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

The Lancet Oncology, July 2018, Volume 19, Issue 7, Pages 953-964

Abstract

Summary

Background

Twice a week carfilzomib at 27 mg/m 2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m 2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib.

Methods

In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m 2 ) or twice a week (27 mg/m 2 ). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m 2 day 1 [cycle 1]; 70 mg/m 2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m 2 days 1 and 2 during cycle 1; 27 mg/m 2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1–9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , number NCT02412878 , and is no longer enrolling patients.

Findings

Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6–13·0] vs 7·6 months [5·8–9·2]; hazard ratio [HR] 0·69, 95% CI 0·54–0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff.

Interpretation

Once weekly carfilzomib at 70 mg/m 2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma.

Funding

Amgen, Inc.

Evidence before this study

The twice weekly dosing regimen can be burdensome for patients because carfilzomib is generally administered as an intravenous infusion at an outpatient institution on 2 consecutive days for 3 weeks out of a four-week treatment cycle. Non-adherent patients are under-dosed and eventually fail to benefit from effective medication. It is crucial to explore a therapeutic regimen aimed at improving the convenience of carfilzomib dosing without impacting efficacy and safety. We searched PubMed for clinical trial studies published in any language between Jan 4, 2012, to Jan 4, 2018, with the search terms: “multiple myeloma”, “carfilzomib”, “relapsed”, “refractory”, and “dosing”. The phase 1/2 CHAMPION-1 study examined whether higher doses of carfilzomib could be safe and efficacious on a once weekly dosing schedule. The CHAMPION-1 study established the maximum tolerated dose of once weekly carfilzomib at 70 mg/m 2 with dexamethasone and was active in patients with relapsed or refractory multiple myeloma. Based on promising results of the CHAMPION-1 study, once weekly carfilzomib at 70 mg/m 2 in combination with dexamethasone was chosen as the experimental group in the A.R.R.O.W. study.

Added value of this study

ARROW is the first phase 3 study that compared carfilzomib (70 mg/m 2 ) administered once weekly with carfilzomib (27 mg/m 2 ) administered twice weekly. In this study, patients given once weekly carfilzomib at 70 mg/m 2 plus dexamethasone had a 3·6 month longer progression-free survival and had higher proportion of patients achieving a response compared with patients given twice weekly carfilzomib at 27 mg/m 2 plus dexamethasone. No additional or new toxic effects were identified in the once weekly treatment group, and the safety profile of the once weekly regimen was consistent with the known safety profile of carfilzomib.

Implications of all the available evidence

Our results show a favourable benefit-risk profile for the once weekly carfilzomib treatment schedule compared with the twice weekly schedule. Furthermore, it is expected that once weekly carfilzomib will provide a more convenient dosing regimen for patients and lead to better adherence to treatment.

Research in context

Introduction

Although the introduction of immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies has improved responses in patients with multiple myeloma, most patients will eventually relapse. 1 2 3 Patients who have received several lines of previous treatment have poorer outcomes as resistance emerges because of genomic instability and clonal heterogeneity of the disease. Treatment options for patients who have multiple relapsed and refractory multiple myeloma are limited.

Carfilzomib is an irreversible and selective epoxyketone proteasome inhibitor approved as a single agent and as combination therapy with dexamethasone or lenalidomide and dexamethasone for the treatment of refractory or relapsed and refractory multiple myeloma. 4 5 Single agent carfilzomib at the 27 mg/m 2 dose was approved in the USA based on results from a phase 2 single-arm study showing that the proportion of patients achieving an overall response was 23·7%, median overall survival was 15·6 months, and that there were predictable adverse events without cumulative toxic effects. 6 Higher doses of carfilzomib administered on a twice weekly schedule were efficacious and tolerable by reducing the occurrence of infusion-related adverse reactions when given over a prolonged infusion and with the addition of dexamethasone. 7 In a phase 1b/2 study, 8 carfilzomib at a maximum tolerated dose of 56 mg/m 2 administered twice weekly with low-dose dexamethasone was well tolerated and efficacious in patients with multiple myeloma, with 50% of patients achieving an overall response when carfilzomib was administered as a 30 min infusion.

The phase 3 ENDEAVOR study, 9 10 which compared carfilzomib given at 56 mg/m 2 twice weekly over a 30 min infusion plus dexamethasone with standard of care (bortezomib and dexamethasone) in patients with relapsed or refractory multiple myeloma, showed significant improvements in both progression-free survival and overall survival with carfilzomib treatment over standard of care. Moreover, the exposure-adjusted incidence of grade 3 or worse adverse events was similar between the groups.

Although clinical evidence suggests that twice weekly carfilzomib treatment has an overall favourable benefit–risk profile, the dosing frequency (two consecutive doses for 3 weeks of a 28-day treatment cycle) associated with the approved twice weekly carfilzomib regimen can be burdensome for patients and health-care providers. Patients are challenged with frequent consecutive day visits to infusion centres to receive treatment, which can result in non-adherence or early treatment discontinuation. With the aim of improving convenience afforded by a less burdensome dosing schedule, the single-arm phase 1b/2 CHAMPION-1 study 11 was initiated to determine the maximum tolerated dose of once weekly carfilzomib with dexamethasone, and to subsequently assess the efficacy of the maximum tolerated dose in patients with relapsed or refractory multiple myeloma who were previously treated with one to three previous lines of therapy. The CHAMPION-1 study 11 explored weekly carfilzomib doses up to 88 mg/m 2 and established the maximum tolerated dose of carfilzomib at 70 mg/m 2 when administered over a 30 min infusion, with an overall response rate of 77% and median progression-free survival of 12·6 months. Grade 3 or worse adverse events occurred in 64 (62%) patients, and 39 (38%) patients had serious adverse events at the maximum tolerated dose. The most common serious adverse events of clinical significance were acute kidney injury (7%), sepsis (6%), and chronic obstructive pulmonary disease (5%). Six (5·2%) patients died on study (one due to cardiorespiratory distress, one due to sepsis, one due to acute respiratory distress syndrome, and three due to disease progression) at the 70 mg/m 2 dose.

