Transitioning to an All Oral Therapy for Multiple Myeloma with the Novel Proteasome Inhibitor Ixazomib

Since their introduction more than 10 years ago, proteasome inhibitors (PI) such as bortezomib and, more recently carfilzomib, have emerged as a mainstay of treatment in multiple myeloma (MM).

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 Bortezomib has been one of the driving forces behind the remarkable continued improvements in survival in MM.

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 Its importance has been demonstrated in all aspects of MM care, from the relapsed and refractory setting to upfront treatment, either as part of induction therapy prior to autologous stem cell transplantation or as part of the treatment in patients who are not eligible for high-dose therapy. However, one of the significant limiting toxicities of bortezomib appreciated during its initial use has been peripheral neuropathy, though this has been largely mitigated through weekly dosing and subcutaneous administration.

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Ixazomib (previously known as MLN9708) is a new oral PI with promising preclinical data showing superior pharmacodynamics and antitumor activity compared with bortezomib.

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 Proteasome inhibitors, when given in combination with immunomodulatory drugs (IMiDs) such as lenalidomide as RVD (lenalidomide, dexamethasone, and bortezomib)

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 or cyclophosphamide as VCD (bortezomib, cyclophosphamide, and dexamethasone),

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 have been extremely effective in producing deep responses with excellent tolerability, and these regimens are standard treatment for newly diagnosed patients who are eligible for high-dose therapy.The phase I/II study by Dr. Shaji Kumar and colleagues evaluates the use of ixazomib as the PI in this triplet combination with lenalidomide and dexamethasone in newly diagnosed patients. In this trial, patients received induction treatment according to a conventional 28-day schedule of lenalidomide 25 mg on days 1 to 21 and dexamethasone 40 mg weekly with ixazomib orally on days 1, 8, 15. After 12 cycles, patients continued ixazomib as maintenance. Stem cell collection and high-dose melphalan and autologous stem cell transplantation were permitted. The study enrolled 65 patients (15 patients in phase I; 50 patients in phase II).This all-oral triplet combination was well tolerated, and the adverse event profile, including rates of neutropenia and thrombocytopenia, was typical of other triplet combinations. Importantly, the rate of grade ≥ 3 peripheral neuropathy was low at 6 percent, though it was comparable to rates observed when bortezomib is administered subcutaneously instead of intravenously. A notable adverse event of this regimen was skin rash in 55 percent of patients, which was grade ≥ 3 in 17 percent. While rash is common with lenalidomide-based regimens, grade ≥ 3 skin-related events are rare, and this was the most common reason for dose reduction in this trial. By comparison, when ixazomib is given weekly as a single agent in patients with relapsed disease, the rate of grade ≥ 3 rash was less (3%).

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 The significance of rash with ixazomib and how it may be potentiated in other MM drug combinations remains to be seen. With a median follow-up of 14.3 months, this regimen was active, similar to RVD, with an overall response rate of 92 percent and a very good partial response rate or better of 58 percent.Treatment paradigms for multiple myeloma are moving toward extended courses of treatment, in both the upfront and in the relapsed setting. These shifts are motivated by the findings in the FIRST trial,

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 which found improved progression-free survival with treatment to progression with lenalidomide-dexamethasone, and in maintenance therapy with lenalidomide after transplantation.

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 For the older patient population, modifications in schedule and dosing (for example, RVD-lite), have allowed the benefits of triplet combination to reach this group which traditionally has been more challenging to treat.

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 Recently, the ASPIRE trial showed unprecedented activity for the combination of carfilzomib with lenalidomide and dexamethasone in relapsed and refractory patients, reaffirming the role of combining a PI and an IMiD.

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 The availability of an oral, active, well-tolerated PI is thus an important and welcome advance for the MM community. Bortezomib and carfilzomib require weekly or twice weekly visits for treatment, and their prolonged schedules of treatment are a major time commitment for patients and their caretakers. As shown in the study by Dr. Kumar and colleagues, ixazomib has a favorable toxicity profile and is effective, and its long half-life affords a convenient weekly schedule. Another oral PI, oprozomib, is also in clinical trials.

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 An oral PI will significantly enhance accessibility and the feasibility of optimal treatment strategies, especially for older patients. We await future trials to determine the best drugs to partner with ixazomib, as well as sequencing and maintenance approaches, and finally, studies of oprozomib and other oral PIs.