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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

46 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-07-10

Study Completion Date

2025-12-01

Brief Summary

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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).

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Detailed Description

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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.

Conditions

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Multiple Myeloma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

All participants will receive E-KRd regimen (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) for up to 12 Cycles.

After Cycle 12, participants that are MRD negative will move to E-Rd (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) maintenance regimen and continue until disease progression. Participants that are MRD positive will continue to receive E-KRd regimen for an additional 6 cycles followed by E-Rd maintenance regimen and continue until disease progression

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Elo-KRd regimen

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.

Group Type EXPERIMENTAL

Lenalidomide

Intervention Type DRUG

Lenalidomide will be given on days 1-21 for all cycles.

Dexamethasone

Intervention Type DRUG

Dexamethasone will be given as follows:

Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22

Elotuzumab

Intervention Type DRUG

Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15

Carfilzomib

Intervention Type DRUG

Carfilzomib will be given on Day 1 and 8 of Cycle 1, Days 1, 8, and 15 of Cycles 2-8, and Days 1 and 15 of Cycles 9 and beyond

Interventions

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Lenalidomide

Lenalidomide will be given on days 1-21 for all cycles.

Intervention Type DRUG

Dexamethasone

Dexamethasone will be given as follows:

Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22

Intervention Type DRUG

Elotuzumab

Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15

Intervention Type DRUG

Carfilzomib

Carfilzomib will be given on Day 1 and 8 of Cycle 1, Days 1, 8, and 15 of Cycles 2-8, and Days 1 and 15 of Cycles 9 and beyond

Intervention Type DRUG

Other Intervention Names

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Empliciti Kryprolis Revlimid

Eligibility Criteria

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Inclusion Criteria

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

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

Exclusion Criteria

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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No