A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone Versus High-Dose Dexamethasone in Subjects With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study

Celgene455 enrolled

Overview

The purpose of this study is to compare efficacy and safety of pomalidomide in combination with low-dose dexamethasone versus high-dose dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

455

Conditions

Multiple Myeloma

Interventions

pomalidomideDRUG

4 mg pomalidomide capsules administered orally

DexamethasoneDRUG

40 mg dexamethasone (or 20 mg for participants \> 75 years of age) tablets administered orally

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Must be ≥ 18 years of age * Subjects must have documented diagnosis of multiple myeloma and have measurable disease * Subjects must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy * Subjects must have either refractory or relapsed and refractory disease defined as documented disease progression during or within 60 days of completing their last myeloma therapy * All subjects must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib * All subjects must have failed treatment with both lenalidomide and bortezomib in one of the following ways: 1) Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or bortezomib, or 2) In case of prior response \[≥ partial response (PR)\] to lenalidomide or bortezomib, subjects must have relapsed within 6 months after stopping treatment with lenalidomide and/or bortezomib-containing regimens, or 3) Subjects who have not had a ≥ minimal response (MR) and have developed intolerance/toxicity after a minimum of two cycles of lenalidomide- and/or bortezomib-containing regimen * Patients must have received adequate prior alkylator therapy * Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 * Females of childbearing potential (FCBP) must not become pregnant for 28 days prior to initiation of study drug, during the study, and for 28 days after discontinuation * Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation * Males must agree to use a latex condom during any sexual during the study and for 28 days following discontinuation from this study * Males must also agree to refrain from donating semen or sperm while on pomalidomide and for 28 days after discontinuation from this study Exclusion Criteria: * Any of the following laboratory abnormalities: * Absolute neutrophil count (ANC) \< 1,000/μL * Platelet count \< 75,000/ μL for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells * Creatinine clearance \< 45 mL/min * Corrected serum calcium \> 14 mg/dL * Hemoglobin ≤ 8 g/dL * Serum glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase (AST) or transaminase, serum glutamic pyruvic (SGPT)/ alanine aminotransferase (ALT) \> 3.0 x upper limit of normal (ULN) * Serum total bilirubin \> 2.0 mg/dL * Previous therapy with pomalidomide * Hypersensitivity to thalidomide, lenalidomide, or dexamethasone * Resistance to high-dose dexamethasone used in the last line of therapy * Peripheral neuropathy ≥ Grade 2 * Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant * Subjects who are planning for or who are eligible for stem cell transplant * Subjects with any one of the following: 1) Congestive heart failure, 2) Myocardial infarction within 12 months prior to starting study treatment, 3) Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris * Subjects who received any of the following within the last 14 days of initiation of study treatment: 1) Plasmapheresis, 2) Major surgery, 3) Radiation therapy, 4) Use of any anti-myeloma drug therapy * Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of treatment * Subjects with conditions requiring chronic steroid or immunosuppressive treatment * Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study * Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide * Subjects unable or unwilling to undergo antithrombotic prophylactic treatment * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the informed consent form * Pregnant or breastfeeding females * Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis A, B, or C

Locations (94)

Outcomes

Primary Outcomes

Progression-free Survival (PFS) - Primary Analysis

Progression-free survival was calculated as the time from randomization to disease progression as determined by the Independent Response Adjudication Committee based on the International Myeloma Working Group Uniform Response criteria (IMWG), or death on study, whichever occurred earlier. Progressive disease required 1 of the following: • Increase of ≥ 25% from nadir in: o Serum M-component (absolute increase ≥ 0.5 g/dl); o Urine M-component (absolute increase ≥ 200 mg/24 hours); o Bone marrow plasma cell percentage (absolute % ≥ 10%); • Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; • Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease.

Time frame: From randomization until the data cut-off date of 07 September 2012. Maximum duration of follow-up for PFS assessments was 57 weeks.

Progression-free Survival (PFS) With a Later Cut-off Date

Progression-free survival was calculated as the time from randomization to disease progression as determined by the Independent Response Adjudication Committee based on the International Myeloma Working Group Uniform Response criteria (IMWG), or death on study, whichever occurred earlier. Progressive disease requires 1 of the following: • Increase of ≥ 25% from nadir in: o Serum M-component (absolute increase ≥ 0.5 g/dl); o Urine M-component (absolute increase ≥ 200 mg/24 hours); o Bone marrow plasma cell percentage (absolute % ≥ 10%); • Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas; • Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dl) attributed solely to plasma cell proliferative disease.

Time frame: From randomization until the data cut-off date of 01 March 2013. Maximum duration of follow-up for PFS assessments was 74 weeks.

Secondary Outcomes

Number of Participants With Adverse Events (AEs)

An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death.

Data from ClinicalTrials.gov

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Mayo Clinic

Rochester, Minnesota, United States

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Peter MacCallum Cancer Institute

East Melbourne, Victoria, Australia

Frankston Hospital

Frankston, Victoria, Australia

Princess Alexandra Hospital

Brisbane, Australia

Royal Prince Alfred Hospital

Camperdown, Australia

Alfred hospital

Melbourne, Australia

Sir Charles Gairdner Hospital

Nedlands, Australia

Calvary Mater Hospital

Waratah, Australia

Border Medical Oncology

Wodonga, Australia

...and 84 more locations

Time frame: From first dose of study drug through to 30 days after the last dose as of the end of the study (29 August 2017); maximum time on treatment was 297, 269, and 239 weeks in the Pomalidomide + LD-Dex, HD-Dex, and cross-over groups respectively.

Overall Survival - Primary Analysis

Overall survival is calculated as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.

Time frame: From randomization until the data cut-off date of 07 September 2012. Maximum time on follow-up for survival was 70 weeks.

Overall Survival With a Later Cut-off Date

Time frame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up for survival was 93 weeks.

Overall Survival Based on the Final Dataset

Time frame: From randomization until the data cut-off date of 29 August 2017. Maximum time on follow-up for survival was 324 weeks.

Percentage of Participants With an Objective Response According to International Myeloma Working Group (IMWG) Uniform Response Criteria

Objective response is defined as a best overall response of stringent complete response (SCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the Independent Response Adjudication Committee: SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, 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 or ≥ 90% reduction in serum M-protein and urine M-protein level \< 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to \< 200 mg/24 hours. In addition to the above, if present at baseline a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required.