Ixazomib in First All-Oral Triplet for Multiple Myeloma

Alexander M. Castellino, PhD

May 02, 2016

The details of the clinical trial showing the efficacy of the first all-oral triplet for relapsed, refractory multiple myeloma have now been published, but with the recent windfall of new agents approved for this disease, the question is when to use which drugs.

The TOURMALINE-MM trial was the registration study that led to a US Food and Drug Administration approval of ixazomib (Ninlaro, Millenium/Takeda) for the treatment of relapsed/refractory multiple myeloma.

The study results, first presented at the 2015 American Society of Hematology (ASH) annual meeting and reported by Medscape Medical News, were published online April 28 in the New England Journal of Medicine.

The trial showed that for patients receiving the oral triplet combination of ixazomib, lenalidomide (Revlimid, Celgene Corporation), and dexamethasone (multiple brands), the risk for disease progression was 26% less than for patients receiving doublet therapy (lenalidomide and dexamethasone [len-dex]).

"Our study shows that the triplet regimen is safe and is a convenient combination in improving the duration of response in patients with relapsed/refractory multiple myeloma," lead author Philippe Moreau, MD, University of Nantes, France, told Medscape Medical News.

"Patients like a convenient dosing regimen, and the triplet is the first all-oral combination for patients in this disease setting,” he added.

But other new drugs have recently been approved for use in this setting.

"Three new drugs were approved in November 2015 for treating relapsed multiple myeloma," S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. In that month, ixazomib was approved, as were elotozumab (Empliciti, Bristol-Myers Squibb) and daratumumab (Darzalex, Janssen Pharmaceuticals, Inc); both latter drugs were granted priority review.

"These combinations provide useful options when patients relapse on a given regimen," Dr Rajkumar said.

How Triplet Regimens May Be Used in Clinical Practice

With several triplet regimens available in the refractory setting of multiple myeloma, two questions are inevitable: which is the go-to regimen, and how are they sequenced in clinical practice?

Dr Moreau told Medscape Medical News: "The use of triplet combination is highly increasing, based on their efficacy. Several of them are available with either len-dex or bortezomib-dex as a backbone."

He pointed out that elotuzumab, ixazomib, and carfilzomib (Kyprolis, Onyx/Amgen) are triplets on the len-dex backbone, whereas pomalidomide (Pomalyst, Celgene Corporation) and panobinostat (Farydak, Novartis Pharmaceuticals Corporation) are triplets on the bortezomib-dex backbone.

Dr Rajkumar echoed similar sentiments when he indicated that there would be no dearth in the number of triplet regimens. "There are numerous triplet regimens to consider, and it becomes a judgment call on the part of the treating physician," he said.

It is not total guesswork, Dr Rajkumar indicated. He pointed out that several factors warrant consideration in determining choice of therapy in the relapsed, refractory setting. Questions to be considered by treating physicians include the following:

  • What regimen was the patient receiving prior to or at the time of relapse?

  • Was the patient on or off therapy at relapse?

  • How many relapses have occurred so far?

  • How aggressive is the relapse?

  • What is the clinical status of the patient? Is the patient frail and needs the convenience of oral therapy, or can the patient withstand a more intense regimen?

  • What are the cytogenetic characteristics of the disease?

  • What were the side effects experienced on the prior regimen?

With respect to side effects, both Dr Moreau and Dr Rajkumar noted that the ixazomib triplet is associated with a lower incidence of peripheral neuropathy compared with bortezomib-based therapy.

"None of the trials has given us an answer as to which triplet is better," Dr Rajkumar said. "Thus, we are making a judgment in the absence of randomized trials," he added. He indicated that cost and the insurance carried by the patient may also make a difference as to which triplet is used, at least in the United States.

Dr Rajkumar pointed out that the collective wisdom of its 30 or more hematologists who have expertise in myeloma guide the Mayo Clinic's recommendations on choice of therapy for patients with relapsed, refractory multiple myeloma. This information can be accessed online at www.mSMART.org. Also available on that website is a presentation that Dr Rajkumar delivered at the 2015 ASH annual meeting titled ASH-FDA Symposium on Newly-Appointed Drugs.

"The mistake often made in assessing the new drugs is to compare the observed PFS [progression-free survival] across trials," Dr Rajkumar said. A comparison is only valid in the context of randomized clinical trials, he added. He conceded that it is unlikely that pharmaceutical companies will launch head-to-head comparisons across the new triplet regimens. "Therefore, it is important that cooperative groups and investigators design and conduct relevant comparative studies," he said.

Dr Rajkumar also indicated that most physicians in the United States are using triplet therapy in the frontline treatment of multiple myeloma. "Bortezomib-len-dex is the gold standard in this setting," Dr Rajkumar said. An Eastern Cooperative Oncology Group trial (E1A11) funded by the National Cancer Institute is comparing bortezomib-len-dex vs carfilzomib-len-dex. For patients in whom bortezomib-len-dex is not feasible, ixazomib-len-dex may be an option in this setting, he suggested.

