Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

• Phase I: Highest tolerated low dose (HTLD) [ Time Frame: during the first 28-day cycle ] [ Designated as safety issue: Yes ]
  azacitidine given at low but increasing doses up to 50mg/m2 twice a week
• Phase II: Response rate as evidence of progressive or new bone lesions [ Time Frame: after 6 months (cycles) of treatment ] [ Designated as safety issue: No ]
  Response according to international response criteria (>= PR) and clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.
• Phase II: Response rate as evidence of progressive or new bone lesions [ Time Frame: after 12 months (cycles) of treatment ] [ Designated as safety issue: No ]
  Response according to international response criteria (>= PR) and clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.

• Progression-free survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
• CD34+ cell yield and time to neutrophil and platelet recovery [ Time Frame: after cycle 1 (28 days) ] [ Designated as safety issue: No ]
  CD34+ cell yield will be calculated based on flow cytometry of mononuclear cells harvested following stem cell mobilization. Time to neutrophil (> 1,000/mm3) and platelet (> 100,000/mm3) recovery will be counted from the day of stem cell infusion (=day 0)
• Promoter demethylation and gene reactivation [ Time Frame: within 7 days before treatment start and at the end of cycle #1 ] [ Designated as safety issue: No ]
  Promoter demethylation and gene reactivation will be measured at least at the HTLD level using the Illumina® HumanMethylation27 BeadChip array on CD138 purified and CD34 purified cells obtained from bone marrow aspirates
• Changes in global gene expression [ Time Frame: before and after the first cycle of therapy ] [ Designated as safety issue: No ]
  The RNA harvested from myeloma cells before and after the first cycle of therapy at the HTLD level will furthermore be used to identify changes in global gene expression using the Illumina® HT12 array.
• Quantify the activity of azacitidine inactivating enzyme cytidine deaminase (CDA) [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
  Plasma from peripheral blood draws will be used to quantify the activity of CDA using an HPLC method.The enzymatic activity is determined by comparison of cytidine deamination achieved by plasma samples with deamination achieved by incubation of cytidine with dilutions of pure CDA enzyme standards.

• Response [ Time Frame: Monthly during the first 12 cycles and every two months thereafter ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
• CD34+ cell yield and time to neutrophil and platelet recovery [ Time Frame: recovery will be counted from the day of stem cell infusion (=day 0) ] [ Designated as safety issue: No ]
  CD34+ cell yield will be calculated based on flow cytometry of mononuclear cells harvested following stem cell mobilization. Time to neutrophil (> 1,000/mm3) and platelet (> 100,000/mm3) recovery will be counted from the day of stem cell infusion (=day 0)
• Promoter demethylation and gene reactivation [ Time Frame: within 7 days before treatment start and at the end of cycle #1 ] [ Designated as safety issue: No ]
  Promoter demethylation and gene reactivation will be measured at least at the HTLD level using the Illumina® HumanMethylation27 BeadChip array on CD138 purified and CD34 purified cells obtained from bone marrow aspirates
• Changes in global gene expression [ Time Frame: before and after the first cycle of therapy ] [ Designated as safety issue: No ]
  The RNA harvested from myeloma cells before and after the first cycle of therapy at the HTLD level will furthermore be used to identify changes in global gene expression using the Illumina® HT12 array.

RATIONALE: Drugs used in chemotherapy, such as azacitidine and dexamethasone, work in different ways to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Giving azacitidine together with lenalidomide and dexamethasone may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of azacitidine when given together with lenalidomide and low-dose dexamethasone in treating patients with relapsed or refractory multiple myeloma.

PRIMARY OBJECTIVES:

Phase I: Define the highest tolerated low dose (HTLD) and safety of azacitidine given at low but increasing doses up to 50mg/m2 twice a week concurrently with standard dose lenalidomide and low dose dexamethasone in patients with relapsed or refractory multiple myeloma.

