Lenalidomide/Bortezomib/Dexamethasone for Multiple Myeloma (MM)

Study Overview
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Brief Summary
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This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational combination of drugs. The purpose is to learn whether the combination of drugs works in treating a specific cancer. Investigational means that the combination of drugs is still being studied. It also means that research doctors are trying to find out more about it. Examples of what they want to learn about are the safest dose to use, the side effects it may cause, and if the combination of drugs works for treating different types of cancer.

Detailed Description
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If you are willing to participate in this study you will be asked to undergo some screening procedures and tests to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care. They may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history, physical exam, performance status, vital signs, neurological exam, bone imaging studies, chest x-ray, bone marrow aspirate, ECG, blood tests and urine tests. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in the research study. For cycles 1-9 (each cycle lasts 35 days) you will receive the following: Lenalidomide-once a day on Days 1-21. You will take Lenalidomide by mouth at the same time each day. Bortezomib- once a day on Days 1, 8, 15 and 22. If you are one of the first ten patients enrolled you will get Bortezomib as an intravenous injection for the first cycle. You will get Bortezomib as an injection under the skin for all other cycles. If you are not one of the first 10 patients enrolled you will get Bortezomib as an injection under the skin for all cycles. Dexamethasone-if you are 75 years old or younger you will get Dexamethasone on Days 1, 2, 8, 9, 15, 16, 22 and 23. If you are more than 75 years old you will get Dexamethasone on Days 1, 8, 15 and 22. You will take Dexamethasone by mouth at the same time each day. For cycles 10-15 (each cycle lasts 28 days) you will receive the following: Lenalidomide-once a day on Days 1-21. You will take Lenalidomide by mouth at the same time each day. Bortezomib-Once a day on Days 1 and 15. You will get Bortezomib as an injection under the skin. You will be given a drug diary to record taking your doses of the drugs. The study staff will tell you how to complete the diary. During the study you will have to come to the clinic for visits. The tests and procedures that will be done at each visit are listed below: Day 1 of all cycles: questions about health, medications etc., physical exam, performance status, vital signs, neurological exam, questionnaires, bone imaging studies, bone marrow aspirate, blood tests, pregnancy test, education and counseling, collection of bone marrow, plasma and serum (cycle 1 only), urine test. Day 8 of cycles 1-9: questions about health, medications etc., vital signs, blood tests. Day 15 of all cycles: questions about health, medications, etc., vital signs, blood tests, pregnancy test. Day 22 of cycles 1-9: questions about health, medications, etc., vital signs, blood tests. After the final dose of the study drug you will have an End of Treatment visit. The following tests and procedures will be done at this visit: questions about health, medications etc., physical exam, performance status, vital signs, neurological exam, questionnaires, bone imaging studies, bone marrow aspirate, blood tests, pregnancy test, education and counseling, collection of bone marrow, plasma and serum, urine test. After your End of Treatment visit, we would like to follow your status every 2 months until your disease gets worse. The following tests and procedures will be done at these follow-up visits: questions about health, medications, symptoms etc., blood tests and urine test. If you are one of the first twenty patients enrolled in the study you will also be asked to provide additional blood samples to study what the body does to the study drug. We will take one sample at five time points during cycle 1 and 2. Collection of these samples may require you to come back into the clinic on additional days when you are not receiving study drugs. You will be in this research study for about 15 months. You can be in this study for a maximum of 15 cycles. If your disease gets worse before the 15th cycle you will be taken off the study.

Official Title
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A Phase II Study of Modified Lenalidomide, Bortezomib and Dexamethasone for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented symptomatic myeloma, with organ damage related to myeloma Myeloma that is measurable either by serum or urine evaluation of the monoclonal component or by assay of serum free light chains Must commit to complete abstinence from heterosexual contact or begin two acceptable method of birth control, one highly effective method and one additional effective (barrier) method Exclusion Criteria: Eligible for autologous stem cell transplantation HIV positive on combination antiretroviral therapy Pregnant or breastfeeding Treated with any prior systemic therapy Primary amyloidosis or myeloma complicated by amyloidosis Receiving other investigational agents within 14 days of the start of this trial or during this trial Known brain metastases Poor tolerability or known allergy to any of the study drugs or similar compounds Intercurrent illness Previous history of another malignant condition except for basal cell carcinoma or stage I cervical cancer Inability to comply with an anti-thrombotic treatment regimen Peripheral neuropathy greater than or equal to grade 2