Based on the promising results from the CHAMPION-1 study and to further explore the once weekly carfilzomib regimen, we aimed to compare the efficacy and safety of carfilzomib once weekly at 70 mg/m 2 plus dexamethasone with twice weekly carfilzomib at 27 mg/m 2 plus dexamethasone in patients with relapsed and refractory multiple myeloma. Because the only approved carfilzomib dose was 27 mg/m 2 at the time of the design of the A.R.R.O.W. study, this dose, administered twice weekly, was used as the control group for A.R.R.O.W.. The addition of equivalent weekly doses of dexamethasone in both treatment groups enabled a clear comparison between high-dose once weekly carfilzomib and standard-dose twice weekly carfilzomib. We present results from the pre-planned interim analysis of the study.

Methods

Study design and participants

A.R.R.O.W. was an open-label, randomised, multicentre trial comparing carfilzomib with dexamethasone once weekly at 70 mg/m 2 versus twice weekly at 27 mg/m 2 in patients with relapsed and refractory multiple myeloma. Patients were recruited from approximately 118 sites (hospital, clinic, oncology or medical centres) across North America, Europe, and Asia ( appendix pp 22–25 ). Eligible patients were patients (aged 18 years and older) refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease (ie, serum M protein ≥0·5 g/dL or urine M protein ≥200 mg/24 h; or in patients without measurable serum or urine M protein, serum-free light chain ≥100 mg/L [involved light chain], and an abnormal serum kappa:lambda ratio), Eastern Cooperative Oncology Group performance status of 0 or 1, who had received two to three previous treatments, and who had previous exposure to a proteasome inhibitor (except carfilzomib or oprozomib) and an immunomodulatory agent. A washout period of 21 days was required before randomisation for previous exposure to proteasome inhibitor and immunomodulatory agent.

Patients were not eligible if they had received cytotoxic chemotherapy in the 28 days before randomisation, glucocorticoid therapy (exceeding a cumulative dose of 160 mg dexamethasone or equivalent) in the 14 days before randomisation, radiation treatment (focal therapy in the 7 days before randomisation or extended field therapy in the 21 days before randomisation). Patients were required to have a documented response of at least partial response to at least one previous line of treatment. Eligible patients were also required to have left ventricular ejection fraction of 40% or higher as assessed by 2-dimensional transthoracic echocardiogram in the 21 days before randomisation, have adequate organ and bone marrow function measured by serum chemistry and haematology panels, and have a negative serum pregnancy test. Patients were excluded if they had Waldenström macroglobulinaemia; multiple myeloma of immunoglobulin M subtype; polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome; plasma cell leukaemia; myelodysplastic syndrome; history or current amyloidosis; second malignancy in the past 5 years (except for treated basal or squamous cell carcinoma, in situ carcinoma of the cervix, prostate cancer, ductal breast carcinoma, treated medullary or papillary thyroid cancer); grade 3 or worse neuropathy in the 14 days before randomisation; active infection; myocardial infarction in the 6 months before randomisation; New York Heart Association Class III or IV heart failure; ascites requiring paracentesis in the 14 days before randomisation; ongoing graft-versus-host disease; uncontrolled hypertension or diabetes mellitus; known cirrhosis; or known HIV infection.

All patients provided written informed consent. The study protocol was approved by the institutional review boards or ethics committees of all participating institutions.

Randomisation and masking

Physicians enrolled the patients. Eligible patients were randomly assigned (1:1) to receive either once weekly carfilzomib at 70 mg/m 2 with dexamethasone treatment regimen (once weekly group) or twice weekly carfilzomib at 27 mg/m 2 with dexamethasone regimen (twice weekly group), through a central interactive voice and web response system. Randomisation was stratified according to international staging system at study entry (stage 1 vs 2 or 3), whether or not patients were refractory to bortezomib treatment (yes vs no), and age (<65 years vs ≥65 years). In each stratum defined by the stratification factors, patients were randomly assigned to treatment based on a blocked randomisation scheme (block size of 4). Because of the different dosing schedules of the treatment regimens, the study was open-label—ie, the allocated treatment was not masked from study investigators or patients. The funder remained masked to treatment results during the study.

Procedures

The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m 2 on day 1 [cycle 1]; 70 mg/m 2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m 2 on days 1 and 2 during cycle 1 and 27 mg/m 2 thereafter). All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles) and 22 (cycles 1–9 only). Study treatment was administered in 28-day cycles and cycles were repeated until disease progression, unacceptable toxicity, or withdrawal of consent. Patients received intravenous hydration consisting of 250–500 mL normal saline or other fluid before each carfilzomib infusion during cycle 1 and at the investigator's discretion thereafter. Antiviral prophylaxis (valacyclovir or an equivalent antiviral agent) was recommended to prevent herpes zoster reactivation during treatment and proton-pump inhibitor to prevent peptic ulcer disease. Patients could be removed from the study because of an adverse event, pregnancy, death, loss to follow-up, non-compliance with study requirements, withdrawal of consent, study termination by sponsor, investigator decision, or disease progression. Carfilzomib and dexamethasone dose reductions were permitted to manage adverse events associated with these drugs. Guidelines for dose modifications were provided for several adverse events ( appendix pp 1–3 ).

