Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

Phase 3 Randomized Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

This is a Phase 3 randomized trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma, eligible to subjects who completed autologous stem cell transplant for symptomatic myeloma who are considered for lenalidomide maintenance.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Lenalidomide (Control); Drug: Lenalidomide; Drug: Carfilzomib; Drug: Dexamethasone

Detailed Description

Primary Objective:

• To compare progression free survival between Kyprolis (Carfilzomib), Revlimid (lenalidomide), Dexamethasone (KRd) arm and lenalidomide arm

Secondary Objectives

• To determine the rate of minimal residual negative disease (MRD) at 6 and 12 months after randomization
• To compare the efficacy (rate of partial response, very good partial response, complete response, and stringent complete response) of KRd vs. Lenalidomide alone after randomization

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 3

Contacts and Locations

Study Locations

• Poland
  • Poznań, Poland
    • Polish Myeloma Consortium
• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University - Karmanos Cacner Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients who completed single autologous stem cell transplant after completion of at most 2 induction regimens (excluding dexamethasone alone) and are in at least stable disease in the first 100 days after stem cell transplantation.
2. Patients must be within 12 months of initiation of induction therapy and must have had not more than 2 prior induction regimens.
3. Bone marrow specimen will be required at study entry; available DNA sample will be used for calibration step for MRD evaluation by gene sequencing.
4. Males and females ≥ 18 years of age
5. ECOG performance status of 0-1
6. Adequate hepatic function, with bilirubin ≤ 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
7. ANC ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.
8. Calculated creatinine clearance (by Cockcroft-Gault) ≥ 50 ml/min or serum creatinine below 2 mg/dL
9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days).

10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study.

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11. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
12. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.
13. Voluntary written informed consent

Exclusion Criteria:

1. Patients who have had more than 12 months of prior therapy. Patients outside of this window may be considered for inclusion on a case-by-case basis.

2. Patients who progressed after initial therapy.

   1. Subjects whose therapy changed due to suboptimal response, intolerance, etc., remain eligible, provided they do not meet criteria for progression.
   2. No more than two regimens for induction will be allowed excluding dexamethasone alone.
3. Evidence of progressive disease as per International Myeloma Working Group (IMWG) criteria
4. Patients who have already started or received post-transplant maintenance or consolidation regimen
5. Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone
6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
7. Plasma cell leukemia
8. Waldenström's macroglobulinemia or IgM myeloma
9. Peripheral neuropathy ≥ Grade 2 at screening
10. Diarrhea > Grade 1 in the absence of antidiarrheals
11. CNS involvement
12. Pregnant or lactating females
13. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.
14. Major surgery within 3 weeks prior to first dose
15. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
16. Prior or concurrent deep vein thrombosis or pulmonary embolism
17. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
18. Uncontrolled hypertension or diabetes
19. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
20. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
21. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
22. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lenalidomide (Control); Treatment with lenalidomide only	Drug: Lenalidomide (Control); Cycles 1-4: Days 1-28. Lenalidomide will begin at a dose of 10 mg PO daily (2 capsules per day). After three months, the dose will be increased, provided ANC ≥ 1,000/µL, platelet count ≥ 75,000/µL, and all nonhematologic toxicity is ≤ grade 1, to 15 mg PO daily (3 capsules per day).; Cycles 5 and beyond: best tolerated dose days 1-28; Other Names: Revlimid
Experimental: Experimental Combination Regimen; Experimental arm using a combination of Carfilzomib, Lenalidomide and Dexamethasone	Drug: Lenalidomide; Cycle 1: 15 mg days 1-21; Cycles 2-4: 25 mg days 1-21 if tolerated, otherwise continue at lower dose; Cycles 5 and beyond: best tolerated dose days 1-21; Other Names: Revlimid; Drug: Carfilzomib; Cycle 1: 20 mg/m2 Days 1, 2; 36 mg/m2 Days 8, 9, 15, 16. Alternatively, intermediate dose escalation (to 27mg/m2 on days 8,9 of cycle 1) will be al12,lowed at the treating physician's discretion.; Cycle 2-4: 36 mg/m2 if tolerated Days 1, 2, 8, 9, 15, 16; Cycles 5-8 (patients that are MRD- and have no risk factors at the end of cycle 6) and Cycle 5 - 36 (for MRD+ patients and high risk patients at the end of cycle 6): best tolerated dose Days 1, 2, 15, 16; Other Names: Kyprolis; Drug: Dexamethasone; Cycles 1 - 4: 20 mg PO or IV per dose Days 1, 8, 15, 22; Cycles 5+: 20 mg or best tolerated dose PO or IV per dose Days 1, 8, 15, 22

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival rates in participants receiving drug combination	Measurement of time to disease worsening as measured by International Myeloma Working Group (IMWG) response criteria.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of minimal residual negative disease (MRD) in participants receiving drug combination	Calculation of number of participants with MRD-negative disease.	3 years
Response rate in participants receiving drug combination	Number of participants with disease response (e.g. improvement) as measured by International Myeloma Working Group (IMWG) response criteria.	3 years
Treatment-related side effects	Number of participants with grade 2 or greater treatment-related side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0	From date of screening until end of treatment

Collaborators and Investigators

• Sponsor: University of Chicago
• Investigators: Principal Investigator: Andrzej Jakubowiak, MD, PhD, University of Chicago

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2016
• Primary Completion (Anticipated): November 1, 2024
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: January 15, 2016
• First Submitted That Met QC Criteria: January 19, 2016
• First Posted (Estimate): January 20, 2016

Study Record Updates

• Last Update Posted (Actual): April 28, 2023
• Last Update Submitted That Met QC Criteria: April 26, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Multiple myeloma; lenalidomide; dexamethasone; carfilzomib; stem-cell transplant; Symptomatic myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide
• Other Study ID Numbers: IRB15-1286