Multiple Myeloma
Conditions
Brief summary
This randomized phase III trial studies melphalan and prednisone with thalidomide to see how well it works compared to melphalan and prednisone together with lenalidomide in treating patients with newly diagnosed multiple myeloma. Drugs used in chemotherapy, such as melphalan and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Thalidomide and lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. It is not yet known whether melphalan and prednisone are more effective when given together with thalidomide or lenalidomide in treating multiple myeloma.
Detailed description
PRIMARY OBJECTIVES: I. To compare progression-free survival between patients receiving melphalan, prednisone, and thalidomide versus melphalan, prednisone, and lenalidomide in newly diagnosed multiple myeloma patients who are not candidates for high-dose therapy. SECONDARY OBJECTIVES: I. To compare overall survival between the arms. II. To compare response rates and depth of response. III. To compare the incidence of toxicities. IV. To validate the translocation classification (TC) of myeloma as a prognostic tool using gene expression profiling at diagnosis. TERTIARY OBJECTIVES: I. To compare quality-of-life (QOL) change between arms based on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) Trial Outcome Index (TOI) from registration (prior to initiation of treatment) to the end of cycle 24 (maintenance therapy). II. To examine the impact of differential treatment response (PFS), if observed, on QOL based on the FACT-Ntx TOI up to cycle 38 (maintenance therapy). III. To obtain prospective data on myeloma specific QOL attributes. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION THERAPY: Patients receive melphalan orally (PO) and prednisone PO once daily (QD) on days 1-4, and thalidomide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive thalidomide PO QD and continue in the absence of disease progression. ARM II: INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO QD on days 1-4, and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive lenalidomide PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression. After completion of study treatment, patients are followed up periodically for 10 years.
Interventions
OTHERLaboratory Biomarker Analysis
Optional correlative studies
DRUGLenalidomide
Given PO
DRUGMelphalan
Given PO
DRUGPrednisone
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
DRUGThalidomide
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a confirmed diagnosis of symptomatic myeloma; for the original diagnosis of myeloma patients should have met the following criteria at one point in their disease course: * Bone marrow plasmacytosis with \>= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma * Patient must have had symptomatic disease at initial diagnosis that prompted the initiation of therapy as well as evidence of end-organ damage at the time of diagnosis namely; at least one of the following: anemia, hypercalcemia, bone disease (lytic bone lesions or pathologic fracture), or renal dysfunction * NOTE: Patients with asymptomatic smoldering myeloma (serum m protein \>= 3 gm/dL or bone marrow plasma cells \>= 10% or greater plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and monoclonal gammopathy of undetermined significance (serum m protein \< 3 gm/dL and bone marrow plasma cells \< 10% plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible * Patients must be \> 65 and have declined alternative treatment OR patients who are \>= 18 \< 65 are eligible if they: * Are not a candidate for autologous stem cell transplantation in the opinion of the treating physician OR * Have declined transplant or other alternative treatment * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * All tests below must be performed within 28 days prior to randomization: * Serum free light chain assay * Kappa free light chain * Lambda free light chain * NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine; measurable disease in the serum is defined as having a serum M-spike \>= 1 g/dL; measurable disease in the urine is defined as having a urine M-spike \>= 200 mg/24 hr * NOTE: urine protein electrophoresis (UPEP) (on a 24 hour collection) is required, no substitute method is acceptable; urine must be followed monthly if the baseline urine M-spike is \>= 200 mg/24 hr; please note that if both serum and urine m-components are present, both must be followed in order to evaluate response * Hemoglobin \> 7 g/dL * Platelet count \> 75,000 cells/mm\^3 * Absolute neutrophil count \> 1000 cells/mm\^3 * Creatinine \< 2.5 mg/dL and creatinine clearance (measured or calculated) \> 60 mL/min * Total bilirubin =\< 1.5 mg/dL * Serum glutamate pyruvate transaminase (SGPT) \[alanine aminotransferase (ALT)\] and serum glutamic oxaloacetic transaminase (SGOT) \[aspartate aminotransferase (AST)\] =\< 2.5 times the upper limit of normal * Patients must be previously untreated for myeloma, although prior treatment for myeloma with prednisone or dexamethasone for less than 4 weeks total dosing alone or in combination with thalidomide or lenalidomide for less than 2 weeks total dosing is allowable * Patients may be receiving bisphosphonates or growth factors (erythropoietin) for multiple myeloma; although erythropoietin is allowed, it is strongly