Multiple Myeloma
Conditions
Brief summary
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
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.
Interventions
DRUGClarithromycin
500mg PO twice daily on days 1-28 for a 28-day cycle.
DRUGLenalidomide
25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle
DRUGDexamethasone
20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger.
Sponsors
Celgene Corporation
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival Duration Without Disease Progression | Until disease progression or death from any cause, for a maximum of approximately 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events Experienced | 2 years | Capture the number of adverse events experienced with BiRd regimen as compared to Rd regimen |
| Overall Survival | 4 years | Survival following treatment to the date of death of subjects on BiRd regimen as compared to Rd. |
| Number of Days After Initiating Treatment With BiRd Regimen to Disease Progression, as Compared to Subjects on Rd Treatment Regimen. | Until disease progression for a maximum of approximately 5 years | Progression is determined by the International Myeloma Working Group Criteria. |
| Number of Patients With Objective Response Rate (CR+PR) | up to 3 years | — |
| Overall Response Rate | 2 years | 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. |
| Number of Days for Event-Free Survival | approximately 5 years | Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms |
| Number of Days for Duration of Response | up to 3 years | Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms |
| Number of Months to Progression-Free Survival 2 | approximately 5 years | 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. |
| Functional Assessment of Chronic Illness Therapy - Fatigue Subscale (FS; Version 4) Score of Patients Receiving BiRd vs Rd Treatment | up to 3 years | 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. |
| Number of Patients With Complete Response Rate (CR) | up to 3 years | Complete response is defined by the International Myeloma Working Group Criteria. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BiRD Treatment Regimen Subjects on the BiRD arm will receive clarithromycin, lenalidomide, and dexamethasone in 28-day cycles.
Clarithromycin: 500mg PO twice daily on days 1-28 for a 28-day cycle.
Lenalidomide: 25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle
Dexamethasone: 20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger. | 7 |
| Rd Treatment Regimen Subjects on the Rd arm will receive lenalidomide and dexamethasone in 28-day cycles.
Lenalidomide: 25 mg PO days 1-21 followed by a 7 day rest period for each 28-day cycle
Dexamethasone: 20 mg PO on Days 1, 8, 15, and 22 for each cycle for subjects 75 years and younger. | 5 |
| Total | 12 |
Baseline characteristics
| Characteristic | BiRD Treatment Regimen | Rd Treatment Regimen | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 7 | 4 / 5 |
| other Total, other adverse events | 7 / 7 | 5 / 5 |
| serious Total, serious adverse events | 6 / 7 | 3 / 5 |
Outcome results
Primary
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.
Time frame: Until disease progression or death from any cause, for a maximum of approximately 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BiRD Treatment Regimen | Survival Duration Without Disease Progression | 661 days |
| Rd Treatment Regimen | Survival Duration Without Disease Progression | 1694 days |
Secondary
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.
Time frame: up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BiRD Treatment Regimen | Functional Assessment of Chronic Illness Therapy - Fatigue Subscale (FS; Version 4) Score of Patients Receiving BiRd vs Rd Treatment | 32.75 Score on a scale |
| Rd Treatment Regimen | Functional Assessment of Chronic Illness Therapy - Fatigue Subscale (FS; Version 4) Score of Patients Receiving BiRd vs Rd Treatment | 37.24 Score on a scale |
Secondary
Number of Adverse Events Experienced
Capture the number of adverse events experienced with BiRd regimen as compared to Rd regimen
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BiRD Treatment Regimen | Number of Adverse Events Experienced | 79 adverse events |
| Rd Treatment Regimen | Number of Adverse Events Experienced | 67 adverse events |
Secondary
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.
Time frame: Until disease progression for a maximum of approximately 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BiRD Treatment Regimen | Number of Days After Initiating Treatment With BiRd Regimen to Disease Progression, as Compared to Subjects on Rd Treatment Regimen. | 661 days |
| Rd Treatment Regimen | Number of Days After Initiating Treatment With BiRd Regimen to Disease Progression, as Compared to Subjects on Rd Treatment Regimen. | 1694 days |
Secondary
Number of Days for Duration of Response
Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms
Time frame: up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BiRD Treatment Regimen | Number of Days for Duration of Response | 308 days |
| Rd Treatment Regimen | Number of Days for Duration of Response | 803 days |
Secondary
Number of Days for Event-Free Survival
Descriptively presented for each treatment group and no formal statistical comparison will be made between treatment arms
Time frame: approximately 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BiRD Treatment Regimen | Number of Days for Event-Free Survival | 336 days |
| Rd Treatment Regimen | Number of Days for Event-Free Survival | 821 days |
Secondary
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.
Time frame: approximately 5 years
Population: Data not collected due to early trial termination due to low accrual.
Secondary
Number of Patients With Complete Response Rate (CR)
Complete response is defined by the International Myeloma Working Group Criteria.
Time frame: up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BiRD Treatment Regimen | Number of Patients With Complete Response Rate (CR) | 2 Participants |
| Rd Treatment Regimen | Number of Patients With Complete Response Rate (CR) | 0 Participants |
Secondary
Number of Patients With Objective Response Rate (CR+PR)
Time frame: up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BiRD Treatment Regimen | Number of Patients With Objective Response Rate (CR+PR) | 7 Participants |
| Rd Treatment Regimen | Number of Patients With Objective Response Rate (CR+PR) | 4 Participants |
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BiRD Treatment Regimen | Overall Response Rate | 7 Participants |
| Rd Treatment Regimen | Overall Response Rate | 4 Participants |
Secondary
Overall Survival
Survival following treatment to the date of death of subjects on BiRd regimen as compared to Rd.
Time frame: 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BiRD Treatment Regimen | Overall Survival | NA days |
| Rd Treatment Regimen | Overall Survival | 1014 days |