Inclusion Criteria:

• ≥ 18 years of age.
• MM patients (for Arm A and Arm B): Patients with Relapsed/Refractory MM per 2016 IMWG criteria, previously treated with at least 1 prior line of therapy for MM. Refractory MM, meanwhile, is defined as disease that fails to reach minimal response (MR) or progresses on salvage therapy or progresses within 60 days of the last treatment. AL amyloidosis patients (for Arm C ONLY): Patients with AL amyloidosis when meeting:
  • histochemical diagnosis based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, the type must have been confirmed unequivocally;
  • have symptomatic organ involvement as defined by Appendix J. Only purpura and/or carpal tunnel syndrome are not acceptable;
  • have at least one prior line of systemic therapy for AL. Patients who do not achieve at least a PR to frontline therapy in 3 months are eligible.
• All MM/AL patients should have measurable disease as defined by at least ONE of the following:
  • Serum monoclonal protein ≥ 1.0 g/dl by protein electrophoresis;
  • > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis;
  • If either serum or urine monoclonal proteins not meet above measurement threshold, patients should be included following FLC concentration:
  • AL patients: Serum differential FLC concentration (dFLC, difference between amyloid forming [involved] and nonamyloid forming [uninvolved] free light chain [FLC]) > 5 mg/dL; OR serum FLC of 7.5 mg/dL provided the κ/λ FLC ratio is abnormal (κ/λ 1.65 for patients with monoclonal κ FLC);
  • MM patients: involved FLC level ≥10 mg/dL provided serum FLC ratio is abnormal (κ/λ 1.65 for patients with monoclonal κ FLC).
• Eastern Cooperative Oncology Group (ECOG) ≤ 2.
• Life expectancy ≥ 6 months.
• Adequate hematologic function defined as:
  • ANC ≥ 1.0 x 10^9/L independent of growth factor support within 7 days of the first dose with study drug;
  • Hemoglobin ≥ 8 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug;
  • Platelet count ≥ 50 x 10^9/L without transfusion support within 7 days of the first dose of study drug.
• Adequate hepatic and renal function defined as:
  • AST and ALT < 3 x ULN (upper limit of normal);
  • Creatinine clearance > 30mL/min;
  • Bilirubin< 1.5 x ULN (Except if considered secondary to Gilbert’s syndrome and primarily indirect bilirubinemia).
• PT/INR ≤ 2 x ULN and PTT (or aPTT) ≤ 2 x ULN.
• Female subjects who are of non-reproductive potential (i.e., post-menopausal by history- no menses for ≥ 2 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
• Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug.
• Ability to complete questionnaire(s) by themselves or with assistance (For AL amyloidosis
  patients only).

Exclusion Criteria:

• 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.
• Subject has received antineoplastic therapy within 2 weeks before the date of initiating study treatment.
• Subject has previously received an allogenic stem cell transplant (regardless of timing).
• 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.
• 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).
• For Arm A/C only: The subjects show evidence of intolerance to pomalidomide, which is defined as subjects discontinued pomalidomide permanently due to recurrent G3 or G4 AEs related to prior pomalidomide treatment (dose interruption or reduction per label is acceptable).
• For Arm B only: The subjects show evidence of intolerance to daratumumab or lenalidomide, which is defined as subjects discontinued daratumumab or lenalidomide permanently due to recurrent G3 or G4 AEs related to prior daratumumab or lenalidomide treatment (dose interruption or reduction per label is acceptable).
• 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.
• 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).
• Plasmapheresis < 35 days prior to the initiation of study drug. (in order to obtain a true baseline M-protein value for efficacy evaluations).
• Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of prior treatment for MM or AL amyloidosis.
• 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.
• 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.
• 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.
• Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug.
• 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).
• 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. 18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/11/24. Questions regarding updates should be directed to the study team contact.