Multiple Myeloma
Conditions
Keywords
multiple myeloma, induction therapy, autologous hematopoietic cell transplantation, KRdD, Daratumumab, Carfilzomib, Lenalidomide
Brief summary
Multiple myeloma (MM), a plasma cell disorder, is the second most common hematologic malignancy in the U.S. No standard curative therapy has yet been found. A variety of therapeutic measures including high dose melphalan, induction therapy, and continuous therapy have been used but the goal of complete response without relapse has not been achieved. More active treatment regimens and better tools for response assessment are needed.
Detailed description
This trial will assess the safety and efficacy of an induction therapy using the combination of dexamethasone, lenalidomide (revlimid), daratumumab (Darzalex) and carfilzomib (Kyprolis) to treat patients with newly diagnosed multiple myeloma. The therapy with KRdD (Kyprolis, Revlimid, dexamethasone, Darzalex) will be followed by autologous hematopoietic cell transplantation (auto-HCT) and KRdD consolidation. Duration of therapy will be guided by eradication of minimal residual disease (MRD). The hypothesis is that the KRdD therapy particularly in combination with the auto-HCT will be safe and lead to deep remission. Patients who become MRD- will discontinue therapy (no maintenance therapy) and be actively monitored for resurgence of MRD or clinical relapse.
Interventions
DRUGKRdD followed by auto-HCT
Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will be followed by autologous hematopoietic cell transplantation and KRdD consolidation.
DRUGKRdD only
Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will not be followed by autologous hematopoietic cell transplantation but will proceed with KRdD consolidation.
Sponsors
Amgen
Janssen Scientific Affairs, LLC
University of Alabama at Birmingham
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study has four cycles (28-days each) of drug therapy prior to being evaluated for auto-HCT. After the completion of induction therapy, the patient will be evaluated for a transplant of their own hematopoietic stem cells. If, after the transplant, the patient still has detectable multiple myeloma, the patient will proceed to a series of consolidation blocks, up to three, consisting of four cycles of the KRdD at specified dosages and time frames. After completion of consolidation therapy, maintenance therapy will begin until disease progression or intolerance.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>18 years with no upper age limit * Diagnosis of newly diagnosed multiple myeloma with indication for initiation of therapy. * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * No prior MM-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib (up to 5.2 mg/m2) and/or cyclophosphamide up to 1000 mg/m2 administered for management of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer than 4 weeks prior to enrollment. If subject received any prior therapy, pretreatment parameters necessary for disease characterization and response assessment must be available. * Measurable disease meeting at least one of the following criteria: 1. Serum monoclonal (M) protein ≥1.0 g/dl 2. ≥ 200 mg of M protein/24h in the urine 3. Serum-free light chain ≥10 mg/dL and abnormal kappa to lambda ratio. * Life expectancy ≥12 months. * Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) within 21 days prior to initiation of therapy. * Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days prior to start of therapy either measured or calculated using a standard formula (eg. Cockcroft and Gault). * Written informed consent in accordance with federal, local, and institutional guidelines. * Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception. Male subjects must agree to practice contraception. * All subjects must agree to comply with and be enrolled in Revlimid REMS program.
Exclusion criteria
* Diagnosis of amyloidosis, Crow-Fukase syndrome, Waldenstrom's macroglobulinemia, smoldering MM. * Major surgery, radiotherapy or infection requiring therapy within 14 days of starting treatment. * Known FEV1 or cDLCO \< 50% of predicted. * Pregnant or lactating females. * Known human immunodeficiency virus infection. * Active hepatitis B (Hepatitis B core antibody positive and subsequent Hepatitis B surface antigen positive or Hepatitis B DNA positive) or C infection (Hepatitis C antibody positive and subsequent detectable viral load). * Unstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association Class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker. * Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior to initiation of therapy * Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. * Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 21 days prior to registration. * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 21 days prior to registration. * Contraindication or intolerance to required supportive care medications (Aspirin and Acyclovir). * Any other clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With MRD(-) Remissions at the Completion of Consolidation Therapy | Baseline until MRD(-) is reached estimated to be up to 15 months. | The primary endpoint of MRD(-) rate, or percentage of patients with MRD(-) remissions, will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With MRD(-) Status at the Completion of Induction Therapy | Baseline until MRD(-) status estimated at 6 months or until disease progression | The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. |
| Percentage of Patients With Auto-HCT That Convert From Positive to Negative MRD | From baseline up to an estimated 9 months | The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. |
| Percentage of Patients Achieving Complete Remission Following Complete Therapy | Baseline up to 15 months | The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. Complete therapy incorporates induction and consolidation therapy. |
| Serious Adverse Events (SAEs) From the KRdD Treatment | Baseline until the progression of disease or MRD(-) status up to an estimated 15 months. | The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used for this assessment. SAEs include events that are Grade 3 and above; non-serious events are Grades 1-2. |
| Progression-free Survival | From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months. | Progression-free survival is defined as the interval from the start of therapy to the earliest occurrence of the following: disease progression, initiation of anti-myeloma therapy that is not an accepted maintenance therapy of lenalidomide or death from any cause. Kaplan-Meier methods will used. |
| Overall Survival | From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months. | Overall survival is defined as the time from date of study enrollment until death from any cause. |
| Percentage of Patients That Convert From MRD(-) to MRD(+) Following Treatment Discontinuation | Baseline to 2 years | The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. |
Countries
United States
Participant flow
Recruitment details
There was no randomization between KRdD followed by Auto-HCT and KRdD alone. Assignment was per suitability for ASCT. In the end all participants were considered suitable for ASCT, hence the enrollment of zero patients in the KRdD arm
Participants by arm
| Arm | Count |
|---|---|
| KRdD Followed by Auto-HCT Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22 (KRd-Dara). Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Days 8 and 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, auto-HCT is done (consolidation 1), then up to two 4-cycle blocks of KRd-Dara consolidation (consolidations 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.