Dr Rajkumar made an important point about the new triplet regimens that have len-dex as the backbone. The registration studies used for the approval for the new triplet regimens were global and included only a small number of patients from the United States, he noted.

"The study population in these studies does not reflect the patient population in the United States," Dr Rajkumar said. Because len-dex is not often used in frontline or maintenance settings outside the United States, patients in most of these registration studies did not experience relapse after having received len-dex-based therapy, he indicated.

In TOURMALINE-MM, for example, in 23% of patients, disease was refractory to immunomodulatory drugs, but only 12% had prior exposure to lenalidomide; 45% had prior thalidomide therapy.

"In the United States, when patients relapse on a len-dex-based therapy, it is not a simple matter of switching them to an approved triplet combination," Dr Rajkumar said. Consideration needs to be given, for example, to whether the triplet therapy should contain pomalidomide rather than lenalidomide, he added.


Of 722 patients enrolled in the study, 360 were randomly assigned to the triplet combination, and 362 to the doublet. Patients enrolled had relapsed, refractory, or both relapsed and refractory multiple myeloma and had received one or more therapies. Patients were not eligible if they had disease that was refractory to prior lenalidomide therapy or proteasome inhibitor–based therapy, or if they had peripheral neuropathy of grade 1 (with pain) or grade 2 or higher.

In 28-day cycles, patients received oral ixazomib 4 mg or matching placebo (days 1, 8, and 15); 25 mg of oral lenalidomide on days 1 through 21; and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. Treatment was continued until disease progression or unaccepatable toxicities occurred. PFS was the primary endpoint of the study.

Study Results

The median age of the patients was 66 years. As determined on the basis of the International Staging System (ISS), 64%, 24%, and 12% had stage I, II, and III disease, respectively. Standard- risk and high-risk cytogenetic abnormalities were noted for 57% and 19% of patients, respectively.

Sixty-one percent of patients had received one prior therapy; 29% and 10% had received two and three prior therapies, respectively; 69% of patients had received prior bortezomib therapy.

Median follow-up was approximately 14.7 months for the two groups at the first data cutoff; median PFS was 20.6 months for patients receiving ixazomib triplet therapy and 14.6 months for those receiving len-dex. With a hazard ratio of 0.74 (95% confidence interval: 0.59 - 0.94; P = 0.01), the patients receiving the ixazomib triplet had a 36% reduced risk for progression.

The benefits were seen in all subgroups, including patients with poor prognoses (ie, high-risk cytogenetics), those with ISS stage III disease, those older than 75 years, and those who had received more than two or three prior therapies.

Patients with multiple myeloma with high-risk cytogenetics had a 46% reduced risk for progression, and those with del(17p) deletion had a 40% reduced risk for progression.

Overall response rates were 78.3% for patients receiving ixazomib-len-dex and 71.5% for patients receiving len-dex.

At the second cutoff date, after a median follow-up of 23 months, median overall survival had not been reached in any of the two groups.

Thrombocytopenia was seen in more patients receiving ixazomib-len-dex (31% vs 16% for the len-dex group; grade 3/4: 12% vs 7%). Gastrointestinal adverse events occurred more often in patients receiving ixazomib-len-dex, but mostly within the first 3 months of starting treatment.

Peripheral neuropathy, a major side effect with bortezomib, was not a major toxicity with ixazomib-len-dex (27% vs 22% for len-dex).

Rash was seen more frequently in patients receiving ixazomib-len-dex (36% vs 23% for len-dex); the difference was mainly in grade 1 and 2 events.

"The addition of ixazomib does not increase the toxicity of the triplet regimen except for thrombocytopenia and rash. Carfilzomib-lex-dex is more toxic, and we have to be cautious in elderly patients with comorbidities, especially in patients with a prior history of cardiac disease," Dr Moreau said.

Ixazomib is currently being tested in the frontline setting in a pivotal study comparing ixazomib-len-dex with len-dex (NCT01850524), Dr Moreau pointed out.

"Some phase 2 trials are also testing ixazomib-len-dex triplet followed by stem cell transplantation in young patients," he added.

The TOURLAMINE-MM study was funded by Millennium/Takeda, manufacturer of ixazomib (Ninlaro). Dr Moreau has received honoraria from Bristol-Myers Squibb, Celgene, Millennium, Janssen-Cilag, and Novartis. Several coauthors report ties with pharmaceutical companies, and several coauthors were employees of Millennium/Takeda. Dr Rajkumar has disclosed no relevant financial relationships.

N Engl J Med. Published online April 28, 2016. Abstract


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