Phase II: Response according to international response criteria (>= PR) and clinical benefit response (>= minor response according to adapted EBMT (European Group for Blood and Marrow Transplantation) criteria). PR=partial response

SECONDARY OBJECTIVES:

• Correlate response with plasma activity of the azacitidine inactivating enzyme cytidine deaminase (CDA)
• Progression-free survival and overall survival
• Peripheral blood hematopoietic progenitor (CD34+) yield and time to neutrophil and platelet recovery in patients undergoing autologous stem cell transplantation
• Promoter demethylation and gene reactivation in myeloma cells and hematopoietic progenitors treated at the HTLD level after cycle 1
• Changes in global gene expression in myeloma cells treated at the HTLD level after cycle 1

OUTLINE:

This is a phase I, dose-escalation study of azacitidine followed by a phase II study.

Patients receive azacitidine subcutaneously once or twice weekly and oral dexamethasone once weekly starting on day 1. Patients also receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

• Drug: azacitidine
  Given SC
  Other Names:

  • 5-AC
  • 5-azacytidine
  • 5-AZC
  • azacytidine
  • ladakamycin
  • Vidaza
• Drug: lenalidomide
  Given orally
  Other Names:

  • CC-5013
  • IMiD-1
  • Revlimid
• Drug: dexamethasone
  Given orally
  Other Names:

  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • Decaspray
  • DM
  • DXM
• Other: DNA methylation analysis
  Correlative studies
• Other: gene expression analysis
  Correlative studies
• Other: bone marrow aspiration
  Correlative studies
• Other: immunohistochemistry staining method
  Correlative studies
  Other Name: immunohistochemistry
• Other: reverse transcriptase-polymerase chain reaction
  Correlative studies
  Other Name: RT-PCR
• Other: flow cytometry
  Correlative studies

Inclusion

• Understand and voluntarily sign an informed consent form
• Age ≥18 years at the time of signing the informed consent form
• Able to adhere to the study visit schedule and other protocol requirements
• Refractory or relapsed multiple myeloma
• Measurable disease defined as at least one of the following: Serum m-spike >= 1g/dL, urine m-spike >= 200mg/24hrs, serum free light chains >= 100mg/L (provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells >= 30%
• Previous therapy with IMiD™ compounds (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study.
• Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, and vinca alkaloids), radiation therapy to the pelvis, and any experimental therapy other than carfilzomib or pomalidomide must have been discontinued at least 28 days prior to entry onto this study.
• ECOG performance status of ≤ 2 at study entry (see Appendix II).

• Laboratory test results within these ranges:

  • Absolute neutrophil count ≥ 1,500 /mm³
  • Platelet count ≥ 75,000/mm³
  • Calculated creatinine clearance (Cockroft-Gault) ≥ 30ml/min.
  • Total bilirubin ≤ 1.5 x ULN
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels ≤2 x ULN
• Disease-free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
• All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
• Females of childbearing potential (FCBP)must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) 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. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) if no additional risk factor for VTE other than myeloma diagnosis according to IMW guidelines
• Able to take low molecular weight heparin or warfarin if >1 additional risk factor for VTE according to IMW guidelines

Exclusion

• Any serious medical condition, laboratory abnormality, 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 or azacitidine)
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Use of any experimental drug or therapy other than carfilzomib and pomalidomide within 28 days of treatment start on this protocol.
• Neuropathy > Grade 2
• Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or lenalidomide drugs
• Concurrent use of other anti-cancer agents or treatments, concurrent radiation to the pelvis. Palliative radiation to areas outside the pelvis is allowed
• Known positive for HIV or infectious hepatitis, type B or C
• Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockroft-Gault at the time of previous lenalidomide treatment (25mg day 1-21 every 28 days if CrCl > 60ml/min, 10mg lenalidomide d1-21 every 28 days if CrCl < 60mL/min but > 30mL/min, lenalidomide 15mg every 48 h d1-21 every 28 days if CrCl < 30mL/min but not requiring dialysis, lenalidomide 5mg daily, day 1-21 every 28 days if CrCl < 30mL/min and requiring dialysis).