Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to study the MRD status after VELCADE based induction therapy (VELCADE, lenalidomide, dexamethasone or VELCADE, liposomal doxorubicin, dexamethasone) in patients with previously untreated multiple myeloma and study the impact of HDC and ASCT on MRD status post-transplant. Our hypothesis is that MRD-status will continue to increase significantly at 3 months post-transplant and will validate that HDC and ASCT needs to be performed even when patients have achieved major response after induction therapy with novel agents.
Interventions
DRUGVELCADE
1.3 mg/m2 by IV on days 1, 4, 8, 11 of each cycle
DRUGLenalidomide
25 mg by mouth on days 1-4 of each cycle
DRUGDexamethasone
20 mg the day before and the day after receiving VELCADE
DRUGDVT prophylaxis
At least one asprin 81 mg per day. Other option per physician's choice
DRUGBisphosphonates
Zoledronic acid by IB or pamidronate by IV can be used as per standard of care.
DRUGLiposomal doxorubicin
30 mg/m2 on day 4 of each cycle
Sponsors
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Confirmed Multiple Myeloma as defined below within 120 days of starting cycle 1: * Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma * Presence of M protein in serum or urine or both. Conventional M spike, serum free light chains, or 24 hour urine study. Non-secretory myeloma is not eligible for this study. * In addition patient must have one of the following organ dysfunction criteria * Hypercalcemia * Renal insufficiency * Anemia * Bone disease manifested by lytic lesion or osteoporosis (if osteoporosis is the only organ dysfunction criteria then BM should have ≥ 30% plasma cells) * Confirmed Multiple myeloma as defined above within 90 days of starting cycle 1 * The following study assessments must be fulfilled and must be obtained with four weeks of starting cycle 1 * Hemoglobin \> 7 g/dL, Platelet count \> 75 X 10 to 9th power/L, and Absolute neutrophil count \> 1 X 10 to 9th power/L * Creatinine \<2.5 mg/dL or calculated creatinine clearance \> 30 ml/min/1.72 m2 * Bilirubin ≤ 1.5 mg/dL X ULN * SGPT (ALT) and SGOT (AST) ≤ 2.5 times the upper limit of normal * Ejection fraction ≥ 45% as measured by a MUGA scan or 2 D echocardiogram * Pulmonary function tests show \>60% predicted values for FVC, FEV1, and DLCO FEV1 must be \> 1 liter. * No prior systemic therapy with the exception of bisphosphonates for MM * Prior glucocorticoid therapy for the treatment of multiple myeloma is not permitted EXCEPT if used in conjunction with palliative radiation to prevent vasogenic edema. In that case steroids should have been used for less than 7 days. Prior steroid use for non-malignant disorders is permitted and should have been restricted to less than the equivalent of prednisone 10 mg per day. Prior or concurrent topical or localized steroid therapy to treat non-malignant disorders is permitted * Prior palliative and/ or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to starting cycle 1. * Patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma and meeting all eligibility criteria for the protocol * ECOG PS 0, 1 or 2 * For women of childbearing potential a negative serum pregnancy test is required within 4 weeks of starting cycle 1 and then every 4 weeks during the first 4 cycles of induction therapy * Women of child bearing potential must be willing to refrain from sexual intercourse or willing to employ a dual method of contraception, one of which is highly effective (IUD, birth control pills, tubal ligation or partner's vasectomy) and another additional method (condom, diaphragm, or cervical cap) during the entire course of the study (start of therapy until 30 days after stem cell transplant). * Sexually active males should be willing to use a condom (even if they have had a prior vasectomy) while having intercourse with any women during the course of the study (start of therapy until 30 days after stem cell transplant). * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
Exclusion criteria
* Patients with smoldering myeloma or monoclonal gammopathy of unknown significance are not eligible * Age \> 70 years or \< 18 years is not eligible * Patient has \> 1.5 × ULN Total Bilirubin * Grade 2 or higher peripheral neuropathy due to ANY cause * High index of suspicion of primary amyloid light chain (AL) amyloidosis. * Patients with uncontrolled inter-current illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance or a prior history of Steven Johnson syndrome * Patients must not have a history of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy * Female patients who are breastfeeding or pregnant. * Patients known to be HIV positive * Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 31.3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. * Patient has hypersensitivity to VELCADE, boron or mannitol. * Patient has received other investigational drugs within 14 days before enrollment * Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percent of Patients With Minimal Residual Disease (MRD) Status Changing to Negative at Day 100 (Post-AHCT), Among Patients With MRD Positive at the End of Induction (EOI). | 6-months post ASCT | Patients were treated with induction therapy (VRD) followed by autologous hematopoietic cell transplant (AHCT). MRD status of a patient with at least partial response was evaluated at the end of induction (EOI) and day 100 (post-AHCT). MRD of a patient is measured by seven-color flow cytometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival by MRD Status at Day 100. | up to 7 years | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Countries
United States
Participant flow
Recruitment details
Participants participated in this trial at Vanderbilt-Ingram Cancer Center in Nashville, TN and the Boston Baskin Cancer Group in Memphis, TN. A total of 52 people consented to take part in this study and 15 were ineligible. One participant had disease progression before beginning treatment and wasn't assigned to a treatment arm.
