BiRd vs. Rd as Initial Therapy in Multiple Myeloma

Study Overview
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Brief Summary
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This is a randomized, open-label, phase III study to investigate the efficacy of combination therapy with an induction phase utilizing a combination clarithromycin (Biaxin®), lenalidomide (Revlimid®), dexamethasone (Decadron®), in multiple myeloma patients who are newly diagnosed and require treatment when compared to patients who receive lenalidomide and dexamethasone alone.

Detailed Description
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This research study is for men and women with newly diagnosed, previously untreated multiple myeloma. The purpose of this study is to observe the how well the different combinations of study drugs work as therapy for patients with newly diagnosed, transplant ineligible, previously untreated multiple myeloma. The study will be done in two arms: BiRd Arm: Clarithromycin 500mg PO twice daily on days 1-28 for a 28-day cycle Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle Dexamethasone 40mg PO will be given on days 1, 8, 15, 22 of a 28-day cycle Rd Arm: Lenalidomide 25mg PO daily on days 1-21 of a 28-day cycle Dexamethasone 40mg PO will be given on days 1, 8, 15, 22 of a 28-day cycle Subjects will be treated in 28-day cycles and may continue treatment as long as they are responding to therapy and not experiencing unacceptable side effects or disease progression. There will be an evaluation at the end of each cycle. Participants will be in the study until disease progression or unacceptable toxicity.

Official Title
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Lenalidomide and Dexamethasone (Rd) Versus Clarithromycin [Biaxin®] / Lenalidomide [Revlimid®] / Dexamethasone (BiRd) as Initial Therapy in Multiple Myeloma

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must voluntarily sign and understand written informed consent. Subject is at least 65 years old at the time of signing the consent form. Subject has histologically confirmed multiple myeloma that has never before been treated Subject has no prior anti-myeloma treatment therapy within 14 days prior to initiation of study treatment except for corticosteroids with a maximum allowed dosage equivalent to three pulses of dexamethasone (40mg daily for 4 days equals one pulse). Patients may have received prior adjuvant antiresorptive therapy (i.e., pamidronate or zoledronic acid) as routine care, or radiation therapy as palliation for pain and/or spinal cord compression. Subject has measurable disease as defined by > 0.5 g/dL serum monoclonal protein, >10 mg/dL involved serum free light chain (either kappa or lambda) provided that the serum free light chain ratio is abnormal, >0.2 g/24 hrs urinary M-protein excretion, and/or measurable plasmacytoma(s) of at least 1cm in greatest dimension as measured by either CT scanning or MRI. Subject has a Karnofsky performance status ≥60% (>50% if due to bony involvement of myeloma (see Appendix IV). Subject is able to take prophylactic anticoagulation as detailed in section 9.1 (patients intolerant to aspirin may use warfarin or low molecular weight heparin). Subject is registered into the mandatory RevAssist® program, and is willing and able to comply with the requirements of RevAssist® program. If subject is a female of childbearing potential (FCBP),† she must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide Subject has a life expectancy ≥ 3 months Subjects must meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥750 cells/mm3 (1.0 x 109/L) Hemoglobin ≥ 7 g/dL Platelet count ≥ 30,000/mm3 (75 x 109/L) Serum SGOT/AST <3.0 x upper limits of normal (ULN) Serum SGPT/ALT <3.0 x upper limits of normal (ULN) Serum total bilirubin <2.0 mg/dL (34 µmol/L) Creatinine clearance ≥ 45 cc/min Exclusion Criteria: Subject has immeasurable MM (no measurable monoclonal protein, free light chains in blood or urine, or measureable plasmacytoma on radiologic scanning). Subject has a prior history of other malignancies unless disease free for ≥ 5 years, except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or localized prostate cancer with Gleason score < 7 with stable prostate specific antigen (PSA) levels. Subject has had myocardial infarction within 6 months prior to enrollment , or NYHA(New York Hospital Association) Class III or IV heart failure (see APPENDIX VI), Ejection Fraction < 35%, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Female subject who is pregnant or lactating. Subject has known HIV infection Subject has known active hepatitis B or hepatitis C infection. Subject has active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program. Subject is unable to reliably take oral medications Subject has known hypersensitivity to dexamethasone, clarithromycin, lenalidomide, or thalidomide Subject has a history of thromboembolic event within the past 4 weeks prior to enrollment. Subject has any clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent. Subject has previously been treated for multiple myeloma

Ages Eligible for Study
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Minimum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BiRD treatment regimen<br>Subjects on the BiRD arm will receive clarithromycin, lenalidomide, and dexamethasone in 28-day cycles. | Drug: Clarithromycin<br>* 500mg PO twice daily on days 1-28 for a 28-day cycle.<br>* Other names: biaxin;Drug: Lenalidomide<br>* 25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle<br>* Other names: Revlimid;Drug: Dexamethasone<br>* 20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger.<br>* Other names: Decadron;|
| Active Comparator: Rd treatment regimen<br>Subjects on the Rd arm will receive lenalidomide and dexamethasone in 28-day cycles. | Drug: Lenalidomide<br>* 25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle<br>* Other names: Revlimid;Drug: Dexamethasone<br>* 20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Duration Without Disease Progression | Calculate rate of progression-free survival for subjects following treatment BiRd regimen compared to Rd treatment regimen. Progression is determined by the International Myeloma Working Group Criteria. | Until disease progression or death from any cause, for a maximum of approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Capture the number of subjects who demonstrate a complete or partial response to treatment with BiRD regimen, as compared to Rd. Complete and partial responses are defined by the International Myeloma Working Group Criteria. | 2 years | 
| Number of Adverse Events Experienced | Capture the number of adverse events experienced with BiRd regimen as compared to Rd regimen | 2 years | 
| Overall Survival | Survival following treatment to the date of death of subjects on BiRd regimen as compared to Rd. | 4 years | 
| Number of Days After Initiating Treatment With BiRd Regimen to Disease Progression, as Compared to Subjects on Rd Treatment Regimen. | Progression is determined by the International Myeloma Working Group Criteria. | Until disease progression for a maximum of approximately 5 years | 
| Number of Patients With Objective Response Rate (CR+PR) |  | up to 3 years | 
| Number of Patients With Complete Response Rate (CR) | Complete response is defined by the International Myeloma Working Group Criteria. | up to 3 years | 
| Number of Days for Event-Free Survival | Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms | approximately 5 years | 
| Number of Days for Duration of Response | Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms | up to 3 years | 
| Number of Months to Progression-Free Survival 2 | Time from study entry until 2nd instance of disease progression. Progression is determined by the International Myeloma Working Group Criteria. Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms. | approximately 5 years | 
| Functional Assessment of Chronic Illness Therapy - Fatigue Subscale (FS; Version 4) Score of Patients Receiving BiRd vs Rd Treatment | The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) is a 40-item measure that assesses self-reported fatigue and its impact upon daily activities and function. The FACIT- Fatigue Subscore (FS) is comprised of 13 items, within the total 40-item FACIT-F, that assess fatigue and its impact. This analysis is only based on the FS score. Items are scored on a 5 point Likert-type scale. Item scores can range from 0 (not at all) to 4 (very much), and the total, summed score from 0 to 52; lower scores indicate greater fatigue. The recall period for each item is the past 7 days. Data is descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms. | up to 3 years |