Measurable disease was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, and serum-free light chain assay when serum and urine M protein concentrations were not high enough to be used to assess response status. Response and disease progression were determined using the International Myeloma Working Group—Uniform Response Criteria. 12 13 Disease assessments were done within 21 days before randomisation to determine eligibility, and then every 28 days (plus or minus 4 days) after day 1 of cycle 1, at the end of treatment, and during long-term follow-up every 28 days (plus or minus  4 days) until progressive disease, subsequent anti-myeloma therapy, or both.

Adverse events were collected for at least 30 days after last dose of study treatment, and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Medical Dictionary for Regulatory Activities (MedDRA; version 20.0) was used for the coding of adverse events. All treatment-related adverse events and serious adverse events were followed up until resolution or stabilisation.

Haematological laboratory and full serum chemistry were done at the central laboratory during screening, on days 1, 8, and 15 of cycles 1 to 4, and at the end of treatment for the once weekly and twice weekly groups ( appendix p 3 ). After cycle 4, laboratory assessments were done on days 1 and 15 of each cycle. Patients were also assessed for cytogenetic risk status using historical fluorescence in-situ hybridisation. Patients were categorised as high risk if they had genetic subtypes t(4:14), t(14:16), or del 17p. Standard-risk patients did not have these genetic subtypes present in their bone marrow.

Radiological disease assessments at baseline were collected after patient eligibility was confirmed. CT and MRI were used to assess extramedullary plasmacytoma and bone lesions. A plasmacytoma evaluation was done at baseline, only if a lesion was suspected clinically. If an extramedullary plasmacytoma was detected, evaluation was repeated during treatment to confirm a response of partial response or better or to assess progressive disease. Skeletal surveys were done at baseline and were repeated if worsening of clinical symptoms occurred or as clinically indicated.

Outcomes

The primary endpoint of progression-free survival was established using the validated Response Computational assessment based on the International Myeloma Working Group-Uniform Response Criteria, 12 13 and was defined as the time from randomisation until disease progression or death due to any cause. The secondary endpoints were overall response (defined as the proportion of patients who achieved partial response, very good partial response, complete response, or stringent complete response according to International Myeloma Working Group Uniform Response Criteria), overall survival (defined as the time from randomisation to death due to any cause), and safety. Exploratory analysis was done for duration of response. Duration of response was calculated as time from the earliest date a response of PR or better was first achieved and subsequently confirmed to the earliest date of confirmed PD or death due to any cause.

A post-hoc analysis was done for time to progression, which was defined as time from randomisation to progression. Definitions of stringent complete response, complete response, very good partial response, minimal response, stable disease, and progressive disease are provided in the appendix ( appendix pp 4, 5 ). The intention-to-treat population consisted of all randomly assigned patients and was the basis for the analysis of efficacy endpoints. Patients were analysed according to initial treatment assignment. The safety population was defined as all randomised patients who received at least one dose of carfilzomib or dexamethasone and was the basis for the analysis of the safety endpoints.

Statistical analysis

350 progression-free survival events were needed to have 83% power to detect a significant difference in progression-free survival between the two treatment groups at a two-sided significance level of 0·05 with one interim analysis performed at approximately 75% information time if the underlying hazard ratio (HR) was 0·73. With a total of 460 patients, it was estimated that 350 progression-free survival events were to be observed approximately 25 months after the first patient was randomly assinged. The interim analysis was scheduled after approximately 263 (75% of the required total) progression-free survival events had occurred. The objective of the interim analysis was to monitor for differences between treatment groups to find evidence of a substantial benefit in the once weekly carfilzomib-plus dexamethasone group. To ensure proper control of type I error, the interim analysis of progression-free survival was to be performed under a group sequential design framework with the stopping boundaries constructed using the Lan-DeMets spending function with an O'Brien-Fleming approach. Boundaries were calculated on the basis of observed progression-free survival events up to the data cut-off for the interim analysis. An independent data and safety monitoring committee, which monitored overall study conduct and assessed safety and efficacy data, reviewed the unmasked study data at the interim analysis. The membership criteria and other details regarding this committee are presented in the appendix (appendix p 5) . If the data monitoring committee determined that the observed p value at the interim analysis of progression-free survival was less than or equal to the stopping boundary (nominal significance level), then the study was regarded as having met its primary endpoint. Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below two-sided 0·05 level. To provide supportive analysis of outcomes, an independent review committee, who were blinded as to the randomisation assignments, centrally reviewed disease-related tests and assessments to evaluate disease progression and response.

Efficacy analysis was done in the intention-to-treat population (consisting of all randomly assigned patients). No patients were excluded from the analyses because they were considered as not assessable. For the primary outcome of progression-free survival and secondary outcome of overall survival, median time-to-event per each treatment group was derived using the unstratified Kaplan-Meier method. Comparisons between the treatment groups were made using the log-rank test. The corresponding HR and its 95% CI were estimated using a Cox proportional hazards model stratified by the randomisation stratification factors. The proportion of patients who achieved an overall response was compared between the treatment groups using the Cochran-Mantel-Haenszel test. Duration of response was summarised descriptively using the Kaplan-Meier method in patients who achieved at least a partial response. The analysis of safety was based on the safety population. Sensitivity analyses for efficacy were done based on investigator and independent review committee assessments.

Sensitivity analyses were also done based on unstratified analyses, and for per-protocol set. Subgroup analyses were done to explore the consistency of the treatment effect for subgroups. For the safety endpoints, patients who did not receive any study drug were considered not assessable for safety endpoints and excluded from the analyses. All reported p values are two-sided. SAS software (version 9.3) was used for the statistical analyses.

This trial is registered with ClinicalTrials.gov , number NCT02412878 .

