Delanzomib (CEP-18770) in Combination With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

MTD was based on the assessment of dose-limiting toxicity (DLT) during cycle 1 only and was defined as the highest dose at which fewer than one-third of participants in a cohort experience DLT. A DLT was defined as any of the following drug-related toxicities occurring during Cycle 1: Hematologic adverse events (AEs) (Grade 4 hematologic AEs, Grade 3 hematologic AEs with sequelae); Grade 3 nonhematologic AEs; Neuropathy (Grade 2 neuropathy, Grade 1 neuropathy with pain, worsening grade of neuropathy or new symptoms of pain associated with neuropathy); Any other toxicity that, in the judgment of the principal investigator, was a DLT; If a participant cannot receive 75% of the planned dose for any of the 3 agents (missing \>1 dose of CEP-18770, or \>5 doses of lenalidomide, or \>1 dose of dexamethasone \[either consecutively or separately\]), due to a drug-related AE, the event was considered a DLT, even if the grade of toxicity was lower than specified DLT determination as described above.

Time frame: Cycle 1 (28 days)

Population: The MTD determination set included all participants who received at least 3 doses of the study drug during the first cycle. In addition, any participant who experienced a drug related DLT during Cycle 1 was considered evaluable regardless of the number of doses received.

The ORR is defined as percentage of participants who achieve a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) during the study. sCR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; \< 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; and absence of clonal cells in bone marrow. CR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; and \<5% plasma cells in bone marrow. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis; 90% or greater reduction in serum M-protein level and urine M-protein level less than 100 milligrams (mg)/24 hours. PR: ≥50% reduction in serum M-protein level; ≥90% reduction in 24-hour urinary M-protein level or reduction to less than 200 mg per 24 hours; and ≥50% reduction in the size of any soft tissue plasmacytomas present at baseline.

Time frame: From the first administration of CEP-18770 up to approximately 1.5 years

Population: The full analysis set included all participants who received at least 1 dose of CEP-18770 at the MTD, including participants treated at the MTD of CEP-18770 in Part 1 and who had at least 1 response assessment, or who discontinued treatment due to toxicity or death. Participants who did not have a response assessment were considered non-responders.

Time frame: Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1

Population: PK analysis set included all participants for whom at least 1 PK parameter can be calculated. Here, number analyzed = participants evaluable at specified timepoint.

DOR was defined as the time interval from the date of first response (sCR, CR, VGPR, or PR) to the date of disease progression. sCR, CR, VGPR, and PR as defined in outcome measure 1. Disease progression was defined as any 1 or more of the following: Increase of 25% or more from lowest response level in any 1 or more of the following: - serum M-component (absolute increase must be ≥0.5 grams \[g\]/deciliter \[dL\]), - urine M-component (absolute increase must be ≥200 mg/24 hours), bone marrow plasma cell percentage ≥10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; and development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that could be attributed solely to the plasma cell proliferation disorder.

Time frame: From the date of first response to the date of disease progression (up to approximately 1.5 years)

Population: The full analysis set included all participants who received at least 1 dose of CEP-18770 at the MTD, including participants treated at the MTD of CEP-18770 in Part 1 and who had at least 1 response assessment, or who discontinued treatment due to toxicity or death. Participants who did not have a response assessment were considered non-responders. Overall number of participants analyzed = participants with a response of sCR, CR, VGPR, or PR.

Time frame: Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1

Population: The pharmacokinetic (PK) analysis set included all participants for whom at least 1 PK parameter can be calculated. Here, number analyzed = participants evaluable at specified timepoint.

An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Time frame: From the first administration of CEP-18770 up to approximately 1.5 years

Population: Safety analysis set included all participants who received at least 1 dose of CEP-18770.

TTP was defined as the time interval from the date of first dose to the date of disease progression. Disease progression was defined as any 1 or more of the following: Increase of 25% or more from lowest response level in any 1 or more of the following: - serum M-component (absolute increase must be ≥0.5 g/dL), - urine M-component (absolute increase must be ≥200 mg/24 hours), bone marrow plasma cell percentage ≥10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; and development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that could be attributed solely to the plasma cell proliferation disorder.

Time frame: From the date of first dose of study drug to the date of disease progression (up to approximately 1.5 years)

Population: The full analysis set included all participants who received at least 1 dose of CEP-18770 at the MTD, including participants treated at the MTD of CEP-18770 in Part 1 and who had at least 1 response assessment, or who discontinued treatment due to toxicity or death. Participants who did not have a response assessment were considered non-responders.

Time frame: Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1

Population: The PK analysis set included all participants for whom at least 1 PK parameter can be calculated. Here, number analyzed = participants evaluable at specified timepoint.