Primary amyloidosis is a challenging hematologic disorder, with clinical features similar to multiple myeloma, but for which there are currently no US Food and Drug Administration (FDA)-approved medications. This condition often affects patients with myeloma, and the global myeloma community is coming together to evaluate the oral proteasome inhibitor MLN9708 as novel therapy for this disease, based on very encouraging results seen with this investigational drug in patients with multiple myeloma.
Millennium: The Takeda Oncology Company recently announced the initiation of an international phase 3 clinical trial evaluating once-weekly oral MLN9708 in patients with relapsed or refractory light-chain primary amyloidosis.
“There is a significant unmet medical need in the treatment of light-chain amyloidosis, which is a rare and usually fatal disease,” said trial investigator Giampaolo Merlini, MD, of the Amyloidosis Research and Treatment Center at the University of Pavia, Italy. “There are currently no approved medications for light-chain amyloidosis.”
The multicenter TOURMALINE-AL1 is a prospective phase 3, randomized, controlled, open-label, multicenter study that includes patients enrolled from centers in North America, Europe, Latin America, and the Asia-Pacific region. Patients will be randomly assigned to once-weekly oral MLN9708 plus dexamethasone or to the investigator’s choice of 1 of the following: dexamethasone alone or dexamethasone plus melphalan, cyclophosphamide, thalidomide, or lenalidomide.
Patients in the treatment arm will receive MLN9708 (4.0 mg) orally on days 1, 8, and 15, plus dexamethasone 20 mg once weekly on days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 40 mg weekly after 4 weeks, if tolerated. Patients can continue to receive treatment until progressive disease or until unacceptable toxicity.
Unique Study Design
The trial is using a unique study design, which Dr Merlini discussed with Value-Based Care in Myeloma.
“Indeed, the study has a unique design, because it includes novel end points, developed by a close collaboration between Millennium, the FDA, and the hematology community. The novelty is that the coprimary end points are overall hematologic response and the rate of 2-year vital organ deterioration and mortality rate,” Dr Merlini said. “The hematologic response rate end point is based on robust clinical evidence that shows a very strong correlation between the depth of hematologic response and survival.”
Secondary end points include safety, overall survival, complete hematologic response, progression-free survival, duration of response, and quality of life.
Dr Merlini speculates that the novel design may establish a standard for future clinical research in systemic amyloidosis. “This is the first oral proteasome inhibitor to be investigated in amyloidosis and in a trial conducted under special protocol assessment from the FDA,” he said.
Why MLN9708 May Be Effective
MLN9708 is a potent proteasome inhibitor. Phase 2 trials using the parent drug bortezomib, alone or in combination with alkylating agents, have shown “unprecedented high response rates, from 70% to 90%,” Dr Merlini noted (Merlini G. Blood. 2012;119:4343-4345).
“There is grounded hope that MLN9708 will produce significant clinical benefits in these patients. The oral administration also is an important added value, particularly in these fragile patients with limited mobility,” he added.
Patient Inclusion Criteria
The patient inclusion criteria for TOURMALINE-AL1 include age ≥18 years with biopsy-proven systemic relapsed or refractory light-chain amyloidosis, which after at least 1 prior therapy requires further treatment, in the investigator’s opinion. Patients must have received a stem-cell transplant at least 3 months posttransplantation and recovered from side effects; measurable disease, defined as serum differential free light-chain concentration ≥40 mg/L and objective measurable organ (heart of kidney) amyloid involvement; and cardiac biomarker risk stage I or II disease and adequate hematologic, hepatic, and renal function. Any Eastern Cooperative Oncology Group performance status (0-2) is acceptable.
The study excludes patients with peripheral neuropathy that is grade 2 or higher and those with severe diarrhea (≥grade 3) not controllable with medication; who require total parenteral nutrition; who have had major surgery within 14 days of the first study dose; and who have certain cardiac conditions as described in the protocol, swallowing or absorption problems, uncontrolled infection requiring systemic antibiotics, HIV, hepatitis B surface antigen–positive status, known or suspected active hepatitis C infection, another malignancy (with certain exceptions), or a serious physical or psychiatric condition that would be an obstacle to compliance. Pregnant or lactating women are excluded from the trial.