Clinical trial NCT02195479: A Study of Combination of Daratumumab and Velcade (Bortezomib) Melphalan-Prednisone (DVMP) Compared to Velcade Melphalan-Prednisone (VMP) in Participants With Previously Untreated Multiple Myeloma
Official title: A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomib) Melphalan-Prednisone (VMP) Compared to Daratumumab in Combination With VMP (D-VMP), 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
Bortezomib
Velcade
Melphalan
Prednisone
Daratumumab
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2014-07-21
Enrollment: 706
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 determine if the addition of daratumumab to velcade (bortezomib) melphalan-prednisone (VMP) will prolong progression-free survival (PFS) compared with VMP alone in participants with previously untreated multiple myeloma who are ineligible for high dose chemotherapy and autologous stem cell transplant (ASCT).

Detailed description: The study consists of 3 phases: Screening Phase (within 21 days prior to randomization), Treatment Phase (Cycle 1 Day 1 to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, withdrawal of consent, or the study ends, whichever occurs first). Treatment phase will include 2 treatments (Treatment A: participants will receive Velcade MelphalanPrednisone (VMP) alone and Treatment B: participants will receive daratumumab in combination with VMP).Two interim analyses are planned. The first will be to evaluate safety after a total of approximately 100 participants have been treated for at least 2 cycles or discontinued the study treatment. The second will be to evaluate cumulative interim safety and efficacy data, and will be performed when approximately 216 PFS events have been accumulated. The final OS analysis will occur when approximately 382 deaths have occurred. Efficacy will be primarily measured by comparison of PFS between the two treatment arms. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Participant must have documented multiple myeloma satisfying the calcium elevation, renal insufficiency, anemia, and bone abnormalities (CRAB) diagnostic criteria, monoclonal plasma cells in the bone marrow greater than or equal to 10 percent (%) or presence of a biopsy proven plasmacytoma, and measurable secretory disease, as assessed by the central laboratory, and defined in protocol
* Participants who are newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation (SCT) due to: being age \>=65 years, or in participants \<65 years: presence of important comorbid conditions likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation
* Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* Meet the clinical laboratory criteria as specified in the protocol
* A woman of childbearing potential must have a negative serum pregnancy test at screening within 14 days prior to randomization
* Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy

Exclusion Criteria:

* Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma
* Participant has a diagnosis of Waldenstrom'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 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 peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the national cancer institute common terminology criteria for adverse events (NCI CTCAE) Version 4
* Participant has a history of malignancy (other than multiple myeloma) within 3 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 3 years)
* Participant has had radiation therapy within 14 days of randomization
* Participant has had plasmapheresis within 28 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), known moderate or severe persistent asthma within the last 2 years or currently has uncontrolled asthma of any classification (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), known to have hepatitis B surface antigen positivity, or history of to have a history of hepatitis C
* Participant has any concurrent medical or psychiatric condition or disease (example active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From randomization to either disease progression or death whichever occurs first (up to 2.4 years)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From randomization to disease progression (up to 2.4 years)
measure: Percentage of Participants With Very Good Partial Response (VGPR) or Better
timeFrame: From randomization to disease progression (up to 2.4 years)
measure: Percentage of Participants With Complete Response (CR) or Better
timeFrame: From randomization to disease progression (up to 2.4 years)
measure: Percentage of Participants With Negative Minimal Residual Disease (MRD)
timeFrame: From randomization to disease progression (up to 2.4 years)
measure: Overall Survival (OS)
timeFrame: From randomization to death (up to approximately 2.4 years)
measure: Progression Free Survival on Next Line of Therapy (PFS2)
timeFrame: From randomization to either disease progression or death whichever occurs first (up to 2.4 years)
measure: Percentage of Participants With Stringent Complete Response (sCR)
timeFrame: From randomization to disease progression (up to 2.4 years)
measure: Time to Disease Progression (TTP)
timeFrame: From randomization to either disease progression or death due to PD whichever occurs first (up to 2.4 years)
measure: Time to Response
timeFrame: From randomization to first documented PR or better (up to 2.4 years)
measure: Duration of Response (DOR)
timeFrame: Up to 2.4 years
measure: Time to Next Treatment (TNT)
timeFrame: Approximately up to 2.4 years
measure: Percentage of Participants With Best M-protein Response
timeFrame: Approximately up to 2.4 years
measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30: Emotional Functioning Score
timeFrame: Baseline, Months 3, 6, 9, 12 and 18
measure: Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L): Visual Analogue Scale (VAS)
timeFrame: Baseline, Months 3, 6, 9, 12 and 18
measure: Change From Baseline in EuroQol 5 Dimensions-5 Level (EQ-5D-5L) Utility Score
timeFrame: Baseline, Months 3, 6, 9, 12 and 18
Other outcomes:
Locations:
city: California City
country: United States
state: California
city: Corona
country: United States
state: California
city: Fountain Valley
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Hialeah
country: United States
state: Florida
city: Orange Park
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Springfield
country: United States
state: Missouri
city: Cleveland
country: United States
state: Ohio
city: Fredericksburg
country: United States
state: Virginia
city: Buenos Aires
country: Argentina
city: Ciudad Autonoma Buenos Aires
country: Argentina
city: Córdoba
country: Argentina
city: Santa Fe
country: Argentina
city: Adelaide
country: Australia
city: Bendigo
country: Australia
city: Camperdown N/a
country: Australia
city: Geelong
country: Australia
city: Gosford
country: Australia
city: Greenslopes
country: Australia
city: Hobart
country: Australia
city: North Adelaide
country: Australia
city: Parkville
country: Australia
city: Antwerpen
country: Belgium
city: Antwerp
country: Belgium
city: Brussel
country: Belgium
city: Charleroi
country: Belgium
city: Gent
country: Belgium
city: Kortrijk
country: Belgium
city: Roeselare
country: Belgium
city: Turnhout
country: Belgium
city: Yvoir
country: Belgium
city: Barretos
country: Brazil
city: Cuiaba - Mount
country: Brazil
city: Fortaleza
country: Brazil
city: Goiania
country: Brazil
city: Natal
country: Brazil
city: Porto Alegre
country: Brazil
city: Ribeirao Preto
country: Brazil
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Vratsa
country: Bulgaria
city: Zadar
country: Croatia
city: Zagreb
country: Croatia
city: Brno
country: Czechia
city: Hradec Kralove
country: Czechia
city: Olomouc
country: Czechia
city: Ostrava-Poruba
country: Czechia
city: Praha 10
country: Czechia
city: Praha 2
country: Czechia
city: Tbilisi
country: Georgia
city: Berlin
country: Germany
city: Dortmund
country: Germany
city: Karlsruhe
country: Germany
city: Potsdam
country: Germany
city: Saarbrücken
country: Germany
city: Stuttgart
country: Germany
city: Würzburg
country: Germany
city: Athens Attica
country: Greece
city: Athens
country: Greece
city: Patra
country: Greece
city: Thessaloniki
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Kaposvar
country: Hungary
city: Pecs N/a
country: Hungary
city: Chiba
country: Japan
city: Hitachi
country: Japan
city: Kanazawa
country: Japan
city: Kawasaki
country: Japan
city: Kobe
country: Japan
city: Kurume
country: Japan
city: Matsuyama
country: Japan
city: Nagoya
country: Japan
city: Narita
country: Japan
city: Ohgaki
country: Japan
city: Okayama
country: Japan
city: Osaka
country: Japan
city: Sendai-shi
country: Japan
city: Shibukawa
country: Japan
city: Shibuya
country: Japan
city: Tachikawa
country: Japan
city: Toyohashi
country: Japan
city: Busan
country: Korea, Republic of
city: Gyeonggi-do
country: Korea, Republic of
city: Hwasun
country: Korea, Republic of
city: Incheon
country: Korea, Republic of
city: Seongnam
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Skopje
country: North Macedonia
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Gdansk
country: Poland
city: Legnica
country: Poland
city: Lublin
country: Poland
city: Opole
country: Poland
city: Slupsk
country: Poland
city: Warszawa Ul
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Lisboa
country: Portugal
city: Lisbon
country: Portugal
city: Porto
country: Portugal
city: Brasov
country: Romania
city: Bucharest
country: Romania
city: Iasi
country: Romania
city: Arkhangelsk
country: Russian Federation
city: Dzerzhinsk
country: Russian Federation
city: Ekaterinbourg
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Saratov
country: Russian Federation
city: Sochi
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Belgrade
country: Serbia
city: Nis
country: Serbia
city: Novi Sad
country: Serbia
city: Sremska Kamenica
country: Serbia
city: Zemun
country: Serbia
city: Andalucía
country: Spain
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: Girona
country: Spain
city: La Laguna
country: Spain
city: Madrid
country: Spain
city: Maranon
country: Spain
city: Murcia N/a
country: Spain
city: Ourense
country: Spain
city: Pamplona
country: Spain
city: Salamanca
country: Spain
city: Sevilla
country: Spain
city: Toledo
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
city: Altindag
country: Turkey
city: Ankara
country: Turkey
city: Aydin
country: Turkey
city: Izmir
country: Turkey
city: Kayseri
country: Turkey
city: Samsun
country: Turkey
city: Tekirdag
country: Turkey
city: Cherkassy
country: Ukraine
city: Dnepropetrovsk
country: Ukraine
city: Ivano-Frankivsk
country: Ukraine
city: Kharkov
country: Ukraine
city: Khmelnitskiy
country: Ukraine
city: Lviv
country: Ukraine
city: Zaporizhzhia
country: Ukraine
city: Birmingham
country: United Kingdom
city: Cambridge
country: United Kingdom
city: Colchester
country: United Kingdom
city: Harlow
country: United Kingdom
city: Leicester
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Woolwich
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Yoon SS, Iosava G, Fujisaki T, Garg M, Iida S, Blade J, Ukropec J, Pei H, Van Rampelbergh R, Kudva A, Qi M, San-Miguel J. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE. Clin Lymphoma Myeloma Leuk. 2021 Nov;21(11):785-798. doi: 10.1016/j.clml.2021.06.005. Epub 2021 Jun 18.
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: Knop S, Mateos MV, Dimopoulos MA, Suzuki K, Jakubowiak A, Doyen C, Lucio P, Nagy Z, Usenko G, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Losava G, Fujisaki T, Garg M, Wang J, Wroblewski S, Kudva A, Gries KS, Fastenau J, San-Miguel J, Cavo M. Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial. BMC Cancer. 2021 Jun 2;21(1):659. doi: 10.1186/s12885-021-08325-2.
citation: Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-141. doi: 10.1016/S0140-6736(19)32956-3. Epub 2019 Dec 10.
citation: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. doi: 10.1056/NEJMoa1714678. Epub 2017 Dec 12.