New Oral Drug in Multiple Myeloma May Be 'Game Changer'

Zosia Chustecka

December 09, 2012

ATLANTA, Georgia — An investigational drug for multiple myeloma, the first oral proteasome inhibitor, has shown promising results in an early phase1/2 clinical trial and has progressed straight into phase 3 clinical trials. If all goes well, it is predicted to reach the market in 2014.

Currently known only as MLN9708 (Millennium), this new drug is taken orally once weekly and will offer an alternative to bortezomib (Velcade, Millennium), the first proteosome inhibitor developed for multiple myeloma, which is now commonly used in the treatment of this disease.

The new drug offers the convenience of oral administration, inasmuch as bortezomib is parenterally administered. Initially it was available only for intravenous infusion, but now a subcutaneous formulation is also available.

In addition, the new drug appears to be associated with a reduced incidence of peripheral neuropathy as an adverse effect when compared with bortezomib.

Shaji Kumar, MD, from the Hematology Division at the Mayo Clinic in Rochester, Minnesota, who is presenting clinical results with MLN9708 here at the American Society of Hematology (ASH) 54th Annual Meeting, said this side effect has been reduced significantly. In an interview with Medscape Medical News, he estimated that bortezomib, when used intravenously twice a week, is associated with an overall rate of neuropathy of about 30% to 40%, but the newer subcutaneous formulation has decreased this to about 10% to 15%.

In the phase 1/ 2 trial that he reported on at the meeting, Dr. Kumar said that mild grade 1 neuropathy was seen in 13 of 65 patients (8.45%); more severe grade 3 neuropathy developed in only 2 of 65 patients (3.07%).

Multiple myeloma is itself associated with peripheral neuropathy, Dr. Kumar noted, and "it is part and parcel of the disease process."

An underlying neuropathy is seen in about 10% to 15% of patients, he said. "Some of these treatments are unmasking that and making it worse," he said, although many of the drugs used are also associated with this adverse effect. It can be dose limiting, and it can also be "duration limiting," because the development of peripheral neuropathy can stop patients from continuing with therapy.

Used in Combination in Newly Diagnosed Patients

The trial was split into 2 parts. The phase 1 trial involved 15 patients and established a maximum tolerated dose as well as the recommended dose to use going forward. The dose selected was 4 mg of MLN9708 taken orally once a week.

The phase 2 part of the trial was conducted in 55 patients with newly diagnosed multiple myeloma.

A triplet of drugs is now commonly used in newly diagnosed multiple myeloma, Dr. Kumar explained at a press briefing, and a popular combination is bortezomib with the immunomodulatory agent lenalidomide (Revlimid, Celgene) and the steroid dexamethasone. "We decided to use a similar combination, but substituting MLN9708 for bortezomib," he explained. In this combination, all 3 drugs were taken orally.

MLN9708 4 mg was given on days 1, 8, and 15, in combination with lenalidomide (25 mg once daily on days 1 to 21) and dexamethasone (40 mg on days 1, 8, 15, and 22).

In the trial, it was initially planned that 12 cycles of the triplet therapy would be administered and that MLN9708 would be administered alone as maintenance treatment on follow-up. For the results that Dr. Kumar presented, a median of 6 cycles had been completed. Patients were allowed to leave the trial to attempt stem cell collection for a transplant, which can be curative; 20 of the 55 participants chose to do so. However, one half of the enrolled patients remain on therapy, he added

Seven patients discontinued treatment because of adverse events. Minor adverse events, including fatigue, nausea, and rash, were reported by about 40% of patients. Two serious adverse events (grade 4) were reported — end-stage renal disease in 1 patient, which the investigators attributed to progressing multiple myeloma, and deep vein thrombosis in another patient. In addition, 1 patient died from pneumonia while on treatment.

"Promising" Results

With regard to overall response rate in the 55 patients, 92% showed a partial response or more; 55% showed a very good partial response; and 23% showed a complete response, Dr. Kumar reported.

However, the results show that the rate and depth of response to therapy increased with the number of cycles completed. For the patients who completed 12 cycles of therapy, the complete response rate had increased to 67%, and the remaining 33% had a very good partial response.

"The depth of the responses at 6 months is promising," Dr. Kumar commented in the interview. These are preliminary results, and patients are expected to continue with the 3-drug regimen for an average of 12 cycles. "The expectation is that these responses will become even deeper."

MLN9708 was "very well tolerated," Dr. Kumar noted. The main serious adverse events (grade 3 or higher) were gastrointestinal upset and skin rash, reported in approximately 5% of patients. These adverse events can be controlled with dose reduction or with other medications, he said.

The results are considered promising enough to go into phase 3 trials. One of these is already in progress, and several others are planned. The phase 3 trials will investigate the drug in both newly diagnosed and relapsed multiple myeloma, he said.

Promises a Number of Advantages

Approached for comment on these new data, David S. Siegel, MD, PhD, chief of multiple myeloma at the John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey, told Medscape Medical News that MLN9708 offers a number of advantages.

"First, and perhaps most importantly, it may be more active than its predecessors," he said. "Responses have been seen in patients who are refractory to bortezomib. In the end, better efficacy is always the goal."

"Second, it also seems to cause less peripheral neuropathy than does bortezomib. While bortezomib is an extremely safe drug, its use is often limited by the development of peripheral neuropathy. While we have figured out ways to abrogate some of that toxicity by changing the schedule and administering the drug subcutaneously, it has remained a problem. The lower peripheral neuropathy rates with MLN9708 may greatly expand its utility and allow us to use the drug longer."

The oral route of administration can be a game changer. Dr. David Siegel

"Third, the oral route of administration can be a game changer," Dr Siegel commented. "It may open up its use to patients who cannot easily present once or twice a week to a doctor's office. It may make its use as a maintenance drug more attractive, and that might truly change how we care for multiple myeloma patients. All oral regimens, such as MLN9207 plus lenalidomide plus dexamethasone, are extremely attractive from the perspective of convenience, quality of life, and efficacy. Oral regimens might ultimately help control costs as well," he said.

The study was funded by Millennium Pharmaceuticals, developers of MLN9708. Dr. Kumar reports receiving research funding from Millennium Pharmaceuticals, Novartis, Genzyme, Cephalon, and Celgene, and honoraria and consultancy for Merck & Co. Several coauthors are employees of Millennium. Dr. Siegel is on the speakers' bureaus for Celgene, Onyx, and Millennium.

American Society of Hematology (ASH) 54th Annual Meeting. Abstract 332.