalidomide/dexamethasone in the front-line setting is being conducted by the Eastern Cooperative Oncology Group, and many more are needed.
More important, we urgently need to develop newer regimens utilizing pomalidomide (Pomalyst) as the backbone, since the type of patients studied in the TOURMALINE trial and other phase III trials of new triplets is uncommon in the United States. Most patients in the United States would have been previously treated with lenalidomide and dexamethasone, and many will be refractory to lenalidomide at first relapse. The true efficacy and relative merits of new regimens in relapsed myeloma cannot be extrapolated or deduced from trials conducted in patients who were predominantly naive to lenalidomide.
The clinical activity, safety, and route of administration of ixazomib will probably ensure that it gains an important role in the treatment of myeloma. Results of several ongoing phase III trials will shed more light on its optimal place in the treatment sequence. Meanwhile, it is indeed excellent news that we can choose from three active proteasome inhibitors based on an individual patient’s needs and circumstances. ■
Disclosure: Dr. Rajkumar reported no potential conflicts of interest.
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