Role of the funding source

The funder in collaboration with the authors designed the trial, collected the data, and analysed and interpreted the data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Between September, 2015, and August, 2016, 578 patients were screened for enrolment at 118 sites in North America, Europe, and Asia. 478 patients were eligible and were enrolled and randomly assigned to receive either once weekly carfilzomib at 70 mg/m 2 with dexamethasone treatment regimen (n=240) or twice weekly carfilzomib at 27 mg/m 2 with dexamethasone regimen (n=238; figure 1 ). Two of the 240 patients in the once weekly group did not receive allocated treatment (adverse event [n=1], disease progression [n=1]). Three of the 238 patients in the twice weekly group did not receive treatment (adverse event [n=1], withdrawal of consent [n=1], other [n=1]). Patients in the once weekly (n=238) and twice weekly (n=235) groups were analysed for safety ( figure 1 ). The cutoff date for the preplanned interim progression-free survival analysis was June 15, 2017. Baseline characteristics were generally balanced between the two treatment groups ( table 1 ), except that a higher proportion of patients in the once weekly group (111 [46%] of 240) were refractory to previous bortezomib treatment compared with the twice weekly group (90 [38%] of 238), probably caused by some patients being misclassified at the time of randomisation.

Figure 1
Trial profile
*Reasons for exclusion are provided in the appendix (p 26) .
Table 1
Baseline characteristics of intention-to-treat population
Once weekly group (n=240) Twice weekly group (n=238)
Sex
Male 132 (55%) 128 (54%)
Female 108 (45%) 110 (46%)
Age (years)
Median (IQR) 66 (59–73) 66 (59–71)
18–64 104 (43%) 104 (44%)
65–74 90 (38%) 102 (43%)
75–84 45 (19%) 32 (13%)
≥ 85 1 (<1%) 0
Geographic region
Asia Pacific 32 (13%) 17 (7%)
Europe 192 (80%) 203 (85%)
North America 16 (7%) 18 (8%)
ECOG performance status
0 118 (49%) 118 (50%)
1 121 (50%) 120 (50%)
2 1 (<1%) 0
ISS stage
Stage 1 94 (39%) 99 (42%)
Stage 2 80 (33%) 81 (34%)
Stage 3 63 (26%) 54 (23%)
Missing 2 (1%) 2 (1%)
Cytogenetic risk by FISH *
High risk 34 (14%) 47 (20%)
Standard risk 47 (20%) 53 (22%)
Unknown 159 (66%) 138 (58%)
Creatinine clearance (mL/min)
Mean (SD) 79·4 (35·8) 75·8 (25·4)
<30 mL/min 2 (1%) 1 (<1%)
30 to <50 mL/min 48 (20%) 34 (14%)
50 to <80 mL/min 91 (38%) 111 (47%)
≥80 mL/min 99 (41%) 91 (38%)
Missing 0 1 (<1%)
Serum β 2 microglobulin (mg/L)
Mean (SD) 4·9 (3·6) 4·6 (3·1)
<3·5 (mg/L) 107 (45%) 106 (45%)
≥3·5 (mg/L) 130 (54%) 128 (54%)
Missing 3 (1%) 4 (2%)
Presence of at least one bone lesion 184 (77%) 182 (77%)
Previous transplant 146 (61%) 157 (66%)
Number of previous regimens
2 116 (48%) 125 (53%)
3 124 (52%) 112 (47%)
Previous treatment
Bortezomib 236 (98%) 237 (100%)
Lenalidomide 207 (86%) 194 (82%)
Thalidomide 119 (50%) 119 (50%)
Refractory to any previous bortezomib 111 (46%) 90 (38%)
Refractory to any previous lenalidomide 186 (78%) 170 (71%)
Refractory to any previous thalidomide 39 (16%) 49 (21%)
Data are n (%) unless otherwise stated. ECOG=Eastern Cooperative Oncology Group. ISS=International Staging System.

* Genetic abnormalities t(4;14), t(14;16), and deletion 17p are in the high-risk group.

At data cutoff, 176 (73%) of 240 patients in the once weekly group and 156 (66%) of 238 patients in the twice weekly group continued in the study. In the intention-to-treat population, 274 events of disease progression or death (126 events in the once weekly group; 148 events in the twice weekly group) occurred as assessed by computational algorithm based on International Myeloma Working Group Uniform Response. The primary endpoint of progression-free survival was met at the prespecified interim analysis. Median follow-up for progression-free survival was 12·6 months (95% CI 11·7–13·8) in the once weekly group and 12·0 months (10·5–12·6) in the twice weekly group. Median progression-free survival was 11·2 months (95% CI 8·6–13·0) in the once weekly group versus 7·6 months (95% CI 5·8–9·2) in the twice weekly group (HR 0·693, 95% CI 0·54–0·88; p=0·0029; figure 2 ). Although not an endpoint in the study, time to progression was longer in the once weekly group than in the twice weekly group (12·4 months vs 8·5 months; HR 0·655, 95% CI 0·50–0·85; 2-sided p=0·0015; appendix p 6 ). We also assessed median progression-free survival in both treatment groups according to several prespecified patient subgroups ( figure 3 ). Progression-free survival HRs favoured the once weekly group over the twice weekly group in these subgroups, except in the subgroup of patients with standard-risk cytogenetics in which the HR of the once weekly versus twice weekly group was 1·00 (95% CI 0·59–1·73). Subgroup analyses according to age and patient characteristics and prior treatments are underway and will be presented in a separate paper.