Participants by arm
| Arm | Count |
|---|---|
| VRD (VELCADE, Lenalidomide, Dexamethasone) VELCADE, Lenalidomide, Dexamethasone
VELCADE: 1.3 mg/m2 by IV on days 1, 4, 8, 11 of each cycle
Lenalidomide: 25 mg by mouth on days 1-4 of each cycle
Dexamethasone: 20 mg the day before and the day after receiving VELCADE
DVT prophylaxis: At least one asprin 81 mg per day. Other option per physician's choice
Bisphosphonates: Zoledronic acid by IB or pamidronate by IV can be used as per standard of care. | 33 |
| VDD (VELCADE, Liposomal Doxorubicin, Dexamethasone) VELCADE, liposomal doxorubicin, dexamethasone
VELCADE: 1.3 mg/m2 by IV on days 1, 4, 8, 11 of each cycle
DVT prophylaxis: At least one asprin 81 mg per day. Other option per physician's choice
Liposomal doxorubicin: 30 mg/m2 on day 4 of each cycle
Dexamethasone: 40 mg by mouth on days 1-4, 8-11, and 15-18 of cycle 1 and days 1-4 on cycle 2-4 | 3 |
| Total | 36 |
Baseline characteristics
| Characteristic | VDD (VELCADE, Liposomal Doxorubicin, Dexamethasone) | VRD (VELCADE, Lenalidomide, Dexamethasone) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 9 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 24 Participants | 27 Participants |
| Age, Continuous | 48 years STANDARD_DEVIATION 4.642796 | 60 years STANDARD_DEVIATION 8.71411 | 58.5 years STANDARD_DEVIATION 8.80389 |
| Region of Enrollment United States | 3 participants | 33 participants | 36 participants |
| Sex: Female, Male Female | 0 Participants | 13 Participants | 13 Participants |
| Sex: Female, Male Male | 3 Participants | 20 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 33 | 3 / 3 |
| serious Total, serious adverse events | 9 / 33 | 0 / 3 |
Outcome results
Primary
The Percent of Patients With Minimal Residual Disease (MRD) Status Changing to Negative at Day 100 (Post-AHCT), Among Patients With MRD Positive at the End of Induction (EOI).
Patients were treated with induction therapy (VRD) followed by autologous hematopoietic cell transplant (AHCT). MRD status of a patient with at least partial response was evaluated at the end of induction (EOI) and day 100 (post-AHCT). MRD of a patient is measured by seven-color flow cytometry.
Time frame: 6-months post ASCT
Population: Newly diagnosed, symptomatic multiple myeloma (MM) patients. Patients were treated with induction therapy VRD followed by AHCT. MRD staus was evaluated for patients with at least partial response at the end of induction (EOI) therapy. Ten of these patients had MRD negative at EOI.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VELCADE, Lenalidomide, Dexamethasone (VRD) | The Percent of Patients With Minimal Residual Disease (MRD) Status Changing to Negative at Day 100 (Post-AHCT), Among Patients With MRD Positive at the End of Induction (EOI). | 30 percentage of participants |
Secondary
Progression Free Survival by MRD Status at Day 100.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: up to 7 years
Population: Patients with MRD status information at the EOI and day 100 (post-AHCT).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VELCADE, Lenalidomide, Dexamethasone (VRD) | Progression Free Survival by MRD Status at Day 100. | 2.64 years |
| VELCADE, Liposomal Doxorubicin, Dexamethasone (VDD) | Progression Free Survival by MRD Status at Day 100. | NA years |