KRdD followed by auto-HCT: Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will be followed by autologous hematopoietic cell transplantation and KRdD consolidation. | 123 |
| KRdD Only Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then @ 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22. Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Day 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, Following induction therapy, patients will receive up to three 4-cycle blocks of KRd-Dara consolidation (consolidations 1, 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.
KRdD only: Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will not be followed by autologous hematopoietic cell transplantation but will proceed with KRdD consolidation. | 0 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Lack of Efficacy | 6 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 0 |
Baseline characteristics
| Characteristic | KRdD Followed by Auto-HCT | Total |
|---|---|---|
| Age, Continuous | 61 years | 61 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 94 Participants | 94 Participants |
| Region of Enrollment United States | 123 participants | 123 participants |
| Sex: Female, Male Female | 53 Participants | 53 Participants |
| Sex: Female, Male Male | 70 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 123 | 0 / 0 |
| other Total, other adverse events | 123 / 123 | 0 / 0 |
| serious Total, serious adverse events | 14 / 123 | 0 / 0 |
Outcome results
Primary
Percentage of Patients With MRD(-) Remissions at the Completion of Consolidation Therapy
The primary endpoint of MRD(-) rate, or percentage of patients with MRD(-) remissions, will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Time frame: Baseline until MRD(-) is reached estimated to be up to 15 months.
Population: Patients with trackable clonogenic sequence by NGS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| KRdD Followed by Auto-HCT | Percentage of Patients With MRD(-) Remissions at the Completion of Consolidation Therapy | 81.4 percentage of patients achieving MRD (-) |
Secondary
Overall Survival
Overall survival is defined as the time from date of study enrollment until death from any cause.
Time frame: From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months.
Population: All participants who started therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Overall Survival | 108 Participants |
Secondary
Percentage of Patients Achieving Complete Remission Following Complete Therapy
The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences. Complete therapy incorporates induction and consolidation therapy.
Time frame: Baseline up to 15 months
Population: All participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Percentage of Patients Achieving Complete Remission Following Complete Therapy | 106 Participants |
Secondary
Percentage of Patients That Convert From MRD(-) to MRD(+) Following Treatment Discontinuation
The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Time frame: Baseline to 2 years
Population: All patients with confirmed MRD negativity transitioning to observation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Percentage of Patients That Convert From MRD(-) to MRD(+) Following Treatment Discontinuation | 23 Participants |
Secondary
Percentage of Patients With Auto-HCT That Convert From Positive to Negative MRD
The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Time frame: From baseline up to an estimated 9 months
Population: Patients with clonogenic sequence and MRD\>= 10-5 post induction
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Percentage of Patients With Auto-HCT That Convert From Positive to Negative MRD | 32 Participants |
Secondary
Percentage of Patients With MRD(-) Status at the Completion of Induction Therapy
The primary endpoint of MRD(-) rate will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.
Time frame: Baseline until MRD(-) status estimated at 6 months or until disease progression
Population: All participants with trackable clonogenic sequences by NGS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Percentage of Patients With MRD(-) Status at the Completion of Induction Therapy | 45 Participants |
Secondary
Progression-free Survival
Progression-free survival is defined as the interval from the start of therapy to the earliest occurrence of the following: disease progression, initiation of anti-myeloma therapy that is not an accepted maintenance therapy of lenalidomide or death from any cause. Kaplan-Meier methods will used.
Time frame: From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months.
Population: All participants who started therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Progression-free Survival | 90 Participants |
Secondary
Serious Adverse Events (SAEs) From the KRdD Treatment
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used for this assessment. SAEs include events that are Grade 3 and above; non-serious events are Grades 1-2.
Time frame: Baseline until the progression of disease or MRD(-) status up to an estimated 15 months.
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KRdD Followed by Auto-HCT | Serious Adverse Events (SAEs) From the KRdD Treatment | 14 Participants |