Study of Initial Treatment With Elotuzumab, Carfilzomib, Lenalidomide and Dexamethasone in Multiple Myeloma

Phase 2

Active, not recruiting

Conditions: Multiple Myeloma

Interventions: Drug: Elotuzumab
Drug: Carfilzomib
Drug: Lenalidomide
Drug: Dexamethasone

Registration Number: NCT02969837

Lead Sponsor: University of Chicago

Brief Summary: This study was a multi-center, open-label, single-arm, Phase 2 study where newly diagnosed Multiple Myeloma requiring systemic chemotherapy will be eligible for enrollment. A total of 46 subjects were enrolled. The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS).

Detailed Description: Primary Objective

• The primary efficacy endpoint will be the rate of sCR and/or the rate of negative MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) at the end of 8 cycles among non-transplant candidates and transplant candidates who agreed to defer transplant

Secondary Objectives

* To evaluate the safety and tolerability of elotuzumab in combination with KRd, when administered to subjects with newly diagnosed multiple myeloma.

* To determine the rate of MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) and by multi-color flow cytometry (MFC) at the end of Cycle 4, 8,and 12 for all subjects, and end of C18 (for subjects who are MRD+ at the end of C8 but MRD- at the end of C12 only), 24 months after C1D1, and yearly after that.

* To estimate time to event, including duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS).

Exploratory Objectives

* GEP, proteomics, and gene sequencing to evaluate the correlation between treatment outcome and pre-treatment subject profile.

* Immunologic correlative studies including FcγRIIIa V genotype.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 46

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. No enrollment waivers will be granted.
1. Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy
  
  a. Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/PI-based regimens does not disqualify the subject (the corticosteroid treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy)
2. Both transplant and non-transplant candidates are eligible.
3. Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment
4. Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma
5. Measurable disease, prior to initial treatment as indicated by one or more of the following:
  1. Serum M-protein ≥ 1 g/dL
  2. Urine M-protein ≥ 200 mg/24 hours
  3. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL)
  4. Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal
6. Screening laboratory values must meet the following criteria and should be obtained within 21 days prior to enrollment WBC ≥ 2000/µL Platelets ≥ 75 x103/µL ANC >1000/µL Hemoglobin > 8.0 g/dL Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min
  1. Use the Cockcroft-Gault formula below):
    
    o Female CrCl = (140 - age in years) x weight in kg x 0.85
    - 72 x serum creatinine in mg/dL
      
      o Male CrCl = (140 - age in years) x weight in kg x 1.00
    - 72 x serum creatinine in mg/dL
  2. Alternatively to Cockcroft-Gault formula of CrCl, 24hr urine CrCl can be used AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) or ≤ 2 x ULN if lenalidomide is being prescribed.
7. Males and females ≥ 18 years of age
8. ECOG performance status of 0-1
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.
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

Subjects meeting any of the following exclusion criteria are not eligible to enroll in this study. No enrollment waivers will be granted.
1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as <1.0 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, and no measurable disease as per IMWG by Freelite.
2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
3. Geriatric assessment score of ≥2 as defined by Palumbo et al.
4. Known or suspected Amyloidosis
5. Plasma cell leukemia
6. Within 4 weeks since any plasmapheresis
7. Within 3 weeks of any corticosteroids except per inclusion criteria #2
8. Waldenström's macroglobulinemia or IgM myeloma
9. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
10. Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone
11. Peripheral neuropathy ≥ Grade 2 at screening
12. Prior CVA with persistent neurological deficit
13. Diarrhea > Grade 1 in the absence of antidiarrheals
14. CNS involvement
15. Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization
16. Pregnant or lactating females
17. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area
18. Major surgery within 3 weeks prior to first dose
19. Subject has clinically significant cardiac disease, including:
  - myocardial infarction within 1 year before Cycle 1 Day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV
  - uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade 2:2) or clinically significant ECG abnormalities
  - screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
20. Uncontrolled HTN 14 days prior to enrollment
21. Prior or concurrent deep vein thrombosis or pulmonary embolism
22. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
23. Uncontrolled hypertension (defined as average systolic blood pressure ≥140 or average diastolic blood pressure ≥90, with blood pressure measured ≥3 times in the two weeks prior to enrollment ) or diabetes
24. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
25. Active infection
26. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are seropositive because of hepatitis B virus vaccine are eligible.
27. 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
28. 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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Elo-KRd regimen	Elotuzumab	Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression.
Elo-KRd regimen	Carfilzomib	Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression.
Elo-KRd regimen	Dexamethasone	Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression.
Elo-KRd regimen	Lenalidomide	Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Stringent Complete Response (sCR)	Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months)	Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required.
Number of Participants With MRD-negativity (10^-5) After C8 Elo-KRd	Landmark evaluations were performed after cycle 8	Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycle 8. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay. The Premarket Notification 510(k) (Number K130373) for the device can be found using the following link. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130373.
The Number of Participants With Stringent Complete Response (sCR) and/or MRD Negative (10^-5) by NGS	Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months)	Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 4,8,12,18 and 24. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events of Elotuzumab in Combination With KRd	AEs were recorded from the day of signed consent through 30 days after the last does of Elo-KRd or initiation of new therapy, an average of 2 years.	AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0)
Duration of Response	Up to two years	These events will be analyzed at differing points of time based on the individual subjects disease progression. It will be measured by the number of cycles of therapy.
Median Progression Free Survival	up to two years	Progression free survival (PFS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment.
Median Overall Survival	up to two years	Overall survival (OS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment.

Trial Locations

Locations (3): University of Chicago
🇺🇸
Chicago, Illinois, United States
NorthShore University Health System
🇺🇸
Evanston, Illinois, United States
University of Michigan Comprehensive Cancer Center
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Ann Arbor, Michigan, United States
University of Chicago
🇺🇸Chicago, Illinois, United States