A Phase 1 Study in Subjects With Relapsed or Refractory Multiple Myeloma

Adverse events, including DLTs, were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT was considered as any of the below, if judged by the investigator to be possibly related to AMG 224: Hematological: * Grade 4 neutropenia lasting \> 7 days * Grade 3 or 4 neutropenia with fever \> 38.5°C * Grade 3 thrombocytopenia with ≥ Grade 2 hemorrhage * Grade 4 thrombocytopenia lasting \> 7 days * Grade 3 anemia with symptoms or required intervention * Grade 4 anemia * Lymphopenia is not considered a DLT Non-hematological: * ≥ Grade 3 nausea, vomiting or diarrhea persisting \> 3 days despite optimal medical support * Grade 3 fatigue persisting \> 7 days * ≥ Grade 3 acute kidney injury lasting \> 3 days * Elevation of aspartate aminotransferase or alanine aminotransferase \>3x to \>8x upper limit of normal (ULT) dependent on criteria * Total bilirubin \> 3x ULN Participants meeting the criteria for Hy's Law case were considered to have a DLT.

Time frame: Day 1 to Day 28

Population: DLT analysis set: all participants who are DLT evaluable. A participant was not DLT-evaluable if the participant discontinued treatment for any reason other than a DLT prior to completing the first 28 days of AMG 224 treatment or did not receive 2 doses of AMG 224 during the 28-day DLT window.

An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that occurred after receiving at least 1 dose of treatment. Treatment-related TEAEs were those considered related to study treatment by the investigator. Any clinically significant changes in ECGs, vital signs, physical examination with a neurologic assessment and clinical laboratory tests were recorded as TEAEs.

Time frame: Day 1 of Cycle 1 to up to the end of Cycle 4, where each cycle is 3 weeks; up to 12 weeks.

Population: Safety analysis set: all participants that are enrolled and received at least 1 dose of AMG 224.

AUC from time zero to 3 weeks (AUC(3 weeks)) was determined for AMG 224 conjugated antibody and total anti-BCMA antibody, and AUC from time zero to 96 hours (AUC(0-96hr)) was determined for DM1.

Time frame: AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycle 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)

Population: The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated. All participants included in the overall number of participants analyzed contributed data to this endpoint.

BOR was the best observed post baseline disease response per IMWG-URC: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to \< 200 mg/24-h. Minor Response (MR): 25-49% reduction of serum M-protein and 50-89% in 24-h urinary M-protein, exceeding 200 mg/24-h. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or Progressive Disease (PD). PD: ≥ 25% increase in serum or urine M-component, development of new or increased size of existing bone lesions or soft tissue plasmacytomas, hypercalcemia attributed to the plasma cell proliferative disorder.

Time frame: Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

Population: Safety analysis set included all participants who received at least 1 dose of AMG 224.

CL of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was determined.

Time frame: AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)

Population: The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated.

DOR was defined as the time between the date of the first observation indicating an objective response as PR (or better) through to the subsequent date of disease progression as classified by the IMWG-URC for Multiple Myeloma or death or where applicable date of censoring. The median DOR was estimated using the Kaplan-Meier method.

Time frame: Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

Population: The safety analysis set included all participants who received at least 1 dose of AMG 224.

Cmax of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured. DM1 is a semi-synthetic derivative of the ansamycin antibiotic, maytansine conjugated to the non-cleavable linker 4-\[N-maleimidomethyl\] cyclohexane-1-carboxylate conjugated to lysine residues in the antibody (MCC).

Time frame: AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, end of infusion (EOI), 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)

Population: The pharmacokinetic (PK) parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated.

Cmin of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.

Time frame: AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)

Population: The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated.

The number of participants who tested positive for pre-existing binding antibodies prior to exposure to AMG 224 and who tested positive for anti-AMG 224 binding antibodies after dosing with AMG 224 are presented. Participants with transient post-baseline results were binding antibody positive post-baseline with a negative or no result at baseline and a negative result at the participant's last timepoint tested.

Time frame: Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

Population: The safety analysis set included all participants who received at least 1 dose of AMG 224.

MRD negative was defined as a tumor load of less than 1 clonal cell in 10\^5 normal cells (as determined by flow cytometry).

Time frame: Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

Population: Safety analysis set: all participants that are enrolled and received at least 1 dose of AMG 224.

The t1/2,z of AMG 224 conjugated antibody, total anti-BCMA antibody and total unconjugated DM1 was measured.

Time frame: AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2)

Population: The PK parameter analysis set included participants who received at least 1 dose of AMG 224 and for whom PK parameters could be adequately estimated. All participants included in the overall number of participants analyzed contributed data to this endpoint.

TTP was the time from the first administration of AMG 224 to the first objective assessment of disease progression as per IMWG-URC or deaths or if applicable date of censoring. The median TTP was estimated using the Kaplan-Meier method

Time frame: Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years

Population: The safety analysis set included all participants who received at least 1 dose of AMG 224.