A Study to Compare MPR With MP in Newly Diagnosed Multiple Myeloma Subjects 65 Years Old or Older.

Celgene Corporation459 enrolled

Overview

The purpose of this study is to determine whether lenalidomide is safe and effective in the treatment of patients with newly diagnosed Multiple Myeloma who are 65 years of age or older.

The three phases for the study as originally defined and as represented in the results of 11 May 2010 are: Double-blind Treatment Phase: Induction Melphalan/prednisone and lenalidomide 10 mg (MPR) (2 treatment arms), or melphalan/prednisone and placebo (MPp) (1 treatment arm) for up to 9 cycles. If disease progression, subjects have the option to enter into the Open-Label Extension Phase. There is also an option to enter into the Follow-Up Phase. If the disease has not progressed, subject can continue on blinded therapy into Maintenance. Double-blind Treatment Phase: Maintenance One MPR treatment arm (MPR+R) will continue taking lenalidomide 10 mg in Maintenance. The other MPR treatment arm (MPR+p) will take placebo in Maintenance. The MP p treatment arm will take placebo in Maintenance (MPp+p). If disease progression, subjects have the option to enter the Open-Label Extension Phase to obtain treatment with lenalidomide, or to enter into the Follow-up Phase. Open-label Extension Phase: Treatment consists of oral lenalidomide (up to 25 mg) with or without dexamethasone until disease progression or treatment is discontinued for any reason until all study subjects are followed for at least 5 years from the date of randomization or have died. Subjects who discontinue from the Open-Label Extension Phase prior to completing a total of 5 years in the study will enter the Follow-up Phase. Follow-up Phase: Subjects are followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects in this study are followed for at least 5 years from randomization or have died. The pre-planned interim analysis for the Independent Data Monitoring Committee (IDMC) showed that the difference in progression-free survival (PFS) between treatment arms MPR+R and MPp+p (the defined primary comparative analysis for this study) surpassed the pre-specified O'Brien-Fleming boundary for superiority. The IDMC recommended the release of this information to the sponsor and also recommended that all patient and physician study participants receive information concerning the full findings of the MM-015 interim analysis. Therefore, due to these recommendations from the IDMC, treatment-arm codes were sent to the clinical trial centers to unblind the treatment arms of their study subjects once the amended protocol was reviewed and approved by the respective country Health Authorities and Ethics Committees. Subject participation in the MM-015 study continued after unblinding to obtain long-term data for all study endpoints, including overall survival. When the study was unblinded, subjects still on protocol therapy had completed the Double-Blind Induction, and were on monotherapy in Double-Blind Maintenance. Subjects in arm MPR+R continued their monotherapy on lenalidomide. Subjects in arms MPR+p and MPp+p discontinued their placebo monotherapy and went into an observation period in which no antimyeloma therapy was taken. If disease progressed for any subject, the investigator had the option of entering the subject in Open Label Extension Phase to receive lenalidomide therapy (up to 25 mg daily) or the Follow-up Phase. All subjects were to be followed for at least 5 years from the start of the study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

459

Conditions

Newly Diagnosed Multiple Myeloma

Interventions

Lenalidomide: Double-blind InductionDRUG

Double-blind Induction: the starting lenalidomide oral dosing regimen was 10 mg once daily on Days 1 through 21 of each 28 day cycle for up to 9 cycles. Dose was reduced if needed due to dose-limiting toxicity.

MelphalanDRUG

Double-blind Induction: the starting melphalan oral dosing regimen in all 3 treatment arms was 0.18 mg/kg daily on Days 1 through 4 of each 28-day cycle for up to 9 cycles. Dose was reduced if needed due to dose-limiting toxicity.

PrednisoneDRUG

Double-blind induction: the starting prednisone oral dosing regimen in all 3 treatment arms was 2 mg/kg daily on Days 1 through 4 of each 28-day cycle for up to 9 cycles. Dose was reduced if needed due to dose-limiting toxicity.

