Combination Treatment Therapy Approaches for the Treatment of High-Risk Multiple Myeloma, REACH Trial

Study Overview
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Brief Summary
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This phase II trial test whether combination chemotherapy works to improve blood test results in patients with high-risk multiple myeloma. Chemotherapy drugs, such as carfilzomib, daratumumab, lenalidomide, and dexamethasone, 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. This trial may help determine if patients who have a small amount of cancer left after the initial treatment, called minimal residual disease, will benefit from the drug combination.

Detailed Description
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PRIMARY OBJECTIVE: I. To estimate the rate of sustained minimal residual disease (MRD) negativity (MRD negative status at any point, with a repeated MRD negative status one year later) in subjects with high-risk multiple myeloma. SECONDARY OBJECTIVES: I. To describe the toxicities associated with this treatment approach in subjects with high-risk multiple myeloma (MM). II. To estimate the overall response rate, very good partial response (VGPR) or better rate and complete response (CR) rate at the end of induction, end of consolidation, end of maintenance and at two years after the completion of treatment. III. To estimate the progression-free survival and overall survival rate. CORRELATIVE RESEARCH OBJECTIVES: I. To describe the clonal architecture through a combination of genomic, epigenomic, proteomic and metabolomic studies before and after treatment, in subjects with high-risk MM. II. To describe the bone marrow microenvironment through various stages of treatment and the time of MRD negative state and at time of relapse. OUTLINE: INDUCTION: Patients receive carfilzomib intravenously (IV) on days 2, 8, and 15 of cycle 1 and days 1, 8, and 15 of cycles 2-12, lenalidomide orally (PO) days 1-21 of each cycle, daratumumab subcutaneously (SC) days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive carfilzomib IV on days 1, 8, and 15, lenalidomide PO days 1-21, daratumumab SC day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive carfilzomib IV on day 1, lenalidomide PO days 1-21, daratumumab day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and biopsy, magnetic resonance imaging (MRI) and, computed tomography/positron emission tomography(CT/PET). After completion of study treatment, patients are followed up every 6 months for up to10 years.

Official Title
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REsponse Adapted Combination Therapy Approaches for High-Risk Multiple Myeloma (REACH)

Conditions
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ISS Stage III Plasma Cell Myeloma, Plasma Cell Myeloma

Intervention / Treatment
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* Procedure: Bone Marrow Aspiration and Biopsy
* Drug: Carfilzomib
* Procedure: Computed Tomography
* Biological: Daratumumab
* Drug: Dexamethasone
* Drug: Lenalidomide
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION-INCLUSION CRITERIA: Age >= 18 years and =< 80 years. Patient must have suspected or confirmed newly diagnosed multiple myeloma by International Myeloma Working Group (IMWG) criteria. Left ventricular ejection fraction (LVEF) >= 40% =< 30 days prior to pre-registration. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Provide informed written consent. Willing to return to enrolling institution for follow-up during the active treatment phase of the trial. Willing to provide blood and bone marrow samples for planned research. Life expectancy > 6 months. Able to take aspirin (325 mg) daily as prophylactic anticoagulation. Note: subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin. REGISTRATION-INCLUSION CRITERIA: High risk myeloma, which is untreated, defined as any two of: International Staging System (ISS) stage 3 Gain or amplification of chr1q del17p) t(4;14) or t(14;16) >= 5% circulating plasma cells Creatinine clearance >= 30 mL/min (using Crockroft-Gault equation) (obtained =< 14 days prior to registration). Absolute neutrophil count (ANC) >= 1000/mm^3 (without the use of growth factors) (obtained =< 14 days prior to registration). Platelet count >= 75000/mm^3 (obtained =< 14 days prior to registration). Hemoglobin >= 8.0 g/dL. Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration). Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (obtained =< 14 days prior to registration). Registration must be completed =< 30 days after pre-registration. Patients must not have received more than one cycle of treatment between pre-registration and registration. Exclusion Criteria: PRE-REGISTRATION EXCLUSION: Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, light chain amyloidosis with organ involvement. Diagnosed or treated for another malignancy =< 1 year prior to pre- registration or previously diagnosed with another malignancy and have any evidence of residual disease. Note: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Other co-morbidity which would interfere with subject's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease. Other concurrent chemotherapy, or any ancillary therapy considered investigational. NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment. Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain =< 30 days prior to registration. Major surgery =< 14 days prior to pre-registration. Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. Note: Prior to trial entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant. New York Heart Association (NYHA) II, III, IV heart failure. Known human immunodeficiency virus (HIV) positive. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. Known or suspected active hepatitis C infection. Any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure) or known sensitivity to mammalian-derived products. Known allergies, hypersensitivity, or intolerance to trial drugs. Inability to comply with protocol/procedures. REGISTRATION-EXCLUSION CRITERIA: If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>INDUCTION: Patients receive carfilzomib IV on days 2, 8, and 15 of cycle 1 and days 1, 8, and 15 of cycles 2-12, lenalidomide PO days 1-21 of each cycle, daratumumab SC days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive carfilzomib IV on days 1, 8, and 15, lenalidomide PO days 1-21, daratumumab SC day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive carfilzomib IV on day 1, lenalidomide PO days 1-21, daratumumab day 1 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and biopsy, MRI and, CT/PET. | Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Carfilzomib<br>* Given IV<br>* Other names: PR-171;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Daratumumab<br>* Given SC<br>* Other names: JNJ-54767414;Drug: Dexamethasone<br>* Given IV/PO<br>* Other names: ZoDex;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: proton magnetic resonance spectroscopic imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of sustained minimal residual disease (MRD) negativity | MRD negative status at any point, with a repeated MRD negative status one year later). All subjects meeting the eligibility criteria, who have signed a consent form and have begun treatment, will be evaluable, with the exception of subjects determined to be a major violation. | At 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (>= confirmed very good partial response ([VGPR]) | Exact binomial 95% confidence intervals for the true response proportion at each time point will be calculated. | End of induction, end of consolidation, and every 3 cycles of maintenance, up to two years or 24. One cycle is 28 days. after treatmentmonths | 
| Overall survival | The distribution of overall survival will be estimated using the method of Kaplan-Meier. | From registration to death due to any cause, assessed up to 10 years | 
| Progression-free survival | The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. | From registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 10 years | 
| Incidence of adverse events | Adverse Events: All eligible subjects that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each subject, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the trial treatment will be taken into consideration. AEs will be summarized overall, as well as by treatment phase (induction, consolidation, maintenance with carfilzomib and lenalidomide and daratumumab). | Up to 30 days after administration of study therapy |