A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects with Relapsed Multiple Myeloma

Summary

This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with relapsed multiple myeloma. The study design is illustrated in the figure below. Eligible subjects will be randomized in a 1:1 ratio to receive a regimen consisting of either lenalidomide and dexamethasone (Rd arm) or carfilzomib, lenalidomide, and dexamethasone (CRd arm). The estimated sample size is 780 subjects. The estimated number of subjects at UTSW to be consented on this protocol is 8, while the number of subjects to enroll is estimated to be 6. The primary endpoint is PFS.

The general treatment plans for the Rd and CRd arms are as follows (cycles are 28 days each):
Rd arm

* Cycles 1 and higher: lenalidomide and dexamethasone
CRd arm

* Cycles 1 through 12: carfilzomib (6 doses per cycle), lenalidomide, and dexamethasone

* Cycles 13 through 18: carfilzomib (4 doses per cycle), lenalidomide, and dexamethasone

* Cycles 19 and higher: lenalidomide and dexamethasone (no carfilzomib)

Subjects will continue their randomized treatment assignment until disease progression or unacceptable toxicity (whichever occurs first). At completion or early discontinuation of treatment, subjects will continue to be followed for 30 additional days or up to the initiation of subsequent treatment (whichever occurs first), after which they will be off the active treatment phase of the study. Long-term follow-up (LTFU) for disease status and survival will proceed until the subject has withdrawn consent, is lost to follow-up, has died, or until the Sponsor makes a decision to close the study.

The total study enrollment period is expected to be approximately 18 months. Subjects will remain on their assigned protocol treatment until disease progression or unacceptable toxicity (whichever occurs first). Subjects will be followed for 30 additional days after completion or early discontinuation of treatment for safety follow-up, after which they will be off the active treatment phase of the study. Post-treatment long-term follow-up for disease status and survival will proceed until the subject has withdrawn consent, is lost to follow-up, has died, or until the Sponsor makes a decision to close the study. Assuming that the last subject has a survival time close to the median expected survival of 42 months for this population, the total study duration including LTFU will be approximately 6.5 years.

Participant Eligibility

Criteria for Inclusion of Subjects:
1. Symptomatic multiple myeloma
2. Measurable disease, as defined by one or both of the following (assessed within 14 days prior to randomization):
•Serum M-protein ≥ 0.5 g/dL
•Urine Bence-Jones protein ≥ 200 mg/24 hours
3. Prior treatment with at least one, but no more than three, regimens for multiple myeloma
4. Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible)
5. Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M protein [or total protein in countries in which electrophoresis is not routinely available])
6. Age ≥ 18 years
7. Life expectancy ≥ 3 months
8. Eastern Cooperative Oncology Group (ECOG) performance status 0–2
9. 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 14 days prior to randomization
10. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization
11. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
12. Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to randomization
13. Creatinine clearance (CrCl) ≥ 50 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) within 7 days prior to randomization
14. Written informed consent in accordance with federal, local, and institutional guidelines.
15. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice reliable contraception as outlined in the RevAssist program
16. Male subjects must agree to practice reliable contraception as outlined in the RevAssist program