Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma

Study Overview
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Brief Summary
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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
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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.

Official Title
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Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma - MASTER Trial

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: KRdD followed by auto-HCT
* Drug: KRdD only


Participation Criteria
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Eligibility Criteria
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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: Serum monoclonal (M) protein ≥1.0 g/dl ≥ 200 mg of M protein/24h in the urine 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KRdD followed by auto-HCT<br>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. | Drug: KRdD followed by auto-HCT<br>* 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.<br>* Other names: KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab);|
| Experimental: KRdD only<br>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. | Drug: KRdD only<br>* 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.<br>* Other names: KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline until MRD(-) is reached estimated to be up to 15 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline until the progression of disease or MRD(-) status up to an estimated 15 months. | 
| 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. | Baseline until MRD(-) status estimated at 6 months or until disease progression | 
| 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. | From baseline up to an estimated 9 months | 
| 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. | Baseline up to 15 months | 
| 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. | Baseline to 2 years | 
| 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. | 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 | Overall survival is defined as the time from date of study enrollment until death from any cause. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, induction therapy, autologous hematopoietic cell transplantation, KRdD, Daratumumab, Carfilzomib, Lenalidomide