Disclosed herein are methods, compositions, and kits for treating a B-cell malignancy comprising administering a combination of a BTK inhibitor (e.g., ibrutinib) and a BET inhibitor. Also disclosed herein are methods, compositions, and kits for treating a BTK-resistant B cell malignancy, or a MYC-driven B cell malignancy comprising administering a combination of a BTK inhibitor (e.g., ibrutinib) and a BET inhibitor. Further disclosed herein are methods of evaluating a patient having a B-cell malignancy for treatment with a combination of a BTK inhibitor (e.g., ibrutinib) and a BET inhibitor based on the MYC expression level of the patient.
