A Study of TTI-622 in Combination With Daratumumab Hyaluronidase-fihj in People With Multiple Myeloma

Inclusion Criteria:

• Patients with relapsed or refractory multiple myeloma, as defined by theinternational myeloma working group (IMWG) updated criteria (Appendix A) who havemeasurable disease defined by one or more of the following:

1. Serum myeloma (M)-protein greater than or equal to 0.5 g/dL (5 g/L).

2. Urine M-protein greater or equal to 200 mg/24 h.

3. Involved light chain (either kappa or lambda) is >10 mg/dL with an abnormalkappa: lambda ratio.

4. A biopsy proven plasmacytoma(s) that is new or definitely increased. Increaseis defined as a 50% and at least 1 cm increase as measured serially by the sumof the products of the cross-diameters of the measurable lesion.

• Patients must have received at least 3 prior lines of therapy not having receivedDaratumumab Hyaluronidase-fihj in the last line of therapy, and have been previouslyexposed to a proteasome inhibitor, an IMiD and be considered refractory to an FDAapproved anti-CD38 mAb used either in combination or as a single agent. Refractoryis defined as progression on or within 60 days of receiving a treatment programcontaining an anti-CD38 monoclonal antibody.

• Female or male patients age ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2. PS-3 ispermitted if PS is due solely to bone pain.

• Adequate hematological function including:

1. Absolute neutrophil count (ANC) >1,000/mm^3 (unless myelosuppression issecondary to bone marrow plasmacytosis expressed by >50% of cellularity).

2. Platelet count >75,000/mm^3 for the dose finding portion, and > 50,000/ mm^3for the expansion part.(transfusion is not permitted within 7 days ofenrollment)

3. Hemoglobin ≥8.0 g/dL (transfusion support is not permitted within 7 days ofenrollment).

• Adequate Renal Function defined by: a. Estimated creatinine clearance >30 mL/min as calculated using the CKD-EPIequation. (If an estimated creatinine clearance CrCl is believed to be inaccuratefor a patient, 24-hour urine collection with actual assessment of CrCl is allowed)

• Adequate Liver Function, including:

1. Aspartate and alanine aminotransferase (AST and ALT) < 2.5 x upper limit ofnormal (ULN); <5.0 x ULN if there is liver involvement by the tumor.

2. Alkaline phosphatase <2.5 x ULN (<5 x ULN in case of bone metastasis).

3. Total bilirubin < 2.0 mg/dL, except in patients with Gilbert Syndrome who musthave a total bilirubin less than 3.0 mg/dL.

• Seronegative for Hepatitis B surface (HBs) or Hepatitis B core (HBc) antigens.Patients with positive antigens must be tested for hepatitis B virus (HBV) byreverse transcription polymerase chain reaction (RT-PCR). Patients who are HBV RNAnegative are eligible.

• Seronegative for hepatitis C antibody. If hepatitis C antibody test is positive,patients must be tested for the presence of antigen by RT-PCR. Patients who arehepatitis C virus (HCV) RNA negative with adequate liver function as described aboveare eligible.

• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤ 1,with the exception of peripheral neuropathy attributable to bortezomib.

• Serum pregnancy test (for females of childbearing potential) negative at screening.Female patients of non-childbearing potential must meet at least 1 of the followingcriteria:

1. Achieved postmenopausal status, defined as follows: cessation of regular mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; status may be confirmed with a serum follicle stimulatinghormone (FSH) level confirming the postmenopausal state.

2. Have undergone a documented hysterectomy and/or bilateral oophorectomy. Havemedically confirmed ovarian failure. All other female patients (includingfemale patients with tubal ligations) are considered to be of childbearingpotential.

• Signed and dated Informed Consent by study participant and/ or Legally AuthorizedRepresentative (LAR).

• Willing and able to comply with scheduled visits, treatment plan, laboratory tests,and other procedures.

Exclusion Criteria:

• Patients with other malignancies in addition to multiple myeloma are not eligible ifthe other malignancy has required treatment within the past 3 years or is not incomplete remission with the exceptions of successfully treated non-metastatic basalcell carcinoma, squamous cell skin carcinoma, or in-situ carcinoma.

• History of active autoimmune disorders (including but not limited to: Crohn'sdisease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave'sdisease) and other conditions that require systemic therapy, which may compromise orimpair the immune system.

• Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

• Patients with active uncontrolled bacterial, fungal or viral infection, includingknown human immunodeficiency virus (HIV) infection or acquired immunodeficiencysyndrome (AIDS) related illness.

• Major surgery within 4 weeks prior to study entry.

• Radiation therapy within 2 weeks prior to study entry (bone lesions requiringradiation may be treated with limited [i.e., ≤ 25% of bone marrow in field]radiation therapy during this period).

• Patients with a history of stem cell transplant (autologous or allogeneic) within 100 days prior to study enrollment.

• Donor Lymphocyte Infusion (DLI) within 30 days prior to study entry.

• Therapy with a monoclonal antibody, including but not limited to antiCD38 antibody,elotuzumab, T or NK cell re-directing therapy (ex. bispecific therapy), orantibody-drug conjugate within 30 days of study treatment initiation. Treatment withother anti-multiple myeloma therapies within 14 days of study treatment initiation.

• Patient known to be refractory to platelet or red blood cell transfusions.

• Any of the following in the previous 6 months: myocardial infarction,severe/unstable angina, coronary/peripheral artery bypass graft, symptomaticcongestive heart failure (CHF, New York Heart Association Class III or IV),cerebrovascular accident, transient ischemic attack or symptomatic pulmonaryembolism.

• Fertile male patients and female patients of childbearing potential who areunwilling or unable to use a highly effective method of contraception as outlined inthis protocol for the duration of the study and for at least 28 days after the lastdose of investigational product.

• Other acute or chronic medical or psychiatric condition, including recent (withinthe past year) or active suicidal ideation or behavior or laboratory abnormalitythat may increase the risk associated with study participation or investigationalproduct administration or may interfere with the interpretation of study resultsand, in the judgment of the investigator, would make the patient inappropriate forentry into this study.