Clinical trial NCT02252172: Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple Myeloma
Official title: A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Daratumumab
JNJ-54767414
Lenalidomide
Dexamethasone
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2014-09-30
Enrollment: 737
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the efficacy of daratumumab in combination with lenalidomide and dexamethasone to that of lenalidomide and dexamethasone in terms of progression-free survival (PFS) in participants with newly diagnosed multiple myeloma (a blood cancer of plasma cells) who are not candidates for high dose chemotherapy (treatment of disease, usually cancer, by chemical agents) and autologous stem cell transplant (ASCT).

Detailed description: This is a Phase 3, randomized (study drug assigned by chance), open-label (participants and researchers are aware about the treatment, participants are receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), parallel-group (each group of participants will be treated at the same time), and multicenter (when more than one hospital or medical school team work on a medical research study) study in participants with newly diagnosed multiple myeloma and who are not candidates for high dose chemotherapy and ASCT. All the eligible participants will be randomly assigned to receive either lenalidomide and dexamethasone (Rd) (Arm A) or daratumumab in combination with lenalidomide and dexamethasone (DRd) (Arm B). Daratumumab (16 milligram per kilogram \[mg/kg\]) will be administered weekly for first 8 weeks (Cycles 1 to 2) of treatment and then every other week for 16 weeks (Cycles 3 to 6), then every 4 weeks (from Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide will be administered at a dose of 25 mg orally on Days 1 through 21 of each 28-day cycle, and dexamethasone will be administered at a dose of 40 mg once a week for both treatment arms. Participants in both treatment arms will continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. All participants randomized to Treatment Arm B (DRd) in this study initially received daratumumab IV formulation; however, following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator. Daratumumab subcutaneous (SC) will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study completion. Participants in Arm A who have sponsor-confirmed disease progression may have the option to receive daratumumab provided by the sponsor (in any subsequent line of therapy) in the Follow-up phase. The study consists of 3 phases: Screening Phase (within 21 days prior to the first dose administration on Day 1), Treatment Phase (Day 1 up to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, consent withdrawal, or study end, whichever occurs first). The maximum duration of study will be 7 years after last participant is randomized. Efficacy will primarily be evaluated by PFS. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Participant must have documented multiple myeloma satisfying the CRAB (calcium elevation, renal insufficiency, anemia and bone abnormalities) criteria, monoclonal plasma cells in the bone marrow greater than or equal to (\>=) 10 percent (%) or presence of a biopsy proven plasmacytoma and measurable disease as defined by any of the following: (a) immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein \[M-protein\] level \>=1.0 gram/deciliter \[g/dL\] or urine M-protein level \>=200 milligram\[mg\]/24 hours\[hrs\]; or (b) IgA, IgM, IgD, or IgE multiple myeloma (serum M-protein level \>=0.5 g/dL or urine M-protein level \>=200 mg/24 hrs); or (c) light chain multiple myeloma without measurable disease in serum or urine (serum immunoglobulin free light chain \>=10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio)
* Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* Participants who are newly diagnosed and not considered for high-dose chemotherapy due to: being age \>=65 years; or participants less than (\<) 65 years with presence of important comorbid condition(s) likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. Sponsor review and approval of participants below 65 years of age is required before randomization
* Women of childbearing potential must commit to either abstain continuously from sexual intercourse or to use 2 methods of reliable birth control simultaneously as deemed appropriate by the Investigator. Contraception must begin 4 weeks prior to dosing and must continue for 3 months after the last dose of daratumumab
* Man, who is sexually active with a woman of child-bearing potential must agree to use a latex or synthetic condom, even if he had a successful vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator, and must also agree to not donate sperm during the study and for 4 weeks after last dose of lenalidomide and 4 months after last dose of daratumumab

Exclusion Criteria:

* Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (presence of serum M-protein \<3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein), or smoldering multiple myeloma (asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage)
* Participant has a diagnosis of Waldenström's disease, or other conditions in which IgM M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
* Participant has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years)
* Participant has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for 4 days) of corticosteroids before treatment
* Participant has had radiation therapy within 14 days of randomization
* Participant has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume in 1 second \[FEV1\] \<50% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (controlled intermittent asthma or controlled mild persistent asthma is allowed)
* Participants with known or suspected COPD must have a FEV1 test during Screening
* Participant is known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\] or antibodies to hepatitis B surface and core antigens \[anti-HBs and anti-HBc, respectively\]) or hepatitis C (anti-HCV antibody positive or HCV-ribonucleic acid \[RNA\] quantitation positive)

Primary outcomes:
measure: Primary: Progression-free Survival (PFS)
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 3.5 years)
Secondary outcomes:
measure: Percentage of Participants With Complete Response (CR) or Better
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Percentage of Participants With Very Good Partial Response (VGPR) or Better
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Percentage of Participants With Negative Minimal Residual Disease (MRD)
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Overall Response Rate (ORR)
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Overall Survival (OS)
timeFrame: From randomization to death, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Time to Disease Progression (TTP)
timeFrame: From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Time to Response
timeFrame: From randomization to first response (PR or better) (up to 7.8 years)
measure: Duration of Response (DoR)
timeFrame: From first response (PR of better) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Time to Subsequent Anti-myeloma Treatment
timeFrame: From randomization to start of first subsequent anti-myeloma treatment, death, withdrawal of consent to study participation or CCO whichever is first (up to 7.8 years)
measure: Progression-free Survival on Next Line of Therapy (PFS2)
timeFrame: From randomization to disease progression on first line of subsequent anti-myeloma therapy, death, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years)
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score to Day 1 of Cycle 3, 6, 9 and 12
timeFrame: Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days)
measure: Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) to Day 1 of Cycle 3, 6, 9 and 12
timeFrame: Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days)
measure: Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score to Day 1 of Cycle 3, 6, 9 and 12
timeFrame: Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days)
Other outcomes:
Locations:
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city: Kurralta Park
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city: Nedlands
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city: Woolloongabba N/a
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city: Innsbruck
country: Austria
city: Linz
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city: Salzburg
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city: Wien N/a
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city: Wien Wien
country: Austria
city: Brugge
country: Belgium
city: Brussels
country: Belgium
city: Brussel
country: Belgium
city: Haine Saint Paul La Louviere
country: Belgium
city: Leuven
country: Belgium
city: Liege
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city: Calgary
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state: Alberta
city: Toronto
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city: Greenfield Park
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state: Quebec
city: Montreal
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city: Montréal
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city: N/a N/a
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city: Aarhus C
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city: Odense
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city: Vejle
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city: Amiens N/a Picardie
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city: Angers
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city: Bayonne Cedex
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city: Bretagne
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city: Caen
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city: Cergy Pontoise
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city: Chalons Sur Saone
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city: Clermont-Ferrand
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city: Creteil
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city: Dijon
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city: Dunkerque Cedex 1
country: France
city: Grenoble Cedex 9
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city: La Roche sur Yon Cedex 9
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city: Le Chesnay Cedex
country: France
city: Le Mans
country: France
city: Lille Cedex
country: France
city: Lille
country: France
city: Limoges
country: France
city: Lyon
country: France
city: Marseille Cedex 9
country: France
city: Metz-Tessy
country: France
city: Montivilliers
country: France
city: Montpellier
country: France
city: Mulhouse
country: France
city: Nantes
country: France
city: Nice N/a
country: France
city: Paris Cedex 12
country: France
city: Paris
country: France
city: PERIGUEUX cedex
country: France
city: Perpignan
country: France
city: Pessac
country: France
city: Poitiers
country: France
city: Reims
country: France
city: Rennes
country: France
city: Rouen Cedex
country: France
city: Saint Brieuc Cedex 1
country: France
city: Saint Priest en Jarez
country: France
city: St Malo Cedex
country: France
city: St Quentin Cedex
country: France
city: Strasbourg
country: France
city: Toulouse Cedex 9
country: France
city: TOURS Cedex 9
country: France
city: Vandoeuvre Les Nancy
country: France
city: Aschaffenburg
country: Germany
city: Bad Berka
country: Germany
city: Bonn
country: Germany
city: Braunschweig
country: Germany
city: Dresden
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Hessen
country: Germany
city: Kiel
country: Germany
city: Koblenz
country: Germany
city: Mainz
country: Germany
city: Mannheim
country: Germany
city: Rostock
country: Germany
city: Schwerin
country: Germany
city: Stuttgart
country: Germany
city: Tuebingen
country: Germany
city: Ulm
country: Germany
city: Villingen-Schwenningen
country: Germany
city: Dublin
country: Ireland
city: Galway
country: Ireland
city: Hadera
country: Israel
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Nahariya
country: Israel
city: Petah Tikva
country: Israel
city: Tel-Aviv
country: Israel
city: Hilversum
country: Netherlands
city: Hoofddorp
country: Netherlands
city: Rotterdam
country: Netherlands
city: Tilburg
country: Netherlands
city: Falun
country: Sweden
city: Göteborg
country: Sweden
city: Halmstad
country: Sweden
city: Helsingborg
country: Sweden
city: Huddinge
country: Sweden
city: Lulea
country: Sweden
city: Lund
country: Sweden
city: Stockholm
country: Sweden
city: Örebro
country: Sweden
city: Aberdeen
country: United Kingdom
city: Canterbury
country: United Kingdom
city: Dundee
country: United Kingdom
city: Leeds
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Oxford
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Southampton
country: United Kingdom
city: Truro
country: United Kingdom
city: Wolverhampton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Mateos MV, Rigaudeau S, Basu S, Spicka I, Schots R, Wrobel T, Cook G, Beksac M, Gries KS, Kudva A, Tromp B, Van Rampelbergh R, Pei H, Wroblewski S, Carson R, Delioukina M, White D. Switching to daratumumab SC from IV is safe and preferred by patients with multiple myeloma. J Oncol Pharm Pract. 2023 Jul;29(5):1172-1177. doi: 10.1177/10781552221103551. Epub 2022 Sep 6.
citation: Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Wang J, Van Rampelbergh R, Uhlar CM, Tromp B, Delioukina M, Vermeulen J, Usmani SZ. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-1596. doi: 10.1016/S1470-2045(21)00466-6. Epub 2021 Oct 13.
citation: Cavo M, San-Miguel J, Usmani SZ, Weisel K, Dimopoulos MA, Avet-Loiseau H, Paiva B, Bahlis NJ, Plesner T, Hungria V, Moreau P, Mateos MV, Perrot A, Iida S, Facon T, Kumar S, van de Donk NWCJ, Sonneveld P, Spencer A, Krevvata M, Heuck C, Wang J, Ukropec J, Kobos R, Sun S, Qi M, Munshi N. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022 Feb 10;139(6):835-844. doi: 10.1182/blood.2021011101.
citation: San-Miguel J, Avet-Loiseau H, Paiva B, Kumar S, Dimopoulos MA, Facon T, Mateos MV, Touzeau C, Jakubowiak A, Usmani SZ, Cook G, Cavo M, Quach H, Ukropec J, Ramaswami P, Pei H, Qi M, Sun S, Wang J, Krevvata M, DeAngelis N, Heuck C, Van Rampelbergh R, Kudva A, Kobos R, Qi M, Bahlis NJ. Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE. Blood. 2022 Jan 27;139(4):492-501. doi: 10.1182/blood.2020010439.
citation: Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, Hulin C, Orlowski RZ, Nahi H, Mollee P, Ramasamy K, Roussel M, Jaccard A, Delforge M, Karlin L, Arnulf B, Chari A, He J, Ho KF, Van Rampelbergh R, Uhlar CM, Wang J, Kobos R, Gries KS, Fastenau J, Weisel K. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021 Jan 20;39(3):227-237. doi: 10.1200/JCO.20.01370. Epub 2020 Dec 16.
citation: Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. doi: 10.1056/NEJMoa1817249.