E3A06: Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients with Asympotomatic High-Risk Smoldering Multiple Myeloma


arm a Lenalidomide

Lenalidomide 25 mg by mouth days 1-21 every 4 weeks (28 days).

aspirin (or alternative prophylaxis) 325 mg/day days 1-28 for each treatment cycle. if not well tolerated, 0-81mg/day is accepted.

all patients on arm a are required to receive prophylaxis against thrombosis. For patients in arm a, physicians should consider prophylaxis with aspirin alone as studies with single agent lenalidomide in the setting of relapsed disease show a relatively low incidence of thrombosis ([Less Than]5%). See Section for acceptable alternative prophylaxis.

Treatment continues until progression to symptomatic myeloma or discontinuation due to toxicity.

For patients with CrCl 30-60 mL per minute, lenalidomide dose is 10 mg per day for days 1-21 every 28 days. Creatinine clearance (CLcr) can either be measured CLcr or estimated by the Cockcroft-Gault method: {[140 x age (yrs)] x [lesser of iBW (kg) or actual weight (kg)]} / [72 x serum creatinine (mg/dL)]; multiply by another factor of 0.85 if female.
The first 34 patients to accrue will be placed on arm a without randomization (Phase ii).

arm B observation
observation continues until progression to symptomatic myeloma. Patients will not recieve lenalidomide and will instead be monitored more closely than what is considered standard.

Both arms
Patients on arm a and arm B will be required to complete a Quality of Life (QoL) assessment before starting treatment or observation and every 6 cycles until cycle 48. QoL will also be assesed at the end of treatment or observation. Patients on both arms will complete the QoL assessment in the same way and on the same schedule.

Participant Eligibility

1. Age >= 18 years.
2. Patients must be diagnosed with asymptomatic high-risk smoldering
multiple myeloma (SMM) within the past 60 months, as confirmed by
both of the following:
1) Bone marrow plasmacytosis with >= 10% plasma cells or sheets of
plasma cells at any time before initiating study treatment, including
a marrow which must be obtained by bone marrow aspiration
and/or biopsy within 4 weeks prior to randomization.
If plasmacytosis, % plasma cells: _____ Date: ___________
If sheets of plasma cells, Date: _____________
2) Abnormal serum free light chain ratio (< 0.26 or > 1.65) by serum
FLC assay. FLC assay must be performed within 28 days of
Serum Free Light Chain Ratio ________ Date of Test _________
3. Patients must have measurable levels of monoclonal protein (M-protein): >=1g/dL on serum protein electrophoresis or >=200 mg of monoclonal protein on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization.
o Both SPEP and UPEP are required to be performed within 28 days prior to randomization.
- Serum M-protein by SPEP __________ (g/dL) Date of Test:________
- Urine M-protein light chain excretion by UPEP_____(mg/24hr) Date of Test: ________

NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is > 200 mg/24 hr. Please note that if both serum and urine M-components are present, both must be followed in order to evaluate response.

4. Patients must have no lytic lesions on skeletal surveys and no hypercalcemia (i.e., > 11 mg/dL).

5. The following laboratory levels must be obtained within four weeks prior to randomization:
- Hemoglobin > 11 g/dL.
Hemoglobin: __________Date:__________
- Platelet count > 100,000 cells/mm3.
Platelet:__________ Date:__________
- Absolute neutrophil count > 1500 cells/mm3.
ANC:__________ Date:__________
- Calculated creatinine clearance > 30 mL/min.
Creatinine clearance:__________ Date:__________
- Bilirubin < 1.5 mg/dL.
Bilirubin:__________ Date:__________
- SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal.
SGPT (ALT):_________ ULN:__________ Date:__________
SGOT (AST):_________ ULN:__________ Date:__________

6. No prior or concurrent systemic or radiation therapy for the treatment of myeloma.

7. Concurrent use of bisphosphonates is not permitted. However, prior bisphosphonates or once-a-year intravenous bisphosphonate given for the treatment of osteoporosis is permitted.

8. Prior or concurrent use of erythropoietin is disallowed.

9. Prior glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted.

10. Prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day.

11. Prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted.

12. Patients must not have active, uncontrolled seizure disorder. Patients must have had no seizures in the last 6 months.

13. Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson Syndrome.

14. ECOG performance status 0, 1, or 2.

15. Patients must not have baseline bone lesions or plasmacytomas.

16. Patients with monoclonal gammopathy of undetermined significance are not eligible.

17. Patients must not have Grade 2 or higher peripheral neuropathy.

18. Patients must not have active, uncontrolled infection.

19. Patients may have a history of current or previous deep vein thrombosis or pulmonary embolism but are required to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation.

20. Patients should not have New York Heart Association classification III or IV heart failure.

21. Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for the time period considered appropriate for cure of the specific cancer.

22. Patients should not be felt to have an immediate need for chemotherapy.

23. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 x 14 days prior to and again within 24 hours of starting cycle 1 of lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). All patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure. (See Appendix VI: Risks Associated with Pregnancy and also Appendix VII: Lenalidomide Education and Counseling Guidance Document).
o Female of childbearing potential (Y/N)? ________ Date of Test: _________

24. HIV infection is not excluded. HIV+ patients must meet the following criteria:
o CD4 cell count > 350/mm3
o No history of AIDS-related illness
o Not currently prescribed zidvoudine or stavudine