Eligibility

Sex: ALLMin age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Must understand and voluntarily sign an informed consent form 2. Age greater than or equal to 65 years at the time of signing the informed consent 3. Newly diagnosed with symptomatic multiple myeloma as defined by the 3 criteria below: MM diagnostic criteria (all of next 3 required) 1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma 2. Monoclonal protein present in the serum and/or urine 3. Myeloma-related organ dysfunction (at least one of the following) \[C\] Calcium elevation in the blood (serum calcium \>10.5mg/dl or upper limit of normal) \[R\] Renal insufficiency (serum creatinine \>2mg/dl) \[A\] Anemia (hemoglobin \<10g/dl or 2g \< normal) \[B\] Lytic bone lesions or osteoporosis AND have measurable disease as defined by the following; IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgA multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgD multiple myeloma: Serum M-protein level greater than or equal to 0.05 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours Light chain multiple myeloma: Serum M-protein level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level greater than or equal to 1.0g/dL or urine M-protein level greater than or equal to 200mg/24hours 4. Karnofsky performance status greater than or equal to 60%. 5. Able to adhere to the study visit schedule and other protocol requirements. 6. Women of Childbearing potential (WCBP) must: a. Have a negative medically supervised pregnancy test prior to the start of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices and continues sexual abstinence. b Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy. 7. Males Subjects must: 1. Agree to use a condom during sexual contact with a WCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after the cessation of study therapy. 2. Agree to not donate semen during study drug therapy and for a period after end of study drug therapy. 8. All subjects must 1. Have an understanding that the study drug could have potential teratogenic risk. 2. Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. 3. Agree not to share study medication with another person. 4. All patients must be counseled about pregnancy precautions and risks of fetal exposure. Female Subjects: Females of childbearing potential (FCBP) with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following discontinuation from the study. In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she is continuing to use two reliable methods of birth control at each visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood. Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation. Females must agree to abstain from breastfeeding during study participation and for at least 28 days after the discontinuation from the study. Male Subjects: Counseling about the requirement for latex condom use during sexual contact with females of childbearing potential and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood, sperm, or semen. If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a study subject during study participation, study drug must be immediately discontinued. Exclusion Criteria 1. Previous treatment with antimyeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \[i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 28 days \[4 weeks\] of randomization\]). 2. Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds experimental the ability to interpret data from the study. 3. Pregnant or lactating females. 4. Radiotherapy within 14 days (2 weeks) of randomization. 5. Plasmapheresis within 28 days (4 weeks) of randomization. 6. Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) \< 1,500 cells/mL (1.5\*10\^9/L) Platelet count \< 75,000 cells/uL (75\*10\^9/L) for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells; but platelet count \<30,000/uL for subjects in whom \>= 50% of bone marrow nucleated cells are plasma cells Haemoglobin \< 8.0 g/dL (80 g/L) Serum creatinine \> 2.5 mg/dL (221 µmol/L) Serum aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) \> 3.0 times upper limit of normal (ULN) 7. Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for greater than or equal to 3 years. Exceptions include the following: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b) 8. Neuropathy of \>= grade 2 severity. 9. Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis, type A, B or C.

Locations (98)

Outcomes

Primary Outcomes

Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC)

Data as of 11 May 2010 cutoff. PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry \[EBMT/IBMTR/ABMTR\] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Time frame: up to 165 weeks

Secondary Outcomes

Kaplan Meier Estimates of Progression-free Survival (PFS) From Start of Maintenance Therapy Period Based on the Response Assessment by the Central Adjudication Committee (CAC)

Data as of 11 May 2010 cutoff. PFS calculated from the start of the Maintenance period to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry \[EBMT/IBMTR/ABMTR\] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Time frame: Approximately week 37 (start of cycle 10) to week 165

Kaplan Meier Estimates of Overall Survival (OS)

Data as of 11 May 2010 cutoff. Overall survival (OS) was defined as the time between randomization and death. Participants who died, regardless of the cause of death, were considered to have had an event. Participants who were lost to follow-up prior to the end of the trial, or who were withdrawn from the trial, were censored at the time of last contact. Participants who were still being treated were censored at the last available date available, or clinical cut-off date, if it was earlier.

