This phase I/II trial is evaluating how safe, tolerable and effective a new targeted therapy (APG-2575) is when combined with other treatment regimens (Pd or DRd) in people with relapsed or refractory multiple myeloma and immunoglobin light chain amyloidosisA Phase Ib/II Open-Label Study of APG-2575 in Combination With Novel Therapeutic Regimens in Subjects With Relapsed or Refractory Multiple Myeloma and Immunoglobin Light Chain Amyloidosis

Exclusion

1. MM patients with newly diagnosed MM, previously untreated for MM or only had been treated with localized palliative treatment or steroids less than equivalent of dexamethasone 40 mg daily for 4 days). AL amyloidosis patients with AL amyloidosis have not been treated with any systemic therapy, or AL amyloidosis clinically overt multiple myeloma i.e. original CRAB criteria. Extent of marrow plasmacytosis is not prohibitive.
2. Subject has received antineoplastic therapy within 2 weeks before the date of initiating study treatment
3. Subject has previously received an allogenic stem cell transplant (regardless of timing)
4. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, i.e., these subjects should not be enrolled in order to reduce disease burden prior to transplant.
5. BCL-2-directed therapy within 4 weeks of initiating study treatment. (BCL-2 directed therapy more than 4 weeks before initiation of study treatment is allowed).
6. For Arm A/C only: The subjects show evidence of intolerance to pomalidomide, which is defined as subjects discontinued due to any AEs related to prior pomalidomide treatment
7. For Arm B only: The subjects show evidence of intolerance to daratumumab or lenalidomide, which is defined as subjects discontinued due to any AEs related to prior daratumumab or lenalidomide treatment
8. Patients with any uncontrolled active systemic infection, including but not limited to active hepatitis B or C virus infection, known human immunodeficiency virus (HIV) positive
9. Subject has peripheral neuropathy ≥grade 3 except caused by AL amyloidosis
10. Subject has plasma cell leukemia (>2.0*10^9/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
11. Plasmapheresis <35 days prior to the initiation of study drug
12. Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior treatment for MM or AL amyloidosis
13. Unable to swallow tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
14. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia (including Frederica corrected QT interval (QTc) ≥470 msec ) or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to initiating study treatment
15. Major surgical procedure within ≤14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment, radiotherapy ≤14 days prior to initiating study treatment, systemic treatment within 14 days before the first dose of APG-2575
16. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug
17. Vaccinated with live, attenuated vaccines within 4 weeks of initiation of APG-2575 (for patients' safety, patients could receive COVID-19 vaccination before or during study period as judged by HCP as beneficial)
18. Subject has any concurrent or recent malignancy ≤ 1 year prior to registration with the exception of: basal or squamous cell skin cancer, any carcinoma in situ. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
19. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
20. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
21. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
22. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study