Figure 2
Progression-free survival
Kaplan-Meier curve and median progression-free survival in the intention-to-treat population as assessed by computational algorithm based on IMWG-URC. HR=hazard ratio. IMWG-URC=International Myeloma Working Group uniform response criteria. PFS=progression-free survival.
Figure 3
Subgroup analysis of progression-free survival
ECOG=Eastern Cooperative Oncology Group. FISH=fluorescence in-situ hybridisation. HR=hazard ratio. ISS=International Staging System. *Genetic abnormalities t(4;14), t(14;16), and deletion 17p are in the high-risk group.†Patients were classified as refractory to bortezomib received in prior regimens if the data collected on prior multiple myeloma therapy CRF indicates any of the following criteria: (A) non-responsive to any regimen containing bortezomib (ie, best overall response was stable or progressive disease) or (B) disease progression within 60 days of bortezomib discontinuation.

The proportion of patients achieving an overall response was 62·9% (95% CI 56·5–69·0) in the once weekly group versus 40·8% (34·5–47·3) in the twice weekly group (odds ratio [OR] 2·49, 95% CI 1·72–3·60; p<0·0001); 82 (34%) patients in the once weekly and 32 (13%) in the twice weekly group had very good partial response or better. 17 (7%) patients in the once weekly group and four (2%) patients in the twice weekly group had a complete response or better ( table 2 ). The median duration of overall response was 15·0 months in the once weekly group (95% CI 12·2 to not estimable) and 13·8 months in the twice weekly group (95% CI 9·5 to not estimable). Median time to response was 1·1 (IQR 1·0–1·9) for the once weekly group and 1·9 months (1·0–2·0) for the twice weekly group.

Table 2
Treatment responses in the intention-to-treat population as assessed by computational algorithm based on IMWG-URC
Once weekly group (n=240) Twice weekly group (n=238)
Overall response * 62·9%(56·5–69·0) 40·8%(34·5–47·3)
Complete response or better 17 (7%) 4 (2%)
Stringent complete response 4 (2%) 0
Complete response 13 (5%) 4 (2%)
Very good partial response or better 82 (34%) 32 (13%)
Very good partial response 65 (27%) 28 (12%)
Partial response 69 (29%) 65 (27%)
Minimal response 14 (6%) 26 (11%)
Stable disease 33 (14%) 75 (32%)
Progressive disease 21 (9%) 22 (9%)
Data are % (95% CI) or n (%). IMW-URC=International Myeloma Working Group uniform response criteria.

* Odds ratio 2·49 (95% CI 1·72–3·60); p<0·0001.

Overall survival data were not yet mature at the interim analysis. Median follow-up time for overall survival was 13·2 months (95% CI 12·6–13·8) in the once weekly group and 12·6 months (11·9–13·4) in the twice weekly group. There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff on June 15, 2017 (HR 0·80, 95% CI 0·56–1·14; p=0·21; figure 4 ). Overall survival at 12 months were 76·6% (95% CI 70·5–81·7) for the once weekly group and 71·9% months (65·3–77·4) for the twice weekly group.

Figure 4
Overall survival
HR=hazard ratio. NE=not estimable. OS=overall survival.

Median carfilzomib treatment exposure was 38·0 weeks (IQR 14·1–54·1) in the once weekly group and 29·1 weeks (13·3–46·3) in the twice weekly group. Median dexamethasone treatment exposure was 37·1 weeks (IQR 14·1–54·1) in the once weekly group and 29·1 weeks (13·1–46·1) in the twice weekly group. Median relative dose intensity of carfilzomib (once weekly 95·7% [IQR 88·4–99·3]; twice weekly, 96·1% [90·4–98·9]) and dexamethasone (once weekly, 96·5% [86·1–100·0]; twice weekly, 97·4% [87·5–100·0]) were similar in the treatment groups.

Any-grade adverse events occurred in 227 (95%) of 238 patients in the once weekly group and 229 (97%) of 235 patients in the twice weekly group. Common adverse events in the safety population are presented in tables 3 and 4 ; all other adverse events are shown in the appendix ( appendix pp 7–9 ). Common any-grade adverse events (≥20% preferred term in either group) were anaemia, pyrexia, diarrhoea, fatigue, insomnia, and hypertension. The incidence of any-grade nausea and vomiting was slightly higher in the once weekly group than the twice weekly group. These events, however, were mostly grade 1 or 2.

Table 3
Adverse events in the safety population
Once weekly group (n=238) Twice weekly group (n=235)
Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Anaemia 21 (9%) 40 (17%) 1 (<1%) 1 (<1%) 33 (14%) 41 (17%) 1 (<1%) 0
Diarrhoea 42 (18%) 2 (1%) 0 0 44 (19%) 3 (1%) 0 0
Nausea 33 (14%) 1 (<1%) 0 0 24 (10%) 2 (1%) 0 0
Pyrexia 53 (22%) 2 (1%) 0 0 34 (15%) 4 (2%) 0 0
Fatigue 37 (16%) 10 (4%) 1 (<1%) 0 42 (18%) 5 (2%) 0 0
Asthenia 21 (9%) 3 (1%) 0 0 23 (10%) 2 (1%) 0 0
Peripheral oedema 18 (8%) 0 0 0 23 (10%) 2 (1%) 0 0
Upper respiratory tract infections 29 (12%) 2 (1%) 0 0 24 (10%) 5 (2%) 0 0
Bronchitis 25 (11%) 2 (1%) 0 0 20 (9%) 5 (2%) 0 0
Back pain 26 (11%) 2 (1%) 0 0 24 (10%) 4 (2%) 0 0
Headache 24 (10%) 1 (<1%) 0 0 22 (9%) 1 (<1%) 0 0
Insomnia 33 (14%) 2 (1%) 0 0 47 (20%) 0 0 0
Cough 33 (14%) 2 (1%) 0 0 30 (13%) 0 0 0
Hypertension 38 (16%) 13 (6%) 0 0 36 (15%) 12 (5%) 0 0
Data are n (%). Adverse events (preferred terms) of grade 1–2 occurring in ≥10% of patients in either treatment group. All grade 3 or worse adverse events not shown are reported in the appendix (p 7) .
Table 4
Adverse events of interest in the safety population
Once weekly group (n=238) Twice weekly group (n=235)
Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Peripheral neuropathy 10 (4%) 0 0 0 15 (6%) 1 (<1%) 0 0
Acute renal failure 8 (3%) 4 (2%) 5 (2%) 0 3 (1%) 7 (3%) 6 (3%) 0
Cardiac failure 2 (1%) 3 (1%) 4 (2%) 0 2 (1%) 4 (2%) 5 (2%) 1 (<1%)
Ischaemic heart disease 2 (1%) 2 (1%) 0 0 1 (<1%) 1 (<1%) 1 (<1%) 0
Pulmonary hypertension 4 (2%) 0 0 0 2 (1%) 1 (<1%) 0 0
Data are n (%). Adverse events are listed as standardised Medical Dictionary for Regulatory Activities Query, narrow scope.

