Treatment Optimization in Patients With Untreated Multiple Myeloma

Inclusion Criteria: 1. Must understand and voluntarily sign an informed consent form. 2. Must be ≥18 years of age at the time of signing the informed consent form. 3. Must be able to adhere to the study visit schedule and other protocol requirements. 4. Previously untreated, symptomatic multiple myeloma as defined by the 3 criteria below: * Multiple Myeloma (MM) diagnostic criteria (all 3 required): * Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma * Monoclonal protein present in the serum and/or urine * Myeloma-related organ dysfunction (at least one of the following): * \[C\] Calcium elevation in the blood (serum calcium \>10.5 mg/dl or upper limit of normal) * \[R\] Renal insufficiency (serum creatinine \>2 mg/dl) * \[A\] Anemia (hemoglobin \<10 g/dl or 2 g \< laboratory normal) * \[B\] Lytic bone lesions or osteoporosis AND have measurable disease by protein electrophoresis analyses as defined by the following: * Immunoglobulin (Ig)G multiple myeloma: Serum monoclonal paraprotein (M-protein) level * 1.0 g/dl or urine M-protein level - 200 mg/24 hours * IgA multiple myeloma: Serum M-protein level - 0.5 g/dl or urine Mprotein level - 200 mg/24 hours * IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200mg/24hours * IgD multiple myeloma: Serum M-protein level - 0.05 g/dl or urine Mprotein level - 200 mg/24 hours * Light chain multiple myeloma: Serum M-protein level - 1.0 g/dl or urine M-protein level - 200 mg/24 hours AND are at least 65 years of age or older or, if younger than 65 years of age, are not candidates for stem cell transplantation because: * The patient declines to undergo stem cell transplantation OR: * Stem cell transplantation is not available to the patient 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 6. Female of childbearing potential (FCBP) † must: * Understand the potential teratogenic risk to the unborn child * Understand the need for effective contraception, without interruption, 4 weeks before starting study treatment, throughout the entire duration of study treatment, dose interruption and 28 days after the end of study treatment * Be capable of complying with effective contraceptive measures and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception: * Highly effective methods\*: * Intrauterine device (IUD)\*\* * Progesterone only hormonal contraceptive (birth control pills, injections, implants)\* * Tubal ligation * Partner's vasectomy * Additional effective methods: * Male condom (partner) * Diaphragm * Cervical Cap * (\*)Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking Lenalidomide and Dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception she should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with Dexamethasone. * (\*\*)Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia. * Be informed about and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy * Agree to have two medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml (milli-International Units per milliliter) prior to starting Lenalidomide. The first pregnancy test must be performed within 10 to 14 days prior to the start Lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of Lenalidomide. The patient will receive Lenalidomide only after the study doctor has verified that the results of these pregnancy tests are negative. She must understand the need to commence the study treatment as soon as study drug is dispensed following the second negative pregnancy test. This requirement also applies to FCBP who practice complete and continued abstinence. * Must understand the need and accepts to undergo pregnancy testing in the frequency as follows: FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following study drug discontinuation. This requirement also applies to FCBP who practice complete and continued abstinence. * Females must agree to abstain from breastfeeding during study participation and for at least 28 days after study drug discontinuation. A FCBP † is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months). Male subjects must: * Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP * Understand the need for the use of a condom and agree to use condoms even if he has had a vasectomy, if engaged in sexual activity with a pregnant female or a female of childbearing potential , while taking study drug, during any dose interruptions and for 28 days after stopping study therapy. * Agree to notify the investigator immediately, if pregnancy or a positive pregnancy test occurs in his partner during study participation. * Agree to abstain from donating semen or sperm during therapy or for at least 28 days following discontinuation of study drug. All subjects must: * Agree to abstain from donating blood while taking study drug therapy and for at least 28 days following discontinuation of study drug therapy. * Agree never to give Lenalidomide to another person and to return all unused study drug to the investigator. Exclusion Criteria: 1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \[i.e., less than or equal to the equivalent of Dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of registration\]). 2. Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, patient with unstable cardiac disease as defined by: Cardiac events such as MI within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; patients with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment. 3. Pregnant or breast feeding females. 4. Any of the following laboratory abnormalities within 1 week prior to registration: * Absolute neutrophil count (ANC) \< 1,000/µL (1.0 x 109/L) without the use of colony stimulating factors within 14 days before the laboratory test. Untransfused platelet count \< 50,000 cells/µL (50 x 109/L) * Hemoglobin \< 7.5 g/dL (4.6 mmol/L) (regardless of transfusion support or prior medication with erythropoietin) * Serum sGOT/AST (serum glutamic-oxaloacetic transaminase/ aspartate aminotransferase) or SGPT(serum glutamate pyruvate transaminase)/ALT \> 3.0 x upper limit of normal (ULN) * Corrected serum calcium \> 14 mg/dL (\> 3.5 mmol/L) 5. Renal failure with creatinine clearance (CLCR)\< 15 ml/min or requiring hemodialysis or peritoneal dialysis. 6. Psychiatric illness that would prevent the subject from signing the informed consent form or from completion of treatment according to the protocol. 7. Patient currently is enrolled in another clinical research study or has been enrolled in such a study within 4 weeks before randomization/registration and/or is receiving an investigational agent for any reason or has received such an agent within 4 weeks before registration. 8. Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for 3 years. Exceptions include the following, if treated with curative intent: * Basal cell carcinoma of the skin * Squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Carcinoma in situ of the breast * Incidental histological finding of prostate cancer (TNM stage of T1a or T1b) 9. Known positive for HIV or active hepatitis A, B or C viral infection. 10. Immunotherapy or antibody therapy within 8 weeks before registration. 11. Major surgery within 4 weeks before registration. 12. Any severe systemic infection requiring treatment. 13. Patients who are unable or unwilling to undergo antithrombotic therapy. 14. Peripheral neuropathy of ≥ grade 3 severity or grade 2 severity with pain. 15. Primary AL (amyloid light chain) amyloidosis and myeloma complicated by amyloidosis.