Possible New Treatment Option for Patients with Relapsed/Refractory Systemic Amyloid Light Chain Amyloidosis

The drug combination of ixazomib and dexamethasone significantly improved outcomes in patients with relapsed or refractory systemic amyloid light chain amyloidosis, but did not improve hematologic response, according to results from a phase 3 clinical trial called TOURMALINE-AL1.

“TOURMALINE-AL1 is the first phase 3 trial in relapsed/refractory systemic amyloid light chain amyloidosis to show significant outcome improvements, suggesting ixazomib/dexamethasone represents a new option for relapsed/refractory patients who have limited access to therapies,” said Angela Dispenzieri, MD, one of the study’s lead investigators.

Clinical trials are designed to test the safety and effectiveness of new drugs. Phase 3 clinical trials like TOURMALINE-AL1 are carried out to confirm and expand on safety and effectiveness results from phase 1 and 2 trials, to compare the new treatment to the standard therapies that have already been approved, and to study the overall risks and benefits of the drug. Trials in this phase can last years, and can involve thousands of people.

The primary end point of this trial was achievement of hematologic response (when blood cell counts go back to normal), and that was not achieved in the patients who were treated with this drug combo. The primary end point is the main result measured at the end of a study to see if a treatment worked. Although the primary end point was not achieved in this study, the investigators were able to learn other important things about the effects of this particular treatment in this particular population of patients, and they saw that it did improve outcomes other than hematologic response.

Currently, no treatments have been approved for amyloid light chain amyloidosis, but doctors typically use treatment strategies that are commonly used for multiple myeloma.

The patients in this trial had systemic amyloid light chain amyloidosis that was relapsed or refractory to other treatments. The term “relapsed” refers to patients whose disease re-appeared or grew again after a period of remission. “Refractory” is used to describe a person whose disease did not respond to treatment, or whose response to treatment did not last very long.

Systemic amyloid light chain amyloidosis is a disease that occurs when a person’s antibody-producing cells don’t function properly (antibodies fight off diseases in the body). But in patients with this disease, the bone marrow produces abnormal antibodies that can’t be broken down. These are deposited into tissues and organs (most often the heart and kidneys), leading to organ dysfunction and failure. However, achievement of hematologic response in these patients results in improved organ function and better survival (the reason it was the primary end point of this study).

The trial included 168 patients with primary systemic amyloid light chain amyloidosis who were relapsed or refractory after 1 or 2 previous therapies. Eighty-five patients received ixazomib/dexamethasone, and 83 patients were given physician’s choice of treatment.

Although hematologic responses were seen in about half of the patients in the study, the rates were not significantly different between the 2 groups, so the primary end point was not met. However, the duration of hematologic response was longer in patients treated with ixazomib/dexamethasone.

But according to Dr. Dispenzieri, the investigators were able to collect other important data that showed a significant benefit with ixazomib/dexamethasone versus physician’s choice.

Higher rates of complete response were achieved with the ixazomib/dexamethasone treatment: 26% versus 18% with physician’s choice. Response rates are one way to tell how effective a treatment is, and responses are divided into categories like “complete” and “partial,” depending on how well a patient did after treatment.

Multiple other outcomes were also improved with ixazomib and dexamethasone, such as overall survival, progression-free survival, time to vital organ deterioration or death, duration of response, time to treatment failure, and time to subsequent therapy. Progression-free survival is the length of time that a person lives with their disease without it getting any worse; overall survival is the length of time from the start of treatment that patients diagnosed with a particular disease—such as cancer—are still alive.

Importantly, vital organ response rates (related to organs like the heart and kidneys) were better with the 2-drug treatment compared with doctor’s choice: 36% versus 11%.

Serious side effects were seen at a slightly higher rate with ixazomib and dexamethasone, but because the treatment was so well-tolerated, patients who were given the 2-drug combo received treatment for twice as long as those who received physician’s choice of treatment, and therefore had more time to experience side effects.

But overall, the new treatment was well-tolerated, and the investigators didn’t observe any new safety concerns.