The incidence of treatment-emergent grade 3 or higher adverse events was 68% (n=161) in the once weekly group and 62% (n=145) in the twice weekly group. Frequent grade 3 or worse adverse events (≥5% preferred term in either group) were anaemia (42 [18%] of 238 patients in the once weekly group vs 42 [18%] of 235 patients in the twice weekly group), pneumonia (24 [10%] vs 16 [7%]), thrombocytopenia (17 [7%] vs 16 [7%]), neutropenia (14 [6%] vs 16 [7%], hypertension (13 [6%] vs 12 [5%]), and decrease in platelet count (10 [4%] vs 12 [5%]). The incidence of treatment-emergent grade 3 or worse sepsis (6 [3%] vs 3 [1%]), septic shock (5 [2%] vs 3 [<1%]), and lung infections (3 [1%] vs 0) was higher in the once weekly versus twice weekly group. Adverse events of interest are shown in table 4 . Grade 3 or higher adverse events of interest (MedDRA grouped term) included peripheral neuropathy, acute renal failure, and cardiac failure. Treatment-emergent serious adverse events occurred in 103 (43%) of patients in the once weekly group and 96 (41%) of patients in the twice weekly group ( appendix p 9 ).

Treatment-related serious adverse events were reported in 50 (21%) in the once weekly group and 31 (13%) patients in the twice weekly group, with pneumonia and tumour lysis syndrome as the most frequently reported treatment-related serious events (≥1% preferred term in either group; appendix p 18 ). Treatment-emergent adverse events leading to carfilzomib discontinuation occurred in 30 (13%) of 238 patients in the once weekly group and 27 (12%) of 235 patients in the twice weekly group ( appendix p 10 ). 35 (15%) of 238 patients in the once weekly group and 27 (12%) of 235 patients in twice weekly group discontinued dexamethasone treatment due to an adverse event ( appendix p 11 ). Treatment-related adverse events leading to discontinuation of carfilzomib occurred in 19 (8%) of patients in the once weekly group and 11 (5%) of patients in the twice weekly group ( appendix p 20 ). Treatment-related adverse events leading to discontinuation of dexamethasone occurred in 25 (11%) patients in the once weekly group and 11 (5%) of patients in the twice weekly group ( appendix p 21 ). Adverse events (preferred term) leading to carfilzomib or dexamethasone dose reduction are shown in the appendix (pp 13–15) . The most common adverse event leading to carfilzomib discontinuation in the study was acute kidney injury, which occurred in 4 (2%) patients in each of the treatment groups ( appendix p 10 ). Treatment-emergent adverse events leading to carfilzomib dose reduction were reported in 25 (11%) of 238 patients in the once weekly group and 11 (5%) of 235 patients in the twice weekly group ( appendix p 13 ). 47 (20%) of 238 patients in the once weekly group and 37 (16%) in the twice weekly group had an adverse event that led to dexamethasone dose reduction ( appendix p 14 ).

Treatment-emergent deaths occurred in 22 (9%) patients in the once weekly group and 18 (8%) patients in the twice weekly group ( appendix p 16 ); disease progression and plasma cell myeloma contributed to the deaths reported in this study. Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1; no further information regarding reason for death was available], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]), and two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]).

The exposure-adjusted incidence of grade 3 or worse adverse events was slightly higher in the once weekly group than in the twice weekly group ( appendix p 17 ). Exposure-adjusted serious adverse events, exposure-adjusted adverse events leading to carfilzomib discontinuation, and exposure-adjusted grade 5 adverse events were similar between the treatment groups ( appendix p 17 ).

Discussion

In this interim analysis of a randomised phase 3 study, patients receiving once weekly carfilzomib at 70 mg/m 2 had a significantly longer progression-free survival than those who received twice weekly carfilzomib at 27 mg/m 2 . Consistent with the overall population, the risk of progression or death was reduced for patients in the once weekly group compared with the twice weekly group irrespective of age, sex, race, geographical region, baseline ECOG status, baseline creatinine clearance (≥50 mL/min), ISS stage, previous transplant, previous treatment, number of previous lines of treatment, or whether patients were refractory to previous treatment. Our findings also showed a progression-free survival benefit for patients with high-risk cytogenetics in the once weekly versus the twice weekly group; however, the risk of progression or death was similar between the treatment groups for patients with standard-risk cytogenetics. However, as historical data was used to analyse cytogenetic risk and a high frequency of patients had unknown cytogenetic risk at baseline, clinical outcomes according to cytogenetic risk should be interpreted with caution.

