Lenalidomide, Thalidomide and Dexamethasone in Treating Participants With Relapsed or Refractory Multiple Myeloma

This phase I/II trial studies the best dose and side effects of lenalidomide and thalidomide, and how well they work with dexamethasone in treating participants with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as lenalidomide, thalidomide and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of lenalidomide and thalidomide and dexamethasone (LTD) in patients with relapsed/refractory multiple myeloma (RRMM). (Phase 1) II. To determine the overall (complete remission \[CR)\]+ very good partial response \[VGPR\]+ partial response \[PR)\] response rate of the combination after 4 cycles of therapy. (Phase 2)

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR). (Phase 1) II. To determine the time to progression (TTP). (Phase 1) III. To determine the progression free survival (PFS). (Phase 1) IV. To determine the time to best response. (Phase 1) V. To determine the CR, VGPR. (Phase 2) VI. To determine the time to progression (TTP). (Phase 2) VII. To determine the progression free survival (PFS). (Phase 2) VIII. To determine the time to best response. (Phase 2) IX. To assess the safety of the combination of LTD in patients with RRMM. (Phase 2) X. Time to next therapy. (Phase 2) XI. Symptom measurement - multiple-symptom assessment tool. (Phase 2)

OUTLINE: This is a dose-escalation study of lenalidomide and thalidomide.

Participants receive lenalidomide orally (PO) on days 1-21 and thalidomide PO once daily (QD) on days 1-28. Participants also receive dexamethasone PO QD on days 1-4, 9-12, and 17-20 of courses 1-2, and days 1, 8, 15, and 22 of subsequent courses. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Participants who have stable or responding disease to treatment receive lenalidomide PO on days 1-21 and thalidomide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Participants may receive dexamethasone at the discretion of the investigator.

After completion of study treatment, patients are followed up at 30 days.

Eligibility Criteria:
Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Relapsed/refractory multiple myeloma (MM) with measurable levels of myeloma paraprotein in serum (\>= 0.5 g/dl), urine (\>= 0.2 g excreted in a 24-hour collection sample), or abnormal free light chain (FLC) ratio
* Serum creatinine =\< 2.5 mg/dl
* Females of childbearing potential (FCBP)\* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mlU/mL within 10-14 days prior to and again within 24 hours of starting 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 female of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.

  * A female of childbearing potential 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).
* Absolute neutrophil count \> 1000 cells/mm\^3
* Platelet count \> 50,000 cells/mm\^3 for patients with \< 50% of bone marrow plasma cells and platelet count \> 25,000 cells/mm\^3 for patients in whom \> 50% of the bone marrow nucleated cells were plasma cells
* Total bilirubin =\< 2.0 mg/dL
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 3 x upper limit of normal (ULN)
* Able to take prophylactic anticoagulation, warfarin or equivalent agent
* Patient is able to understand and comply with the terms and conditions of the lenalidomide and thalidomide counseling program
* All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist, AND the S.T.E.P.S. program

Exclusion Criteria:

* Any serious medical condition, or psychiatric illness that would prevent the subject from signing the informed consent form
* Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide)
* Use of any cancer therapy within 21 days prior to beginning cycle 1 day 1 of therapy (radiation therapy allowed within 5 days of completion of radiation therapy).
* Known hypersensitivity to thalidomide, lenalidomide and dexamethasone.
* The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.