NCT02412878 · CITED IN SOURCE DOCUMENTS

Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2022-09-23

The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Overall Response Rate

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outcome · POSTED

Progression Free Survival

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outcome · POSTED

Overall Survival

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outcome · POSTED

Number of Participants With Adverse Events (AEs)

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outcome · POSTED

Plasma Carfilzomib Concentration During Cycle 2

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Key Inclusion Criteria: 1. Relapsed multiple myeloma 2. Refractory multiple myeloma defined as meeting 1 or more of the following: * Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or * Disease progression within 60 days of discontinuation from most recent therapy 3. At least 2 but no more than 3 prior therapies for multiple myeloma 4. Prior exposure to an immunomodulatory agent (IMiD) 5. Prior exposure to a proteasome inhibitor (PI) 6. Documented response of at least partial response (PR) to 1 line of prior therapy 7. Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization: * Serum M-protein ≥ 0.5 g/dL * Urine M-protein ≥ 200 mg/24 hours * In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) \> 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio 8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 9. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization 10. Adequate organ and bone marrow function within the 21 days prior to randomization defined by: * Bilirubin \< 1.5 times the upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN * Absolute neutrophil count (ANC) ≥ 1000/mm³ (screening ANC should be independent of growth factor support for ≥ 1 week) * Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell \[RBC\] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.) * Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is \> 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.) * Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min Key Exclusion Criteria: 1. Waldenström macroglobulinemia 2. Multiple myeloma of Immunoglobin M (IgM) subtype 3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 4. Plasma cell leukemia (\> 2.0 × 10⁹/L circulating plasma cells by standard differential) 5. Myelodysplastic syndrome 6. Second malignancy within the past 5 years except: * Adequately treated basal cell or squamous cell skin cancer * Carcinoma in situ of the cervix * Prostate cancer \< Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months * Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins) * Treated medullary or papillary thyroid cancer * Similar condition with an expectation of \> 95% five-year disease-free survival 7. History of or current amyloidosis 8. Cytotoxic chemotherapy within the 28 days prior to randomization 9. Immunotherapy within the 21 days prior to randomization 10. Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone 11. Radiation therapy: * Focal therapy within the 7 days prior to randomization * Extended field therapy within the 21 days prior to randomization 12. Prior treatment with either carfilzomib or oprozomib 13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) 14. Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment 15. Active congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment 16. Active infection within the 14 days prior to randomization requiring systemic antibiotics 17. Pleural effusions requiring thoracentesis within the 14 days prior to randomization 18. Ascites requiring paracentesis within the 14 days prior to randomization 19. Ongoing graft-versus-host disease 20. Uncontrolled hypertension or uncontrolled diabetes despite medication 21. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization 22. Known cirrhosis
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
label
Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
type
EXPERIMENTAL
description
Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
label
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
type
EXPERIMENTAL

interventions

arm Group Labels
Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
description
Carfilzomib was administered as an IV infusion
name
Carfilzomib
other Names
PR-171
PR171
Kyprolis® (carfilzomib) for Injection
type
DRUG
arm Group Labels
Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
description
Commercially available dexamethasone was obtained by the investigational site.
name
Dexamethasone
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 478
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
measure
Progression Free Survival
time Frame
From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively.

secondary Outcomes

description
Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein \<100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to \< 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
measure
Overall Response Rate
time Frame
Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively.
description
Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive.
measure
Overall Survival
time Frame
From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively.
description
The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.
measure
Number of Participants With Adverse Events (AEs)
time Frame
From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
description
Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.
measure
Plasma Carfilzomib Concentration During Cycle 2
time Frame
Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion

Full study description

brief Summary: The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).

Source references

references

citation
Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1. Epub 2018 Jun 1.
pmid
29866475
type
BACKGROUND
citation
Facon T, Niesvizky R, Mateos MV, Siegel D, Rosenbaum C, Bringhen S, Weisel K, Ho PJ, Ludwig H, Kumar S, Wang K, Obreja M, Yang Z, Klippel Z, Mezzi K, Goldrick A, Tekle C, Dimopoulos MA. Efficacy and safety of carfilzomib-based regimens in frail patients with relapsed and/or refractory multiple myeloma. Blood Adv. 2020 Nov 10;4(21):5449-5459. doi: 10.1182/bloodadvances.2020001965.
pmid
33166401
type
BACKGROUND
citation
Dimopoulos MA, Niesvizky R, Weisel K, Siegel DS, Hajek R, Mateos MV, Cavo M, Huang M, Zahlten-Kumeli A, Moreau P. Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis. Blood Cancer J. 2020 Mar 9;10(3):35. doi: 10.1038/s41408-020-0300-y.
pmid
32152297
type
BACKGROUND
citation
Moreau P, Stewart KA, Dimopoulos M, Siegel D, Facon T, Berenson J, Raje N, Berdeja JG, Orlowski RZ, Yang H, Ma H, Klippel Z, Zahlten-Kumeli A, Mezzi K, Iskander K, Mateos MV. Once-weekly (70 mg/m2 ) vs twice-weekly (56 mg/m2 ) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: A post hoc analysis of the ENDEAVOR, A.R.R.O.W., and CHAMPION-1 trials. Cancer Med. 2020 May;9(9):2989-2996. doi: 10.1002/cam4.2945. Epub 2020 Feb 28.
pmid
32108443
type
BACKGROUND
citation
Moreau P, Kumar S, Boccia R, Iida S, Goldschmidt H, Cocks K, Trigg A, Zahlten-Kumeli A, Yucel E, Panjabi SS, Dimopoulos M. Convenience, satisfaction, health-related quality of life of once-weekly 70 mg/m2 vs. twice-weekly 27 mg/m2 carfilzomib (randomized A.R.R.O.W. study). Leukemia. 2019 Dec;33(12):2934-2946. doi: 10.1038/s41375-019-0480-2. Epub 2019 May 15.
pmid
31092895
type
BACKGROUND
citation
Kumar SK, Majer I, Panjabi S, Medhekar R, Campioni M, Dimopoulos MA. Cost-effectiveness of once weekly carfilzomib 70 mg/m2 plus dexamethasone in patients with relapsed and refractory multiple myeloma in the United States. Expert Rev Hematol. 2020 Jun;13(6):687-696. doi: 10.1080/17474086.2020.1746639. Epub 2020 Apr 6.
pmid
32249621
type
BACKGROUND
citation
Dimopoulos MA, Moreau P, Iida S, Huang SY, Takezako N, Chng WJ, Zahlten-Kumeli A, Sersch MA, Li J, Huang M, Lee JH. Outcomes for Asian patients with multiple myeloma receiving once- or twice-weekly carfilzomib-based therapy: a subgroup analysis of the randomized phase 3 ENDEAVOR and A.R.R.O.W. Trials. Int J Hematol. 2019 Oct;110(4):466-473. doi: 10.1007/s12185-019-02704-z. Epub 2019 Aug 6.
pmid
31388932
type
DERIVED