Inclusion Criteria:

• Informed consent signed by the patient.
• ≥ 18 years of age.
• Confirmed diagnosis of symptomatic MM per IMWG criteria.
• Measurable disease as defined by one or more of the following:
  • Serum M-protein ≥ 0.5 g/dL;
  • Urine M-protein ≥ 200 mg/24 hours;
  • Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL provided serum FLC ratio is abnormal;
  • In cases where SPEP is unreliable, serum quantitative immunoglobulin (qIgA) ≥ 500 mg/dL (0.5 g/dL) is acceptable;
  • In patients with non-secretory disease, bone marrow plasmacytosis of ≥ 30%. Patients must have bi-dimensional measurable disease.
• Relapsed or refractory [Rajkumar 2011] to at least 3 prior systemic lines of therapy for MM, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), chemotherapies, or monoclonal antibodies, and not a candidate for, or intolerant to established therapy known to provide clinical benefit:
  • Relapse defined as progression of disease after an initial response (MR or better) to previous treatment, more than 60 days after cessation of treatment;
  • Refractory disease defined as < 25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment;
  • Progressed on the final line of therapy received before being considered for this study.
• If not menopausal or surgically sterile (female and male), patients must be willing to practice at least two highly effective methods of birth control for at least one of their or their partner’s menstrual cycle before and for 3 months after study drug administration.
• Eastern Cooperative Oncology Group status 0-1.
• Resolution of prior therapy-related AEs (including immune-related AEs but excluding alopecia) to ≤ Grade 1 (except for Grade 2 peripheral neuropathy) per CTCAE.
• Minimum of 2 weeks or 5 half-lives since last dose of other systemic cancer therapy or radiotherapy. Palliative radiation to localized sites is permitted in Phase 2.
• Adequate organ function as indicated by the following lab values:
• Hematological:
  • Neutrophils ≥ 1,000/µL;
  • Platelets ≥ 100,000/µL;
  • Hemoglobin* ≥ 9g/dL.
• Renal:
  • eGFR (CKD-EPI calculation) ≥ 30 mL/min/1.73m^2.
• Hepatic:
  • Serum total bilirubin ≤ 1.5 x ULN; or
  • Direct bilirubin ≤ ULN for patients with total bilirubin >1.5 x ULN.

Exception for elevated bilirubin secondary to Gilbert’s disease. Confirmation of Gilbert’s diagnosis requires: elevated unconjugated (indirect) bilirubin values; normal CBC in previous 12 months), blood smear and reticulocyte count; normal transaminases and alkaline phosphatase in previous 12 months.

• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases.
  Transfusion and/or erythropoietin not permitted within 1 week prior to blood draw

• Patient consents to a fresh bone marrow biopsy at screening (once all other entry criteria have been satisfied).
• Patient consents to a potential on-treatment bone marrow biopsy.
• Able and willing to comply with the protocol and the restrictions and assessments therein.

Exclusion Criteria:

• < 18 years of age.
• Monoclonal gammopathy of undetermined significance, smoldering myeloma, Waldenstrom’s macroglobulinemia.
• History of plasma cell leukemia.
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome.
• Previous Grade 3-4 infusion or hypersensitivity reaction (not immunotoxicity) to treatment with another mAb.
• Previous history of severe asthma, or within the past year, history of exacerbations of chronic obstructive pulmonary disease requiring either hospital admission or steroids.
• History of clonal mast cell disorder.
• Hereditary alpha tryptasemia (Screening tryptase result must be available prior to starting AO-176 study drug).
• Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4, etc.) within 4 weeks.
• Prior treatment with a therapeutic agent that targets the CD47 axis.
• Autologous stem cell transplant, chimeric antigen receptor T-cell treatment, or bone marrow transplant within 12 weeks prior to first dose of study drug.
• Platelet or RBC transfusion within 1 week of Screening blood draw.
• Patients at high thrombotic risk in whom antithrombotic medications cannot be withheld for short periods. These include, but are not limited to, patients with a history of multiple or clinically severe venous thromboembolism (VTE), or a severely hypercoagulable condition such as antiphospholipid antibody syndrome. Patients receiving dual antiplatelet therapy (DAPT) are excluded.
• Prior organ transplant.
• History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
• History of any condition known to be associated with reduced RBC lifespan (e.g., thalassemia trait, G6PD deficiency).
• History of Evans syndrome.
• Active autoimmune disease or history of severe allergic diathesis or anaphylaxis.
• Bleeding diathesis, or other known risk for acute blood loss.
• Known active central nervous system myeloma.
•  Active known second malignancy with the exception of any of the following:
  • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer;
  • Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for ≥ 2 years;
  • Low-risk prostate cancer with Gleason score 350/mm^3 and undetectable viral load) are eligible.
• Current active liver disease from any cause, including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative.
• Use of systemic corticosteroids (> 10 mg prednisone or equivalent) within 15 days (except for prophylaxis for radiodiagnostic contrast reactions), or other immunosuppressive drugs within 30 days, prior to start of the study (except for IRR prophylaxis).
• Phase 1 Part 1 Expansion (Cohort 1E), Phase 1 Part 2 (Cohorts 2A, 2B), and Phase 2 Part 2 only:
  • Presence of condition for which dexamethasone is contraindicated (e.g., active viral or fungal disease, uncontrolled psychoses, receipt of live viral vaccine in prior 30 days); or
  • Prior adverse reaction or intolerance to dexamethasone that resulted in treatment discontinuation.
• Receipt of an investigational product or been treated with an investigational device within 30 days prior to first drug administration.
• Any of the following within 6 months before Baseline Day 1:
  • Myocardial infarction;
  • Unstable angina;
  • Unstable symptomatic ischemic heart disease;
  • New York Heart Association Class III or IV heart failure;
  • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events);
  • Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease).
• Electrocardiogram (ECG) QT interval corrected for heart rate (QTc) > 480 msec, measured by Fridericia's formula [QTcF = QT/(RR^0.33)]. If the QTc is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the Medical Monitor.
• Any other medical or psychiatric condition that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives of the protocol or completion of treatment per protocol.
• Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of participation in the study.
• Phase 1 Part 2 (Cohorts 2A and 2B), and Phase 2 Part 2 only: patients with a history of bortezomib hypersensitivity.
• Phase 1 Part 2 (Cohorts 2A and 2B) and Phase 2 Part 2 only: patients with a history of bortezomib-related hypotension. (Hypotension, as indicated by systolic blood pressure 20 mmHg decrease in systolic blood pressure 1 minute or more after assuming upright position).
• Phase 1 Part 2 (Cohorts 2A and 2B) and Phase 2 Part 2 only: use of St. John’s Wort within 2 weeks prior to Cycle 1 Day 1.