Overall survival data were not yet mature at the time of this interim analysis. Patients will continue to be followed for mortality until the study is complete. There was a trend of improved survival in the once weekly group versus the twice weekly group. The 12-month overall survival rates were higher in the once weekly group compared with the twice weekly (76·6% vs 71·9%).

The proportion of patients achieving an overall response was approximately 22% higher in the once weekly group than in the twice weekly group with a median duration of response that was 8% longer in the once weekly group. Furthermore, best responses, including complete response or better and very good partial response or better were higher in the once weekly group. These results are encouraging as a positive relationship between depth of response and improved survival has been shown in several phase 3 studies. 10 14 15 16 17

In our study, treatment-emergent grade 3 or worse adverse events, serious adverse events, adverse events leading to carfilzomib discontinuation, and deaths were slightly more frequent in the once weekly group compared with the twice weekly group. Treatment-related serious adverse events, treatment-related adverse events leading to carfilzomib discontinuation, and adverse events leading to carfilzomib dose reduction were more common in the once weekly group compared with the twice weekly group. Although the frequency of events was small, a higher proportion of patients in the once weekly than the twice weekly group had treatment-related deaths. The exposure-adjusted incidence rates of grade 3 or worse adverse events were presented to take into account the difference in the duration of treatment exposure between the once weekly and twice weekly treatment groups. Median treatment exposure was longer in the once weekly group than in the twice weekly group, hence, when adjusted for this difference, the difference in the incidence of adverse events between the two treatment groups was less prominent.

Any grade adverse events (preferred terms) that were reported more frequently in the once weekly group than the twice weekly group included thrombocytopenia, nausea, vomiting, pyrexia, increase in blood creatinine, hypokalaemia, and bone pain. A higher frequency of treatment-emergent grade 3 or worse pneumonia, hypertension, fatigue, decrease in neutrophil count, hypokalaemia, sepsis, septic shock, and lung infections were reported in the once weekly group versus the twice weekly group. The most common adverse event leading to carfilzomib or dexamethasone discontinuation in either treatment groups was acute kidney injury. In the A.R.R.O.W. study, the proportion of patients with grade 3 or higher cardiac failure was slightly lower with once weekly carfilzomib at the 70 mg/m 2 dose (3%) compared with twice weekly treatment at 27 mg/m 2 (4%). The incidence of grade 3 or wose cardiac failure in the once weekly group in A.R.R.O.W. was similar to that reported in the CHAMPION-1 study (2%) at the maximum tolerated dose of 70 mg/m 2 . 11 Importantly, no new cardiovascular safety risks were identified with once weekly carfilzomib treatment at the 70 mg/m 2 dose.

To our knowledge, A.R.R.O.W. is the first randomised phase 3 study comparing once weekly carfilzomib at 70 mg/m 2 plus dexamethasone with twice weekly carfilzomib at 27 mg/mg 2 plus dexamethasone for the treatment of patients with relapsed and refractory multiple myeloma. Aside from once weekly carfilzomib treatment showing comparable safety and superior efficacy compared with twice weekly treatment, once weekly carfilzomib treatment also offered a more time-efficient and thus more convenient dosing schedule. This more convenient dosing schedule could be equally important for elderly patients with restricted mobility or those who are working. A study based on qualitative interviews of patients with relapsed multiple myeloma that explored patients' experiences with the course of their treatment and its effect on health-related quality of life revealed that the ability to maintain an active lifestyle while on treatment was a crucial factor to patients' quality of life. 18 The convenience of the once weekly carfilzomib dosing schedule could thus provide patients more time to uphold meaningful activities.

One limitation of the A.R.R.O.W. study was the open-label design of this study, which had the potential to introduce bias. Additionally, carfilzomib at 27 mg/m 2 plus dexamethasone which was used for the control group of this study is not a current standard of care in all regions. The approved standard for carfilzomib as doublet combination (ie, the ENDEAVOR regimen of twice weekly carfilzomib at 56 mg/m 2 with dexamethasone), 4 9 was not used for the control group because this dose was not yet approved during the design and most of the enrolment period of the A.R.R.O.W. study. However, analysis of real-world data from the oncology electronic health records contained in Oncology Services Comprehensive Electronics Records database indicated that carfilzomib at 27 mg/m 2 with dexamethasone was the most common carfilzomib-based treatment regimen used from 2012–14. 19 These results could support the clinical relevance of the active control group in this study. Nevertheless, we plan to address the gap in the A.R.R.O.W. study in a future analysis by comparing once weekly carfilzomib at 70 mg/m 2 plus dexamethasone with the approved standard of twice weekly carfilzomib at 56 mg/m 2 plus dexamethasone.

Other data supporting once weekly carfilzomib at 70 mg/m 2 in a triplet regimen was described in a phase 1 study 20 evaluating the safety and efficacy of the monoclonal antibody daratumumab in combination with once weekly carfilzomib at 70 mg/m 2 plus dexamethasone in patients with relapsed multiple myeloma. The median follow-up was only 4·5 months in this phase 1 study; however, the addition of daratumumab to carfilzomib and dexamethasone resulted in a safety profile that was consistent with that of the individual therapies. Overall response was 84%, but median progression-free survival was not reached. Additionally, once weekly carfilzomib (70 mg/m 2 ), cyclophosphamide, and dexamethasone induction treatment in elderly patients with newly diagnosed multiple myeloma appeared safe and efficacious. 21 The proportion of patients achieving an overall response during induction was 88%. The most common grade 3 or higher adverse events were neutropenia, anaemia, and thrombocytopenia.

