The purpose of this study is to determine the maximum-tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ION251 in patients with relapsed/refractory multiple myeloma.

This is a two-part, multi-center first in human study of ION251 in up to 80 participants. Part 1 will use a 3+3 dose-escalation scheme in sequential cohorts to determine the MTD and RP2D during repeated 28-day treatment cycles. MTD will be determined by the number of participants with AEs meeting the dose-limiting toxicity (DLT) criteria during Cycle 1. The MTD determined in Part 1 will be used with other variables to inform a RP2D for participants proceeding to Part 2 for further assessments in the safety, tolerability and anti-myeloma activity.

Inclusion Criteria:

1. Aged ≥ 18 years at the time of informed consent
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
3. Measurable multiple myeloma (MM)
4. In need of systemic treatment for MM and either is refractory to or has failed treatment with, is intolerant to or has refused, or is not otherwise a candidate in the opinion of the Investigator, for any of the currently available established therapies known to provide clinical benefit in relapsed/refractory MM. Refractory to treatment is defined as documented MM disease progression while on or within 60 days from the last dose (LD) of treatment

Exclusion Criteria:

1. Screen laboratory results as follows, or any other clinically significant abnormalities in screen laboratory values that would render a participant unsuitable for inclusion

   • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN)
   • Total bilirubin > 1.3 × ULN
   • Absolute neutrophil count ≤ 1.0 1000/cubic millimeter (k/mm^3)
   • Platelet count < 50 k/mm^3
   • Hemoglobin < 8.0 g/dL
   • Estimated glomerular filtration rate (eGFR) < 50 milliliters per minute (mL/min)/1.73 square meter (m^2)
   • Urine albumin creatinine ratio > 100 mg/g

2. History of or current plasma cell leukemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, and skin changes) syndrome, solitary bone or extramedullary plasmacytoma as the only evidence for plasma cell dyscrasia, myelodysplastic syndrome or a myeloproliferative neoplasm

3. Uncontrolled hypertension (systolic pressure ≥ 160 mm of mercury (mm Hg) and/or diastolic pressure ≥ 100 mm Hg)

4. Presence of a bleeding disorder or an underlying disease state associated with active bleeding.