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

Study Overview
=================
Brief Summary
-----------------
Compare carfizomib, dexamethasone, and daratumumab (KdD) to Carfilzomib and dexamethasone (Kd) in terms of progression free survival (PFS) in participants with multiple myeloma who have relapsed after 1 to 3 prior therapies.

Detailed 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.

Official Title
-----------------
A 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

Conditions
-----------------
Relapsed Multiple Myeloma, Refractory Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Dexamethasone
* Drug: Daratumumab
* Drug: Carfilzomib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Kd - Carfilzomib and Dexamethasone<br>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<br>* 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.<br>Drug: Carfilzomib<br>* Carfilzomib for infusion was supplied as a lyophilized, sterile product in single-use vials. The lyophilized product was reconstituted with preservative-free sterile water for injection, the reconstituted solution contained carfilzomib 2 mg/mL. IV injections lasted approximately 30 minutes. Dose could be modified based on a >20% change in body weight or toxicity.<br>* Other names: KYPROLIS®;|
| Experimental: KdD - Carfilzomib, Dexamethasone and Daratumumab<br>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<br>* 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.<br>Drug: Daratumumab<br>* Daratumumab was supplied as a concentrated solution for infusion in single-use vials.<br>* Other names: DARZALEX®;Drug: Carfilzomib<br>* Carfilzomib for infusion was supplied as a lyophilized, sterile product in single-use vials. The lyophilized product was reconstituted with preservative-free sterile water for injection, the reconstituted solution contained carfilzomib 2 mg/mL. IV injections lasted approximately 30 minutes. Dose could be modified based on a >20% change in body weight or toxicity.<br>* Other names: KYPROLIS®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 
| 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). | 12 Months (8- to 13-month window) | 
| 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. | Up to 58 months after the first participant was enrolled (at FA DCO, a median of 40.29 weeks of treatment [any study drug] in the Kd group and 79.29 weeks of treatment [any study drug] in the KdD group; FA DCO was 15 Apr 2022) | 
| 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. | PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks | 
| 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. | From Day 1 until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 
| 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. | PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks | 
| 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. | From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 
| 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. | Randomization to Months 3, 6, 12, and 18 | 
| 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. | From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 
| 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. | PA DCO: the longest treatment duration as of the PA DCO was 102.3 weeks; FA DCO: the longest treatment duration as of the FA DCO was 236.3 weeks | 
| 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. | From randomization until the PA DCO date of 14 July 2019; the longest treatment duration as of the DCO was 102.3 weeks | 
| 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. | 12 Months (8- to 13-month window) | 
| 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). | Baseline (Day 1 pre-dose) up to 236.3 weeks (longest treatment duration as of the FA DCO) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Carfilzomib, Dexamethasone, Daratumumab