Efficacy and Safety of Carfilzomib in Combination with Ibrutinib Compared with Ibrutinib Alone in Waldenström's Macroglobulinemia

Waldenström macroglobulinemia (WM) is a slow-growing form of B-cell non-Hodgkin lymphoma (NHL). NHLs are malignant diseases of the lymphatic system that can affect the bone marrow, lymph nodes, and many other organs and tissues in the body. What makes WM unique is that the affected cells produce antibodies, which normally play an important role in the body’s immune defense. In WM, however, these antibodies cause additional, sometimes dangerous symptoms. Symptoms may include fatigue, anemia, an increased tendency to bleed, hearing and vision loss, nerve-related symptoms, kidney dysfunction, swollen lymph nodes, and an enlarged liver and spleen. Other symptoms that may be observed include fever, weight loss, and night sweats. The exact causes of WM are not yet fully understood, but genetic mutations play a role in the development and progression of the disease. Treatment is often necessary (at least during the course of the disease) and may involve chemotherapy, immunotherapy, or targeted therapy. “Targeted” means that medications recognize specific structures within the malignant cells and cause the cancer cells to be destroyed. This includes, for example, treatment with ibrutinib. Ibrutinib inhibits an enzyme that promotes the proliferation of cancer cells and was approved by the European Medicines Agency (EMA) in 2015 for the treatment of WM. The problem is that, to date, none of the available therapies consistently halt the progression of the disease, although ibrutinib is currently one of the most effective treatments.

Carfilzomib is a so-called proteasome inhibitor that disrupts the metabolism of cancer cells, causing them to die. The drug is already approved for other conditions.

The goal of this Phase 2 study is to compare the efficacy of treatment with carfilzomib in combination with ibrutinib to that of ibrutinib monotherapy. As part of the study, patients will be randomly assigned to 2 groups. Both groups will receive daily doses of ibrutinib in tablet form. Group 1 will additionally receive carfilzomib as an intravenous infusion over 24 cycles during the first 2 years. After the two years, treatment in both groups will continue with ibrutinib alone and will be discontinued if the disease progresses again or if intolerable side effects occur. The study is open-label, meaning that both the doctor and the patient know which medication is being administered. The primary endpoint of the study is the complete remission rate and very good partial remission rate after 12 months. The study will evaluate the efficacy of the therapy and the occurrence of side effects from the various medications over a total duration of up to 7 years. The key factor is whether or when the disease progresses again during treatment.

Patients aged 18 and older who have Waldenström macroglobulinemia (WM) are eligible to participate in the study; there are no restrictions regarding specific characteristics of the WM or prior treatments.