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Induction (Cycles 1-9): Lenalidomide orally, days 1-21. Bortezomib injection, days 1, 8, 15, 22. Dexamethasone orally, days 1, 2, 8, 9, 15, 16, 22, 23 (for subjects 75 years of age or younger), or Dexamethasone orally days 1, 8, 15, 22 (for subjects greater than 75 years of age) Consolidation (cycles 10-15): Lenalidomide po daily (1-21). Bortezomib sc on days 1, 15 | Drug: Lenalidomide<br> <br> * Other names: Revlimid;Drug: Bortezomib<br> <br> * Other names: Velcade;Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Participants are considered to have achieved an objective response if they meet the International Myeloma Working Group uniform response criteria for any of the following: Stringent CR: Same as CR plus normal free light chain ratio and absence of clonal cells plasma cells in bone marrow (BM) CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in BM VGPR: 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 <100 mg per 24 hours PR: ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 hours. If the serum and urinary M-protein are not measurable, additional criteria are used to assess PR that will not fit in the space provided here. If present at baseline, a ≥50% reduction in the size of plasmacytomas is also required | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or Higher Treatment Related Adverse Events | A summary of the number of participants with grade 3 or higher treatment related adverse events for adverse events that had an overall incidence of greater than 15% (any grade) as assessed by Common Terminology Criteria for Adverse Events (CTCAE 4). | 2 years | 
| Median Progression Free Survival | The median amount of time as measured from the start of treatment until either death or progression. Progressive disease requires 1 or more of the following: >=25% increase from lowest response level in serum M-protein (>=0.5 g/dL absolute increase) and/or urine M-component (>=200 mg/24hr absolute increase) >=25% increase in the difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL). Only for use in patients without measurable serum and M-protein levels. >=25% increase in bone marrow plasma cell percentage (absolute percentage >=10%) New or increase in existing bone lesions or soft tissue plasmacytomas Hypercalcemia (serum calcium >11.5 mg/dL) due solely to the plasma cell proliferative disorder. | From the start of treatment until death or progression or until 3 years after the last participant is enrolled | 
| Median Overall Survival | The median overall survival as measured from the start of treatment until the time of death due to any cause. | From the start of treatment until death or until 5 years after the time of disease progression | 
| Median Time to Response | Median amount of time from the start of treatment until first documented response as defined by the International Myeloma Working Group uniform response criteria Stringent CR: Same as CR plus normal free light chain ratio and absence of clonal cells plasma cells in bone marrow (BM) CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in BM VGPR: 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 <100 mg per 24 hours PR: ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 hours. If the serum and urinary M-protein are not measurable, additional criteria are used to assess PR that will not fit in the space provided here. If present at baseline, a ≥50% reduction in the size of plasmacytomas is also required | From the start of treatment until the time of first documented response, median duration of 1.1 months | 
| Response Rate With Respect to Cytogenetic Characteristics | Response rate was assessed using the International Myeloma Working Group uniform response criteria. Stringent complete response, Complete Response, Very Good Partial Response, and Partial Response are defined in outcome measure 1. MR included participants in whom some, but not all, criteria for PR were fulfilled, providing the remaining criteria satisfied the requirements for MR. Required all of the following: ≥25% to ≤ 49% reduction in the level of serum monoclonal protein for at least two determinations six weeks apart. If present, a 50 to 89% reduction in 24-hour light chain excretion, which still exceeds 200 mg/24 h, for at least two determinations six weeks apart. 25-49% reduction in the size of plasmacytomas (by clinical or radiographic examination) for at least six weeks. No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). Stable Disease: Not meeting the criteria for minimal response or | 2 years | 
| Mean Plasma Bortezomib Concentration Following Intravenous and and Subcutaneous Injection | The pharmacokinetic profile of intravenous and subcutaneous bortezomib administration in combination with lenalidomide and dexamethasone. | Day 1 (5 min, 30min, 5 hours post dose), Days 8, 15, Day 22 (pre dose and 5 min, 30 min, 5 hrs post dose), cycle 2 day 1 pre dose | 
| Pharmacogenomic Markers of Neuropathy | To evaluate pharmacogenomic markers among patients with treatment related polyneuropathy. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed