Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma.

Recruitment Status
COMPLETED - HAS RESULTS
(See Contacts and Locations)Verified April 2025 by Amgen
Sponsor
Amgen
Information Provided by (Responsible Party)
Amgen
Clinicaltrials.gov Identifier
NCT03158688
Other Study ID Numbers:
20160275
First Submitted
May 8, 2017
First Posted
May 17, 2017
Results First Posted
July 12, 2020
Last Update Posted
May 8, 2025
Last Verified
April 2025

ClinicalTrials.gov processed this data on April 2025. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

This is a phase 3 multicenter, open-label, randomized study in participants with relapsed or refractory multiple myeloma (RRMM) who have received 1 to 3 prior therapies.

Participants receive the treatment determined by randomization for a maximum of approximately 5 years, up to 30 days prior to the final analysis data cutoff (DCO) date or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or death (whichever occurs first). No crossover between the treatment arms is allowed.

This was an open-label study. However, the assessment of response and disease progression for the primary analysis was determined by an Independent Review Committee (IRC) in a blinded manner. Sensitivity analyses of response and disease progression were determined centrally by the sponsor using a validated computer algorithm (Onyx Response Computational Assessment \[ORCA\]) in a blinded manner.

Following progression or discontinuation of study drug(s), participants will have 1 follow-up visit (30 days \[+3} after last dose of all study drug\[s\]). After disease progression, data on survival status and subsequent antimyeloma therapy will be gathered at long-term follow-up (LTFU) visits every 12 weeks (+/-2 weeks) until the Final Analysis DCO.

Condition or DiseaseIntervention/Treatment
Relapsed Multiple MyelomaRefractory Multiple Myeloma
Drug: DexamethasoneDrug: Dexamethasone

Study Design

Study TypeInterventional
Actual Enrollment466 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingNone (Open Label)
Primary PurposeTreatment
Official TitleA Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma
Study Start DateJune 12, 2017
Actual Primary Completion DateJuly 13, 2019
Actual Study Completion DateApril 14, 2022

Groups and Cohorts

Group/CohortIntervention/Treatment
Kd - Carfilzomib and Dexamethasone
Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16. Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles.
Drug: Dexamethasone
Commercially available oral and IV formulas were obtained by investigative sites. Amgen supplied IV or PO dexa for some countries (Poland, Hungry, Romania, Bulgaria, Korea). Dosage modification rules applied based on participant age (participants \> 75 years were given lower doses), dexa-related toxicities, and discontinuation of carfilzomib.
KdD - Carfilzomib, Dexamethasone and Daratumumab
Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16. Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. The administration of dexamethasone was given on carfilzomib and/or daratumumab IV infusion days. Daratumumab was administered by IV at 8 mg/kg on Cycle 1: days 1 and 2; at 16 mg/kg on Cycle 1: days 8, 15 and 22, and Cycle 2: days 1, 8, 15, and 22. The 16 mg/kg dosage was continued on Cycles 3-6: days 1 and 15. The 16 mg/kg was further continued on Cycles 7+: day 1 only.
Drug: Dexamethasone
Commercially available oral and IV formulas were obtained by investigative sites. Amgen supplied IV or PO dexa for some countries (Poland, Hungry, Romania, Bulgaria, Korea). Dosage modification rules applied based on participant age (participants \> 75 years were given lower doses), dexa-related toxicities, and discontinuation of carfilzomib.

Outcome Measures

Primary Outcome Measures
  1. Progression-free Survival (PFS) as Assessed by the Independent Review Committee (PA DCO Only)
    Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC). The duration of PFS was right censored for participants who met any of the following conditions: 1. no baseline/post-baseline disease assessments; 2. started a new anti myeloma therapy before documentation of progressive disease or death; 3. progressive disease or death immediately after more than 70 days without disease assessment visit or; 4. alive without documentation of disease progression before the analysis trigger date (PA DCO); 5. lost to follow-up or withdrawn consent.
Secondary Outcome Measures
  1. Overall Response (OR) as Assessed by the Independent Review Committee (PA DCO Only)
    Overall response rate was defined as the percentage of participants in each treatment group who achieve partial response (PR) or better per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) as their best response. Complete Response (CR): No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-component with urine M-component \<100 mg/24 hours. Partial Response (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. 95% CIs for proportions were estimated using the Clopper-Pearson method.
  2. Minimal Residual Disease Negative Complete Response Rate (MRD[-]CR) at 12 Months as Assessed by the Independent Review Committee
    MRD\[-\]CR at 12 months was defined as achievement of CR per IMWG-URC by IRC and MRD\[-\] status as assessed by next-generation sequencing (NGS; at a 10\^-5 level) at the 12 months landmark (8 to 13 month window).
  3. Overall Survival
    Overall survival was defined as the time from randomization until death from any cause. Deaths collected via public source, after end of study were included. Medians were estimated using the Kaplan-Meier method. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. Participants still alive were censored at the date last known to be alive.
  4. Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    Treatment-emergent adverse events are defined as any adverse event with an onset after the administration of the first dose of any study treatment and within the end of study or 30 days of the last dose of any study treatment, whichever occurs earlier. 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 Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are treatment-emergent adverse events considered related to at least one study drug by the investigator, including those with unknown relationship.
  5. Kaplan-Meier Estimate for Duration of Response (DOR) (PA DCO Only)
    Duration of response (DOR) was defined as the time (in months) from first evidence of partial response (PR) or better per IMWG-URC by IRC to the earlier of disease progression or death due to any cause for participants with a best response of PR or better. For those who are alive and have not experienced disease progression at the time of data cutoff for analysis, duration of response was right-censored. Medians were estimated using the Kaplan-Meier method. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
  6. Kaplan-Meier Estimate for Time to Next Treatment (TTNT)
    Time to next treatment was defined as the time (in months) from randomization to the initiation of subsequent non-protocol anti-cancer treatment for multiple myeloma. Time to next treatment for participants who do not start the subsequent treatment for multiple myeloma was censored at the date when the participant's information was last available. Medians of TTNT duration were estimated using the Kaplan-Meier method. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
  7. Kaplan-Meier Estimates for Time to Progression (TTP) as Assessed by the Independent Review Committee (PA DCO Only)
    Time to progression was defined as the time (in months) from randomization to documented disease progression. Participants who did not have documented disease progression were censored at the date when data was last available.
  8. Time to Progression (TTP): Percentage of Participants Who Had Not Had Disease Progression as Assessed by the Independent Review Committee at Months 3, 6, 12, and 18 (PA DCO Only)
    Time to progression was defined as the time (in months) from randomization to documented disease progression. This outcome reports TTP as the percentage of participants who were event free (that is, they had not had disease progression) at the specified time frames. Independent Review Committee assessment for this outcome measure was not planned after the primary analysis. 95% CIs for event-free rates were estimated using the method by Kalbfleisch and Prentice (1980) with log-log transformation.
  9. Time to Overall Response as Assessed by the Independent Review Committee (PA DCO Only)
    Time to overall response was defined as the time from randomization to the earliest date a response of partial response (PR) or better as per IMWG-URC is first achieved and subsequently confirmed for participants with a best response of PR or better.
  10. Percentage of Participants Who Achieved and Maintained a Minimal Residual Disease Negative Complete Response (MRD[-]CR) for 12 Months or More
    A measure of the persistence of the CR (includes strict CR) per International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and MRD\[-\] status as assessed by next-generation sequencing (NGS; at a 10\^-5 level) for 12 months or more after achieving MRD\[-\]CR status. 95% confidence intervals (CIs) for proportions were estimated using the Clopper-Pearson method.
  11. Percentage of Participants With a Complete Response (CR) as Assessed by the Independent Review Committee (PA DCO Only)
    The percentage of participants in each treatment group who achieved stringent complete response (sCR) or CR per IMWG-URC, as assessed by the IRC, as their best response is presented.
  12. Percentage of Participants Who Achieved Minimal Residual Disease Negative (MRD[-]) Status as Assessed by Next Generation Sequencing at 12 Months
    MRD\[-\] at 12-month was defined as achievement of MRD\[-\] status as assessed by next-generation sequencing (NGS; at a 10\^-5 level) at the 12 months landmark (from 8 months to 13 months window). 95% confidence intervals (CIs) for proportions were estimated using the Clopper-Pearson method.
  13. Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores For Baseline Up to the First Follow-Up Visit After the Last Dose
    Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life. QLQ-C30 questionnaire was administered prior to dosing every 28 ± 7 days starting from cycle 1 day 1 through first follow-up visit (30 days \[+3\] after last dose of all study drugs).

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
Criteria 1 Relapsed or progressive multiple myeloma after last treatment
Criteria 2 Males or females ≥ 18 years of age
Criteria 3 Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:
IgG multiple myeloma: serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL,
IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL,
urine M-protein ≥ 200 mg/24 hours,
in subjects without measurable serum or urine M- protein, serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
Criteria 4 Received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy
Criteria 5 Prior therapy with carfilzomib is allowed as long as the patient had at least a partial response (PR) to most recent therapy with carfilzomib, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not proteasome inhibitors or CD38 antibodies during this 6-month carfilzomib treatment free interval)
Criteria 6 Prior therapy with anti-CD38 antibodies is allowed as long as the patient had at least a PR to most recent therapy with CD38 antibody, was not removed due to toxicity, did not relapse within 60 days from intensive treatment (at least every other week) of CD38 antibody therapy, and will have at least a 6 month CD38 antibody treatment-free interval from last dose received until first study treatment
Other inclusion criteria may apply
Exclusion Criteria
Criteria 1 Waldenström macroglobulinemia
Criteria 2 Multiple myeloma of IgM subtype
Criteria 3 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
Criteria 4 Plasma cell leukemia (\> 2.0 \
10\^9/L circulating plasma cells by standard differential)
Criteria 5 Myelodysplastic syndrome
Criteria 6 Known moderate or severe persistent asthma within the past 2 years
Criteria 7 Known chronic obstructive pulmonary disease (COPD) with a FEV1 \< 50% of predicted normal
Criteria 8 Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc) of \> 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization
Other exclusion criteria may apply

Contacts and Locations

Sponsors and CollaboratorsAmgen
Locations
Lynn Cancer Center Boca Raton Regional Hospital, Lynn Cancer Institute | Boca Raton Florida, United States, 33486Emory University Winship Cancer Institute | Atlanta Georgia, United States, 30322University of Chicago Medical Center - Multiple Myeloma Research Consortium | Chicago Illinois, United States, 60637-6613Fort Wayne Medical Oncology and Hematology | Fort Wayne Indiana, United States, 46845Hattiesburg Clinic Hematology/Oncology | Hattiesburg Mississippi, United States, 39401Hackensack University Medical Center | Hackensack New Jersey, United States, 07601New York Presbyterian Hospital, Weill Cornell Medical College | New York New York, United States, 10021Levine Cancer Institute | Charlotte North Carolina, United States, 28204Gabrail Cancer Center, LLC | Dover Ohio, United States, 44622Charleston Oncology | Charleston South Carolina, United States, 29414Baylor Charles A Sammons Cancer Center at Dallas | Dallas Texas, United States, 75246Liverpool Hospital | Liverpool New South Wales, Australia, 2170St Vincents Hospital Sydney | St Leonards New South Wales, Australia, 2065Westmead Hospital | Westmead New South Wales, Australia, 2145Royal Brisbane and Womens Hospital | Herston Queensland, Australia, 4029Princess Alexandra Hospital | Woolloongabba Queensland, Australia, 4102Royal Adelaide Hospital | Adelaide South Australia, Australia, 5000Epworth Healthcare | East Melbourne Victoria, Australia, 3002St Vincents Hospital Melbourne | Fitzroy, VIC Victoria, Australia, 3065Barwon Health, University Hospital Geelong | Geelong Victoria, Australia, 3220The Alfred Hospital | Melbourne Victoria, Australia, 3004Medizinische Universitaet Graz | Graz , Austria, 8036Landeskrankenhaus Salzburg | Salzburg , Austria, 5020Ziekenhuis Netwerk Antwerpen Stuivenberg | Antwerp , Belgium, 2060Universitair Ziekenhuis Brussel | Brussels , Belgium, 1090Grand Hôpital de Charleroi | Charleroi , Belgium, 6000Universitair Ziekenhuis Gent | Ghent , Belgium, 9000Universitair Ziekenhuis Leuven - Campus Gasthuisberg | Leuven , Belgium, 3000University Multiprofile Hospital for Active Treatment Sveti Georgi EAD | Plovdiv , Bulgaria, 4002University Multiprofile Hospital for Active Treatment Sveti Ivan Rilski EAD | Sofia , Bulgaria, 1431Specialized Hospital for Active Treatment of Hematology Diseases EAD | Sofia , Bulgaria, 1756Tom Baker Cancer Centre | Calgary Alberta, Canada, T2N 4N2Cross Cancer Institute | Edmonton Alberta, Canada, T6G 1Z2Ottawa Hospital Research Institute | Ottawa Ontario, Canada, K1H 8L6Princess Margaret Cancer Centre | Toronto Ontario, Canada, M5G 2M9Hopital Maisonneuve-Rosemont | Montreal Quebec, Canada, H1T 2M4Fakultni nemocnice Brno | Brno , Czechia, 625 00Fakultni nemocnice Hradec Kralove | Hradec Králové , Czechia, 500 05Fakultni nemocnice Ostrava | Ostrava-Poruba , Czechia, 708 52Fakultni nemocnice Plzen | Pilsen , Czechia, 304 60Vseobecna fakultni nemocnice v Praze | Prague , Czechia, 128 08Centre Hospitalier Départemental les Oudairies | La Roche-sur-Yon , France, 85925Centre Hospitalier de Versailles - Hopital Andre Mignot | Le Chesnay , France, 78157Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez | Lille , France, 59037Centre Hospitalier Universitaire de Nantes | Nantes , France, 44093Centre Hospitalier Universitaire de Bordeaux - Hopital Haut Leveque | Pessac , France, 33604Centre Hospitalier Lyon Sud | Pierre-Bénite , France, 69495Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie | Poitiers , France, 86021Centre Hospitalier Universitaire de Nancy - Hopital de Brabois | Vandœuvre-lès-Nancy , France, 54511General Hospital Evangelismos | Athens , Greece, 10676Alexandra Hospital | Athens , Greece, 11528General University Hospital of Patras Panagia i Voithia | Pátrai , Greece, 26504Theagenion Cancer Hospital of Thessaloniki | Thessaloniki , Greece, 54007Bekes Megyei Kozponti Korhaz Dr Rethy Pal Tagkorhaz | Békéscsaba , Hungary, 5600Semmelweis Egyetem | Budapest , Hungary, 1088Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet | Budapest , Hungary, 1097Debreceni Egyetem Klinikai Kozpont | Debrecen , Hungary, 4032Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont Altalanos Orvostudomanyi Kar | Szeged , Hungary, 6725Nagoya City University Hospital | Nagoya Aichi-ken, Japan, 467-8602Toyohashi Municipal Hospital | Toyohashi Aichi-ken, Japan, 441-8570Tesshokai Kameda General Hospital | Kamogawa-shi Chiba, Japan, 296-8602National Hospital Organization Kyushu Cancer Center | Fukuoka Fukuoka, Japan, 811-1395Kyushu University Hospital | Fukuoka Fukuoka, Japan, 812-8582Ogaki Municipal Hospital | Ogaki-shi Gifu, Japan, 503-8502Gunma University Hospital | Maebashi Gunma, Japan, 371-8511National Hospital Organization Shibukawa Medical Center | Shibukawa-shi Gunma, Japan, 377-0280University Hospital Kyoto Prefectural University of Medicine | Kyoto Kyoto, Japan, 602-8566Niigata Cancer Center Hospital | Niigata Niigata, Japan, 951-8566National Hospital Organization Okayama Medical Center | Okayama Okayama-ken, Japan, 701-1192Osaka University Hospital | Suita-shi Osaka, Japan, 565-0871Saitama Medical Center | Kawagoe-shi Saitama, Japan, 350-8550Tochigi Cancer Center | Utsunomiya Tochigi, Japan, 320-0834Tokushima Prefectural Central Hospital | Tokushima Tokushima, Japan, 770-8539Cancer Institute Hospital of Japanese Foundation for Cancer Research | Koto-ku Tokyo, Japan, 135-8550Japanese Red Cross Medical Center | Shibuya-ku Tokyo, Japan, 150-8935InterHem | Bialystok , Poland, 15-732Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich w Chorzowie | Chorzów , Poland, 41-500Centrum Onkologii Ziemi Lubelskiej im Swietego Jana z Dukli | Lublin , Poland, 20-090Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K Marcinkowskiego w Poznaniu | Poznan , Poland, 60-569Instytut Hematologii i Transfuzjologii | Warsaw , Poland, 02-776Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego we Wroclawiu | Wroclaw , Poland, 50-367Policlinica de Diagnostic Rapid | Brasov , Romania, 500152Spitalul Clinic Colentina | Bucharest , Romania, 020125Fundeni Clinical Institute | Bucharest , Romania, 022328Coltea Clinical Hospital | Bucharest , Romania, 030171Bucharest Emergency University Hospital | Bucharest , Romania, 050098Profesor Dr Ion Chiricuta Institut of Oncology | Cluj-Napoca , Romania, 400124Spitalul Clinic Municipal Filantropia Craiova | Craiova , Romania, 200143SBHI of Nizhny Novgorod region Regional Clinical Hospital of Nizhny Novgorod na N A Semashko | Nizhny Novgorod , Russia, 603126SBHI of Republic of Karelia Republic Hosiptal n a V A Baranov | Petrozavodsk , Russia, 185019State Budget Educational Institution of High Professional Skills Samara State Medical University | Samara , Russia, 443079Clinic of professional pathology and hematology | Saratov , Russia, 410028National Cancer Center | Goyang-si, Gyeonggi-do , South Korea, 10408Chonnam National University Hwasun Hospital | Hwasun, Jeollanam-do , South Korea, 58128Seoul National University Hospital | Seoul , South Korea, 03080Severance Hospital Yonsei University Health System | Seoul , South Korea, 03722Asan Medical Center | Seoul , South Korea, 05505Samsung Medical Center | Seoul , South Korea, 06351The Catholic University of Korea Seoul St Marys Hospital | Seoul , South Korea, 06591Hospital Clinico Universitario de Salamanca | Salamanca Castilla León, Spain, 37007Hospital Universitari Germans Trias i Pujol | Badalona Cataluña, Spain, 08916Hospital Clinic i Provincial de Barcelona | Barcelona Cataluña, Spain, 08036Clinica Universidad de Navarra | Pamplona Navarre, Spain, 31008Hospital Universitario 12 de Octubre | Madrid , Spain, 28041National Taiwan University Hospital | Taipei , Taiwan, 10002Taipei Veterans General Hospital | Taipei , Taiwan, 11217Hacettepe Universitesi Tip Fakultesi | Ankara , Turkey (Türkiye), 06100Ankara Universitesi Tip Fakultesi Cebeci Hastanesi | Ankara , Turkey (Türkiye), 06590Ege University Faculty of Medicine | Izmir , Turkey (Türkiye), 35040Ondokuz Mayis Universitesi Tip Fakultesi | Samsun , Turkey (Türkiye), 55139St James University Hospital | Leeds , United Kingdom, LS9 7TFUniversity College London Hospital | London , United Kingdom, NW1 2PGChristie Hospital | Manchester , United Kingdom, M20 4BX
Investigators
Study Director: MD, Amgen
Study Documents (Full Text)
Documents provided by Amgen: Study Protocol  March 16, 2021Documents provided by Amgen: Statistical Analysis Plan  July 14, 2019