Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65

Phase 3Active Not RecruitingNCT01208662

Paul Richardson, MD729 enrolled

Overview

In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.

The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Please note that Bortezomib and Lenalidomide are provided to patients participating in this trial at no charge. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma. After screening procedures determine if a patient is eligible for this research study, the patient will be randomized into one of the study groups: lenalidomide, bortezomib and dexamethasone without autologous stem cell transplantation, followed by lenalidomide maintenance (Arm A) or lenalidomide, bortezomib and dexamethasone with autologous stem cell transplantation, followed by lenalidomide maintenance (Arm B). There is an equal chance of being placed in either group. Randomization was stratified by International Staging System (ISS) disease stage (I, II, or III) and cytogenetics (high-risk \[presence of 17p deletion, t(4;14), or t(14;16) on fluorescence in-situ hybridization\], standard-risk \[absence of high-risk abnormalities\], or undetermined \[test failure\]) assessed locally in a screening bone marrow sample, with positivity cut-offs per institutional standards.

Interventions

LenalidomideDRUG

oral administration

BortezomibDRUG

intravenous or, following protocol amendment, subcutaneous administration

DexamethasoneDRUG

oral administration Dose of 20 mg/day for first 3 cycles. Dose of 10 mg/day for remaining cycles.

Autologous Stem Cell TransplantPROCEDURE

Autologous refers to stem cells that are harvested from the participant to be a source of new blood cells after high-dose chemotherapy with melphalan.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of Multiple Myeloma, according to the International Myeloma Foundation 2003 Diagnostic Criteria * Documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration * Myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains. * ECOG performance status \</= 2 * Negative HIV blood test * Voluntary written informed consent Exclusion Criteria: * Pregnant or lactating female * Prior systemic therapy for MM (localized radiotherapy allowed if at least 7 days before study entry, corticosteroids allowed if dose \</= equivalent of 160 mg dexamethasone over 2 weeks) * Primary amyloidosis (AL) or myeloma complicated by amylosis * Receiving any other investigational agents * Known brain metastases * Poor tolerability or allergy to any of the study drugs or compounds of similar composition * Platelet count \<50,000/mm3, within 21 days of registration * ANC \<1,000 cells/mm3, within 21 days of registration * Hemoglobin \<8 g/dL, within 21 days of registration * Hepatic impairment (\>/= 1.5 x institutional ULN or AST (SGOT), ALT (SGPT), or alkaline phosphatase \>2 x ULN). Patients with benign hyperbilirubinemia are eligible. * Renal insufficiency (serum creatinine \>2.0 mg/dl or creatinine clearance \<50 ml/min, within 21 days of registration) * Respiratory compromise (DLCO \< 50%) * Clinical signs of heart or coronary failure or LVEF \< 40%. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities * Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements * Previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer. If malignancy was experienced more than 2 years ago and confirmed as cured, these participants may be considered for the study on case by case basis with PI discussion. * Inability to comply with an anti-thrombotic treatment regimen * Peripheral neuropathy \>/= Grade 2

Locations (46)

University of Alabama at Birmingham

Birmingham, Alabama, United States

Arizona Comprehensive Cancer Center

Tucson, Arizona, United States

City of Hope

Duarte, California, United States

University of California at San Diego

La Jolla, California, United States

University of California, San Francisco

San Francisco, California, United States

Outcomes

Primary Outcomes

Median Progression-Free Survival (PFS)

PFS was estimated using the Kaplan-Meier (KM) method and defined as time from randomization to the earlier of disease progression (PD) as determined by central review or death from any cause (events). Patients who started non-protocol therapy (NPT) were censored at the date of NPT initiation if available or date treatment ended if date of NPT was missing. Deaths occurring beyond 1 year from the date last known progression-free are not counted as events and censored at date of last disease evaluation. Patients who had not started NPT, progressed, or died were censored at the date of last disease evaluation. PD was based upon the International Myeloma Working Group (IMWG) uniform response criteria. \[Kumar S, et al Lancet Oncol 2016;17(8):e328-e346\].

Time frame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months.

Secondary Outcomes

Partial Response (PR) Rate

The PR rate is the percentage of participants achieving PR or better on treatment and was evaluated based on the IMWG criteria. PR was defined as \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a \> 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \> 30%. In addition to the above listed criteria, if present at baseline, a \> 50% reduction in the size of soft tissue plasmacytomas was also required. Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.

Time frame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.

Very Good Partial Response (VGPR) Rate

The VGPR rate is the percentage of participants achieving VGPR or better on treatment and was evaluated based on IMWG criteria. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hours.