In summary, the results of the first interim analysis of A.R.R.O.W. show that patients with relapsed and refractory multiple myeloma given once weekly carfilzomib at 70 mg/m 2 plus dexamethasone had significantly improved progression-free survival, higher overall response, and deeper responses compared with patients who received twice weekly carfilzomib at 27 mg/m 2 with dexamethasone. The incidence of adverse events was comparable between the treatment groups. Overall, in comparison with twice weekly carfilzomib treatment, once weekly carfilzomib treatment showed a favourable benefit–risk profile with a more convenient dosing regimen for the treatment of patients with relapsed and refractory multiple myeloma. These results provide encouragement to investigate once weekly carfilzomib at 70 mg/m 2 in combination with lenalidomide and dexamethasone in future studies.

This online publication has been corrected. The corrected version first appeared at thelancet.com on August 1, 2018

Contributors

PM and M-VM were involved in the design of the trial. PM, M-VM, KW, AL, KS, and MAD obtained data and participated in the analysis and interpretation of the data. JRB, MH, AZ-K, and AKS contributed to the analysis and interpretation of the data. All authors participated in the drafting and revising of the manuscript and approved the final version before submission.

Declaration of interests

PM has received honoraria and consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis, Onyx Pharmaceuticals, and Takeda. M-VM has received honoraria and consulting fees from Amgen, Celgene, Janssen, and Takeda. JRB has served on the speakers' bureau, and received research funding, honoraria and consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda; has received research funding and consulting fees from Incyte; is employed by, has leadership role, and is stockholder in OncoTherapeutics and OncoTracker; and has patents pending for OncoTracker. KW has received research funding from Amgen, Celgene, Janssen, and Sanofi; consulting fees from Amgen, Bristol-Myers Squib, Celgene, Janssen, Novartis, Sanofi, and Takeda; and honoraria from Bristol-Myers Squib, Celgene, Janssen, Novartis, and Takeda. AL has received research funding from Amgen and research funding and consulting fees from Celgene. KS has received honoraria from Amgen, Celgene, Janssen, Otsuka, and Takeda; consulting fees from Amgen, Celgene, and Takeda; and research funding from Celgene and Janssen. MAD has received honoraria and consulting fees from Amgen, Celgene, Janssen, Novartis, and Takeda, and research funding from Genesis Pharma. MH and AZ-K are employees and stockholders of Amgen. AKS has received research funding and consulting fees from Amgen, Celgene, Roche, and Seattle Genetics, and has received consulting fees from Bristol-Myers Squib, Janssen, and Takeda.

Acknowledgments

This study was supported by Amgen. We thank the A.R.R.O.W. investigators; Jacqueline Sayyah, Amgen, for medical writing support; and Ashfield Healthcare Communications, part of UDG Healthcare, for editorial assistance.

Supplementary Material

Supplementary appendix

References

  • 1 RF Cornell, AA Kassim. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant. 2016;51:479-491
  • 2 P Sonneveld, E De Wit, P Moreau. How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients?. Crit Rev Oncol Hematol. 2017;112:153-170
  • 3 IS Nijhof, NW van de Donk, S Zweegman, M Henk. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs. 2018;78:19-37
  • 4 US FDA. Kyprolis: Product Information. (US FDA, Maryland, USA, 2016)
  • 5 EMEA. Kyprolis: Product Information. (EMEA, London, UK, 2016)
  • 6 DS Siegel, T Martin, M Wang, et al. A phase 2 study of single-agent carfilzomib (PX-171–003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825
  • 7 AJ Jakubowiak. Evolution of carfilzomib dose and schedule in patients with multiple myeloma: a historical overview. Cancer Treat Rev. 2014;40:781-790
  • 8 KP Papadopoulos, DS Siegel, DH Vesole, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015;33:732-739
  • 9 MA Dimopoulos, P Moreau, A Palumbo, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomized, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27-38
  • 10 MA Dimopoulos, H Goldschmidt, R Niesvizky, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomized, phase 3 trial. Lancet Oncol. 2017;18:1327-1337
  • 11 JR Berenson, A Cartmell, A Bessudo, et al. CHAMPION-1: a phase 1/2 study of once weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127:3360-3368
  • 12 BG Durie, JL Harousseau, JS Miguel, et al., International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-1473
  • 13 SV Rajkumar, JL Harousseau, B Durie, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695
  • 14 AA Chanan-Khan, S Giralt. Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol. 2010;28:2612-2624
  • 15 HJ Van de Velde, X Liu, G Chen, A Cakana, W Deraedt, M Bayssas. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica. 2007;92:1399-1406
  • 16 S Lonial, KC Anderson. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia. 2014;28:258-268
  • 17 DS Siegel, MA Dimopoulos, H Ludwig, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. JCO. 2018;36:728-734
  • 18 GL Mortensen, M Salomo. Quality of life in patients with multiple myeloma: a qualitative study. J Cancer Sci Ther. 2016;8:289-293
  • 19 C Kim, W Werther, KS Iskander, M Gruber, K Mezzi. Demographic and clinical characteristics of multiple myeloma (MM) patients treated with carfilzomib-based regimens in a real world setting. Blood. 2017;130:5441
  • 20 S Lonial, JF San-Miguel, J Martinez-Lopez, et al. Daratumumab in combination with carfilzomib and dexamethasone in patients with relapsed multiple myeloma. Blood. 2017;130:1869
  • 21 S Bringen, LD De Paoli, A Larocca, et al. Weekly carfilzomib, cyclophosphamide and dexamethasone (WKCYD) followed by maintenance with weekly carfilzomib (WK) in elderly patients with newly diagnosed multiple myeloma (NDMM). Haematologica. 2016;101:2

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