Refractory Multiple Myeloma
Conditions
Brief summary
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.
Detailed description
PRIMARY OBJECTIVES: 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 Glomerular filtration rate (GFR)-adjusted lenalidomide and low dose dexamethasone in patients with relapsed or refractory multiple myeloma. SECONDARY OBJECTIVES: * Response according to international response criteria (≥PR) and clinical benefit response (≥minor response according to adapted EBMT criteria) * 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 / HTLD-CKD level after cycle 1 * Changes in global gene expression in myeloma cells treated at the HTLD / HTLD-CKD 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.
Interventions
DRUGazacitidine
Given by subcutaneous injection (SC)
DRUGlenalidomide
Given orally
DRUGdexamethasone
Given orally
OTHERDNA methylation analysis
Correlative studies
OTHERgene expression analysis
Correlative studies
OTHERbone marrow aspiration
Correlative studies
OTHERimmunohistochemistry staining method
Correlative studies
OTHERreverse transcriptase-polymerase chain reaction
Correlative studies
OTHERflow cytometry
Correlative studies
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Understand and voluntarily sign an 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. * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry. * Laboratory test results within these ranges: * Absolute neutrophil count ≥ 1,500 /mm³ * Platelet count ≥ 75,000/mm³ * Calculated creatinine clearance (Cockcroft-Gault) ≥ 30ml/min. * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) levels ≤2 x ULN * 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. * 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 venous thromboembolic event (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 criteria
* 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 * Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockcroft-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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Highest Tolerated Low Dose (HTLD) | During the first 28-day cycle | Azacitidine given at low but increasing doses up to 50mg/m2 twice a week. Maximum tolerated dose reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Clinical Benefit and Response According to International Response Criteria | at 6 months | Percent of participants with response according to international response criteria (\>= PR) and percent of participants with 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. |
| Median Progression-free Survival (PFS) | Up to 3 years | Median PFS, measured in months from study entry to progression as defined by international response criteria or death of any cause, whichever comes first |
| Overall Survival | up to 3 years | Overall survival will be measured from study entry to death from any cause - median months survival will be reported |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Global Gene Expression | before and after the first cycle of therapy | 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) | at 6 months | 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. |
| Promoter Demethylation and Gene Reactivation | within 7 days before treatment start and at the end of cycle #1 | 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 |
| CD34+ Cell Yield and Time to Neutrophil and Platelet Recovery | after cycle 1 (28 days) | 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) |
Countries
United States
Participant flow
Pre-assignment details
The 11 phase II participants were a separate population from phase I
Participants by arm
| Arm | Count |
|---|---|
| Arm A (GFR>=60mL/Min) Dose Level DL 1 Azacitidine (AZA) 30mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week Azacitidine/Lenalidomide/Dexamethasone 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.
lenalidomide: Given orally
dexamethasone: Given orally
DNA methylation analysis: Correlative studies
gene expression analysis: Correlative studies
bone marrow aspiration: Correlative studies
immunohistochemistry staining method: Correlative studies
reverse transcriptase-polymerase chain reaction: Correlative studies
flow cytometry: Correlative studies | 3 |
| Arm A (GFR>=60mL/Min) Dose Level 2 Azacitidine 40mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week 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
lenalidomide: Given orally
dexamethasone: Given orally
DNA methylation analysis: Correlative studies
gene expression analysis: Correlative studies
bone marrow aspiration: Correlative studies
immunohistochemistry staining method: Correlative studies
reverse transcriptase-polymerase chain reaction: Correlative studies
flow cytometry: Correlative studies | 3 |
| Arm A (GFR>=60mL/Min) Dose Level 3 Azacitidine 30mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week 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. | 4 |
| Arm A (GFR>=60mL/Min) Dose Level 4 Azacitidine 40mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week 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. | 6 |
| Arm A (GFR>=60mL/Min) Dose Level 5 Azacitidine 50mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week 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. | 7 |
| Arm B (GFR 30-59mL/Min - CKD) Dose Level -1 Azacitidine 30mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week 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. | 0 |
| Arm B (GFR 30-59mL/Min - CKD) Dose Level 1 Azacitidine 40mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week | 3 |
| Arm B (GFR 30-59mL/Min - CKD) Dose Level 2 Azacitidine 50mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week | 7 |