discouraged due to increased risk of thrombosis when employed alongside thalidomide and/or lenalidomide therapy * Patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they 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 starting 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; a FCBP 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); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure * Patients must not have uncontrolled inter-current illness that would limit compliance with the study including: * Uncontrolled hypertension * Symptomatic congestive heart failure * Unstable angina * Uncontrolled cardiac arrhythmia * Uncontrolled psychiatric illness or social situation * Prior history of Stevens Johnson syndrome * Patients must not have grade 2 or higher peripheral neuropathy * Patients must not have an active, uncontrolled infection * Female patients MUST NOT be pregnant or breastfeeding; the use of these drugs in this patient population is ABSOLUTELY CONTRAINDICATED; for women of childbearing potential, a negative serum pregnancy test is required within 10-14 days prior to randomization; for female patients of childbearing potential a negative serum pregnancy test must be repeated within 24 hours prior to initiation of treatment, weekly for the first 4 weeks of treatment and then every 4 weeks if the patient's periods are regular or every 2 weeks if they are not; women of childbearing potential must be willing to refrain from sexual intercourse or must be willing to employ a dual method of contraception, one of which is highly effective \[intrauterine device (IUD), birth control pills, tubal ligation or partner's vasectomy\] and another additional method (condom, diaphragm or cervical cap) starting 4 weeks prior to and while taking lenalidomide and thalidomide and for four weeks after discontinuing this therapy; the male partner of a female using a single form of birth control should use a condom regardless of his vasectomy status * Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking lenalidomide and thalidomide and for 4 weeks after stopping treatment * Patients must not have had a second active malignancy requiring treatment within the last 2 years, with the exceptions of basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization. | PFS is defined as the time from randomization to the earlier of progression or death of any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization. | Overall survival was defined as time from randomization to death from any cause. |
| Very Good Partial Response (VGPR) Rate | Assessed every cycle (1 cycle=28 days) for the first 12 cycles, and then every 2 cycles while on treatment. Post treatment assessed every 3 months < 2 years from study entry, every 6 months if 2-5 years, every 12 months if 6-10 years from study entry. | Response evaluation was based on the International Myeloma Working Group (IMWG) response criteria. VGPR rate was defined as patients achieving at least VGPR which include patients who achieving complete response (CR) and VGPR. CR refers to patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow. VGPR refers to patients who meet the following criteria: Serum and urine M-component detectable by immunofixation but not on electrophoresis; Or 90% or greater reduction in serum M-component plus urine M-component \<100 mg per 24 hours; If the serum and urine M protein are unmeasurable and the immunoglobulin free light chain parameter is being used to measure response, a ≥ 90% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M protein criteria. |
| Change in Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) Score From Baseline to Cycle 12 | Administered at registration, the beginning of cycle 7 d1, the end of cycle 12 d28, then at the end of cycle 18, 24, and 38 d28. For patients who discontinue treatment early, assessed at time of discontinuation and at the next quarterly follow-up visit. | A combined scale was used to assess the quality of life (QOL) comprising of the well established and validated functional well-being (FWB) and physical well-being (PWB) components of FACT-G version 4 (14 questions), which will address the physical and functional well-being of multiple myeloma patients plus the FACT-neurotoxicity (NTX, 11 questions), which will evaluate symptoms of neurotoxicity. This pooled scale is referred to as the FACT Ntx TOI. The FACT-Ntx TOI has 25 items and the score ranges from 0 (worst possible outcome) to 100 (best possible outcome). |
Countries
Israel, United States
Contacts
PRINCIPAL_INVESTIGATORAlexander K Stewart
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
The study was activated on February 29, 2008 and closed to accrual on November 30, 2011 with final accrual of 306 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (MPT-T) Patients receive melphalan, prednisone and thalidomide induction plus thalidomide maintenance (MPT-T).
INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO daily on days 1-4, and thalidomide PO daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive thalidomide PO daily and continue in the absence of disease progression.
melphalan: Given PO
prednisone: Given PO
thalidomide: Given PO | 154 |
| Arm II (mPR-R) Patients receive lower-dose melphalan, prednisone and lenalidomide (Revlimid®) induction plus lenalidomide maintenance (mPR-R).
INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO daily on days 1-4, and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression.
melphalan: Given PO
prednisone: Given PO
lenalidomide: Given PO | 152 |
| Total | 306 |
Baseline characteristics
| Characteristic | Arm I (MPT-T) | Arm II (mPR-R) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 145 Participants | 146 Participants | 291 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 6 Participants | 15 Participants |
| International Staging System (ISS) Stage I | 45 participants | 36 participants | 81 participants |
| International Staging System (ISS) Stage II | 58 participants | 70 participants | 128 participants |
| International Staging System (ISS) Stage III | 49 participants | 46 participants | 95 participants |
| International Staging System (ISS) Unknown/Missing | 2 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 68 Participants | 71 Participants | 139 Participants |
| Sex: Female, Male Male | 86 Participants | 81 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 29 / 148 | 34 / 151 |
| serious Total, serious adverse events | 110 / 148 | 88 / 150 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS is defined as the time from randomization to the earlier of progression or death of any cause.
Time frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization.
Population: Intention-to-treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (MPT-T) | Progression-Free Survival (PFS) | 21.0 months |
| Arm II (mPR-R) | Progression-Free Survival (PFS) | 18.7 months |
Comparison: Since mPR-R was expected to be considerably less toxic and to confer slightly longer PFS, a non-inferiority design with superiority alternative was used.90% CI: [0.67, 1.045]
Secondary
Change in Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) Score From Baseline to Cycle 12
A combined scale was used to assess the quality of life (QOL) comprising of the well established and validated functional well-being (FWB) and physical well-being (PWB) components of FACT-G version 4 (14 questions), which will address the physical and functional well-being of multiple myeloma patients plus the FACT-neurotoxicity (NTX, 11 questions), which will evaluate symptoms of neurotoxicity. This pooled scale is referred to as the FACT Ntx TOI. The FACT-Ntx TOI has 25 items and the score ranges from 0 (worst possible outcome) to 100 (best possible outcome).
Time frame: Administered at registration, the beginning of cycle 7 d1, the end of cycle 12 d28, then at the end of cycle 18, 24, and 38 d28. For patients who discontinue treatment early, assessed at time of discontinuation and at the next quarterly follow-up visit.
Population: Patients who completed both baseline and cycle 12 QOL assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (MPT-T) | Change in Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) Score From Baseline to Cycle 12 | -2.8 units on a scale | Standard Deviation 15 |
| Arm II (mPR-R) | Change in Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) Score From Baseline to Cycle 12 | 3.3 units on a scale | Standard Deviation 13.7 |
p-value: 0.007Wilcoxon (Mann-Whitney)
Secondary
Overall Survival
Overall survival was defined as time from randomization to death from any cause.
Time frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization.
Population: Intention-to-treatment (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (MPT-T) | Overall Survival | 52.6 months |
| Arm II (mPR-R) | Overall Survival | 47.7 months |
p-value: 0.476Log Rank
Secondary
Very Good Partial Response (VGPR) Rate
Response evaluation was based on the International Myeloma Working Group (IMWG) response criteria. VGPR rate was defined as patients achieving at least VGPR which include patients who achieving complete response (CR) and VGPR. CR refers to patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow. VGPR refers to patients who meet the following criteria: Serum and urine M-component detectable by immunofixation but not on electrophoresis; Or 90% or greater reduction in serum M-component plus urine M-component \<100 mg per 24 hours; If the serum and urine M protein are unmeasurable and the immunoglobulin free light chain parameter is being used to measure response, a ≥ 90% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M protein criteria.
Time frame: Assessed every cycle (1 cycle=28 days) for the first 12 cycles, and then every 2 cycles while on treatment. Post treatment assessed every 3 months < 2 years from study entry, every 6 months if 2-5 years, every 12 months if 6-10 years from study entry.
Population: Intention-to-treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (MPT-T) | Very Good Partial Response (VGPR) Rate | 0.247 proportion of participants |
| Arm II (mPR-R) | Very Good Partial Response (VGPR) Rate | 0.316 proportion of participants |
p-value: 0.204Fisher Exact