Data from ClinicalTrials.gov

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AspirinDRUG

Double-blind induction: low-dose aspirin 75 mg to 100 mg daily for all treatment arms. Double-blind maintenance: at the investigator's discretion

PlaceboDRUG

Double-blind induction: participants in treatment arm MPp+p received placebo once daily on Days 1 through 21 of each 28-day cycle for up to 9 cycles. Double-blind maintenance: participants in treatment arms MPR+p and MPp+p received placebo once daily on Days 1 through 21 of each 28-day cycle from cycle 10 to disease progression.

Lenalidomide: Double-blind MaintenanceDRUG

Single-agent oral lenalidomide 10 mg once daily on Days 1 through 21 of each 28-day cycle from cycle 10 to disease progression.

Lenalidomide: Open-labelDRUG

Any study participant who had progressive disease had the option of open-label lenalidomide up to 25 mg daily on Days 1 through 21 of each 28-day cycle.

Hematology Oncology Clinics of Australia, Level 5, Mater Medical Centre

South Brisbane, Queensland, Australia

Royal Adelaide Hospital Institute of Medical and Veterinary Science

Adelaide, South Australia, Australia

Royal Prince Alfred Hospital

Camperdown, Australia

Peter MacCallum Cancer Centre Divsion of Haematology Medical Oncology

East Melbourne, Australia

Frankston Hospital

Frankston, Australia

The Alfred Hospital

Melbourne, Australia

Sir Charles Gairdner Hospital

Nedlands, Australia

Princess Alexandra Hospital

Woolloongabba, Australia

University Hospital Innsbruck

Innsbruck, Austria

University Hospital of Salzburg St Johanns Spital

Salzburg, Austria

...and 88 more locations

Time frame: up to 177 weeks

Kaplan Meier Estimates of Time to Progression (TTP) Based on the Response Assessment by the Central Adjudication Committee (CAC)

Data as of 11 May 2010 cutoff. TTP was the time between randomization and disease progression as determined by the CAC. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry \[EBMT/IBMTR/ABMTR\] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Time frame: up to 165 weeks

Number of Participants in Disease Response Categories Representing Their Best Response During the Double-blind Treatment Period

Data as of 11 May 2010 cutoff. Best response was determined by the Central Assessment Committee (CAC) based on the European Group for Blood and Marrow Transplantation (EBMT) criteria: Complete Response (CR)-absence of serum and urine monoclonal paraprotein for 6 weeks, plus no increase in size or number of bone lesions, plus other factors); Partial Response (PR)-not all CR criteria, plus \>=50% reduction in serum monoclonal paraprotein plus others; Stable Disease (SD)- not PR or PD; Progressive Disease (PD)- reappearance of monoclonal paraprotein, bone lesions, other; Not Evaluable (NE).

Time frame: Up to 165 weeks

Time to First Response

Data as of 11 May 2010 cutoff. Time to first response was defined as the time from start of treatment until first response as assessed by the Central Assessment Committee (CMC) based on European Group for Blood and Marrow Transplantation (EBMT) criteria.

Time frame: Up to 66 weeks

Kaplan Meier Estimates for Duration of Response as Determined by the Central Adjudication Committee (CAC)

Data as of 11 May 2010 cutoff. Duration of myeloma response was defined as the time from the initial response date to the earlier of progressive disease (PD) as determined by the CAC or death on study. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry \[EBMT/IBMTR/ABMTR\] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Time frame: Up to 149 weeks

Kaplan Meier Estimates for Time to Next Antimyeloma Therapy

Data as of 11 May 2010 cutoff. Time to the next antimyeloma therapy was defined as time from randomization to the start of another non-protocol antimyeloma therapy. Participants who do not receive another anti-myeloma therapy were censored at the last assessment or follow-up visit known to have received no new therapy.

Time frame: Up to 168 weeks

Summary of Participants With Treatment-Emergent Adverse Events (TEAE) During the Double-Blind Treatment Period

Data as of 11 May 2010 cutoff. Participant counts in different categories of TEAEs during the double-blind treatment period. A TEAE is as any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. Dose reduction includes reduction with or without interruption.

Time frame: Up to 169 weeks (Double-blind therapy period plus 4 weeks)

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Quality of Life Scale

Data as of 11 May 2010 cutoff. EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life.