| Arm A or B GFR >= 30mL/ Min Expansion Dose (50 BIW) Azacitidine 50mg/m2 2x week + Lenalidomide (10mg if CKD, 25mg if non-CKD) d1-21 every 28d + Dexamethasone 40mg once a week | 11 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Phase I | Screen failure - did not start treatment | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 |
| Phase I | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Arm A (GFR>=60mL/Min) Dose Level 2 | Arm A (GFR>=60mL/Min) Dose Level 3 | Arm A (GFR>=60mL/Min) Dose Level DL 1 | Arm A (GFR>=60mL/Min) Dose Level 4 | Arm A (GFR>=60mL/Min) Dose Level 5 | Arm B (GFR 30-59mL/Min - CKD) Dose Level -1 | Arm B (GFR 30-59mL/Min - CKD) Dose Level 1 | Arm B (GFR 30-59mL/Min - CKD) Dose Level 2 | Arm A or B GFR >= 30mL/ Min Expansion Dose (50 BIW) |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 3 Participants | 4 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants | 7 Participants | 0 Participants | 3 Participants | 7 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 40 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 5 Participants | 0 Participants | 3 Participants | 6 Participants | 11 Participants |
| Region of Enrollment United States | 44 participants | 3 participants | 4 participants | 3 participants | 6 participants | 7 participants | — | 3 participants | 7 participants | 11 participants |
| Sex: Female, Male Female | 25 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 0 Participants | 1 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 19 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 4 / 4 | 5 / 6 | 6 / 6 | 0 / 0 | 3 / 3 | 5 / 6 | 10 / 11 |
| other Total, other adverse events | 3 / 3 | 1 / 3 | 2 / 4 | 2 / 6 | 3 / 6 | 0 / 0 | 1 / 3 | 4 / 6 | 9 / 11 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 2 / 4 | 2 / 6 | 1 / 6 | 0 / 0 | 1 / 3 | 1 / 6 | 1 / 11 |
Outcome results
Primary
Phase I: Highest Tolerated Low Dose (HTLD)
Azacitidine given at low but increasing doses up to 50mg/m2 twice a week. Maximum tolerated dose reported.
Time frame: During the first 28-day cycle
Population: Participants in phase 1 portion of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Phase I: Highest Tolerated Low Dose (HTLD) | 50 mg/m^2 |
| Arm B - CKD Azacitidine/Lenalidomide/Dexamethasone | Phase I: Highest Tolerated Low Dose (HTLD) | 50 mg/m^2 |
Secondary
Median Progression-free Survival (PFS)
Median PFS, measured in months from study entry to progression as defined by international response criteria or death of any cause, whichever comes first
Time frame: Up to 3 years
Population: Evaluable participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Median Progression-free Survival (PFS) | 3.1 months |
Secondary
Overall Survival
Overall survival will be measured from study entry to death from any cause - median months survival will be reported
Time frame: up to 3 years
Population: Evaluable participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Overall Survival | 18.6 months |
Secondary
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Percent of participants with response according to international response criteria (\>= PR) and percent of participants with 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.
Time frame: at 12 months
Population: Response-evaluable participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | International response criteria (>= PR) | 22 percentage of participants |
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | clinical benefit response (>= minor response) | 32 percentage of participants |
| Arm B - CKD Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | International response criteria (>= PR) | 23 percentage of participants |
| Arm B - CKD Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | clinical benefit response (>= minor response) | 32 percentage of participants |
Secondary
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Percent of participants with response according to international response criteria (\>= PR) and percent of participants with 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.
Time frame: at 6 months
Population: Response-evaluable participants. Data from different dose levels were combined for the analysis as pre-specified in the study protocol
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | international response criteria (>= PR) | 20 percentage of participants |
| Arm A - Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | clinical benefit response (>= minor response) | 32 percentage of participants |
| Arm B - CKD Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | international response criteria (>= PR) | 23 percentage of participants |
| Arm B - CKD Azacitidine/Lenalidomide/Dexamethasone | Percent of Participants With Clinical Benefit and Response According to International Response Criteria | clinical benefit response (>= minor response) | 32 percentage of participants |
Other Pre-specified
CD34+ Cell Yield and Time to Neutrophil and Platelet Recovery
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)
Time frame: after cycle 1 (28 days)
Other Pre-specified
Changes in Global Gene Expression
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.
Time frame: before and after the first cycle of therapy
Other Pre-specified
Promoter Demethylation and Gene Reactivation
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
Time frame: within 7 days before treatment start and at the end of cycle #1
Other Pre-specified
Quantify the Activity of Azacitidine Inactivating Enzyme Cytidine Deaminase (CDA)
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.
Time frame: at 6 months