Complete Response (CR) Rate

The CR rate is the percentage of participants achieving CR or better on treatment and was evaluated based on IMWG criteria. CR was defined as the negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Confirmation with repeat bone marrow biopsy was not needed.

Median Duration of Response: Partial Response (DOR PR)

DOR PR was estimated using the KM method and defined as the time from documented best response as CR to documented disease progression per IMWG criteria. Patients who have not progressed or died were censored at the date last known progression-free.

5-Year Time to Progression (TTP)

TTP was estimated using the KM method and defined as time from randomization to time of documented IMWG disease progression or censoring time (time of last disease evaluation for those alive, time to death among those who died). Patients initiating non-protocol therapy prior to progression or death were censored at the date of non-protocol therapy in the TTP analysis. The 5-year TTP endpoint is a probability.

5-Year Overall Survival (OS)

OS was estimated using the KM method and defined as time from randomization to death due to any cause. Patients alive were censored at date last known alive. The 5-year OS endpoint is a probability.

Time frame: In long-term follow-up, survival follow-up every 2 months until death. Median (maximum) OS follow-up was 76 and 129 months.The probability estimate is at 5 years.

Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate

Safety was evaluated throughout trial treatment, including ASCT, and through 30 days after receipt of the last dose of a trial drug. Treatment attribution and grade were based on the NCI CTCAE v4. The Grade 3 or Higher Treatment-Related Non-Hematologic AE Rate is percentage of participants who experienced any grade 3-5 treatment-related (possible, probable or definite attribution) non-hematologic adverse event based on CTCAEv4 as reported on case report forms. The difference in the rate of all grade 3 or higher toxicities was compared between the two groups using Fisher's exact test.

Time frame: AEs was assessed every cycle on treatment. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.

5-year Cumulative Incidence of Second Primary Malignancy (SPM)

Second primary malignancy (SPM) is defined as the development of another new, unrelated cancer, regardless of treatment for previous malignancy attribution. The cumulative incidence of SPMs was estimated with death as a competing risk. SPMs were collected using an SAE form or MEDWATCH 3500A form, with intensity determined by using the NCI CTCAE version 4 as a guideline.

Time frame: 5 years

Median Treatment Duration

Treatment duration estimated using the KM method is defined as the time from registration (C1) to the time off treatment (event) or censored at date of last treatment.

Time frame: Up to 134 months

Median Maintenance Treatment Duration

Maintenance treatment duration estimated using the KM method is defined as the time from start of maintenance to the time off maintenance (event) or censored at date of last maintenance treatment.

Time frame: Up to 128 months

Subsequent Therapy Rate

Subsequent therapy rate was the percentage of participants who discontinued treatment and initiated subsequent non-protocol therapy.

Time frame: Up to 129 months

Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX)

The FACT/GOG-NTX assessment consists of 11 questions that are all used to construct 1 subscale to summarize symptoms of peripheral neuropathy, including sensory, motor, and auditory problems and cold sensitivity. (https://www.facit.org/measures/FACT-GOG-NTX) Each question has 4 possible responses from 0 (Not at all) to 4 (Very Much) which are reverse-scored and summed. This sum is then scaled by the number of questions answered by multiplying by 11 and then dividing by the number of questions that are non-blank, in order to keep all final scores proportional to one another even if some questions are left blank. The aggregate score ranges from 0 to 44, with higher scores indicating less neurotoxicity and lower scores indicating more neurotoxicity. Change from baseline is the difference

Time frame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline

Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale

The EORTC QLQ-C30 assessment consists of 30 questions that are used to construct 15 distinct sub-scales (five function scales, nine symptom scales, and a global health status/QoL scale). The global health status/QoL scale is comprised of two questions each with a range of 6 (1=Very Poor to 7=Excellent). Scores on all sub-scales range from 0 to 100 after linear transformation of the raw scores, with higher scores representing better global health status and quality of life.

Time frame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline

Quality-Adjusted Life Years (QALYs)

QALYs were estimated with a model beginning at initiation of first-line therapy by arm. A lifetime horizon, as well as subsequent lines of therapy, was examined using open-source Amua 0.3.0 software. Base case analysis was performed using 10,000 first-order Monte Carlo simulations. Conditional probabilities were extracted from Kaplan-Meier curves from pivotal clinical trials using WebPlotDigitizer. Costs were estimated from RED BOOK and DFCI charge reporting in US Dollars ($) after inflation adjustment to 2022 and 3% discounting, and QALYs effects were measured using EQ-5D data from Hatswell et al.

Time frame: Maximum observation of survival for this study cohort was 129.4 months.

Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65

Overview

Conditions

Interventions

Eligibility

Locations (46)

Outcomes

Primary Outcomes

Secondary Outcomes