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. 2021 Jan 11;18(1):e1003454. doi: 10.1371/journal.pmed.1003454

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial

Graham H Jackson 1,*,#, Charlotte Pawlyn 2,3,#, David A Cairns 4, Ruth M de Tute 5, Anna Hockaday 4, Corinne Collett 4, John R Jones 6, Bhuvan Kishore 7, Mamta Garg 8, Cathy D Williams 9, Kamaraj Karunanithi 10, Jindriska Lindsay 11, Alberto Rocci 12,13, John A Snowden 14, Matthew W Jenner 15, Gordon Cook 4,16, Nigel H Russell 9, Mark T Drayson 17, Walter M Gregory 4, Martin F Kaiser 2,3, Roger G Owen 5, Faith E Davies 18,‡, Gareth J Morgan 18,‡; the UK NCRI Haemato-oncology Clinical Studies Group
Editor: Peter N Mollee19
PMCID: PMC7799846  PMID: 33428632

Abstract

Background

Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.

Methods and findings

The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10−5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.

Conclusions

The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.

Trial registration

ClinicalTrials.gov ISRCTN49407852.

Graham Jackson and co-workers study a combination induction treatment including carfilzomib for patients with transplant-eligible myeloma.

Author summary

Why was this study done?

  • Although outcomes for myeloma patients have improved over recent decades, many patients will eventually relapse, and finding new treatment regimens that keep patients in first remission for longer is imperative.

  • Treatment combinations aim to target myeloma using different mechanisms of action. This aims to prevent resistant cells remaining and leading to relapse.

  • Carfilzomib has been shown to be effective in the treatment of relapsed myeloma when given in combination with lenalidomide.

  • We performed this study to compare the outcomes of newly diagnosed myeloma patients treated with the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) to those of patients treated with immunomodulatory-agent-based triplet control combinations.

What did the researchers do and find?

  • A total of 1,056 patients with newly diagnosed myeloma were randomised between KRdc and control.

  • Patients receiving the quadruplet KRdc combination were more likely to achieve at least a very good partial response and had longer progression-free survival than patients receiving control treatments.

  • Side effects were not significantly increased with the quadruplet combination compared to control.

What do the findings mean?

  • The results suggest that KRdc can elicit deep responses and long periods of progression-free survival with tolerable side effects in newly diagnosed myeloma patients.

  • Further studies are needed to compare KRdc to combinations of other new agents for the treatment of newly diagnosed myeloma patients.

Introduction

Multiple myeloma is a malignancy of plasma cells that can lead to bone destruction, anaemia, renal dysfunction, and/or hypercalcaemia. Outcomes for patients with myeloma have improved considerably in the last few decades following the introduction of immunomodulatory agents and proteasome inhibitors, the use of autologous stem cell transplantation (ASCT), and improvements in supportive care strategies. There is a strong rationale for delivering induction treatment using combinations of agents with different mechanisms of action to overcome intra-clonal heterogeneity [1,2]. However, the additional toxicities of combinations of 3, 4, or more drugs can limit their clinical utility. Carfilzomib is a second-generation irreversible proteasome inhibitor that is structurally and mechanistically distinct from the first-generation proteasome inhibitor, bortezomib [3]. Carfilzomib has been shown to be safe and effective in relapsed multiple myeloma, both in a doublet combination with dexamethasone (Kd) in the ENDEAVOR trial [4,5] and in triplets such carfilzomib, lenalidomide, and dexamethasone (KRd), evaluated in the ASPIRE trial [6,7]. The impressive results of these studies support the investigation of carfilzomib and lenalidomide given in combination for induction treatment in newly diagnosed, transplant-eligible patients. We report the results of a planned interim analysis of Myeloma XI+, a phase III randomised trial of the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) in comparison to an immunomodulatory-agent-based triplet control for newly diagnosed multiple myeloma patients destined for ASCT.

Methods

Study design and participants

The Myeloma XI+ trial is a multi-centre, randomised, open-label, phase III trial. This planned interim analysis reports the first of 2 co-primary outcomes—progression-free survival (PFS)—and secondary and safety outcomes. The study is closed for accrual, but follow-up continues for planned long-term analysis. All authors contributed to the development of the manuscript, approved the final version, and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. A completed CONSORT checklist is available (Text A in S1 Text). The study is registered with the ISRCTN registry (ISRCTN49407852) and EU Clinical Trials Register (2009-010956-93).

Eligible patients were recruited from 88 National Health Service sites across the UK (Table A in S1 Text) between 5 December 2013 and 20 April 2016. These sites ranged from academic medical centres to local district general hospitals. Inclusion criteria allowed the enrolment of patients who were 18 years or older and had newly diagnosed symptomatic myeloma. Patients were excluded if they had previous or concurrent active malignancies (including myelodysplastic syndrome), peripheral neuropathy of grade 2 or greater, acute renal failure (characterised by creatinine > 500 μmol/l, urine output < 400 ml/day, or requirement for dialysis and unresponsive to up to 72 hours of rehydration), or active or prior hepatitis C virus infection. Further details regarding the inclusion and exclusion criteria can be found in the protocol (Text B in S1 Text).

Myeloma XI+ followed the Myeloma XI trial using a seamless adaptation to implement a novel treatment approach soon after it became available. Myeloma XI had pathways for both transplant-eligible and -ineligible patients. Patients in the transplant-eligible pathway were randomised between thalidomide, dexamethasone, and cyclophosphamide (Tdc) and lenalidomide, dexamethasone, and cyclophosphamide (Rdc), with subsequent response-adapted intensification and maintenance randomisations that were also carried forward into Myeloma XI+. Myeloma XI+ was only for transplant-eligible patients and was designed and opened before Myeloma XI data had matured; as such, the primary outcome was the comparison between KRdc and the triplet approaches studied in Myeloma XI and continued into Myeloma XI+. Results of the Tdc versus Rdc randomisation in transplant-eligible patients from Myeloma XI showed a small, but statistically significant improvement in PFS and overall survival (OS) associated with receiving Rdc [8]; results of the cyclophosphamide, bortezomib, and dexamethasone (CVD) intensification randomisation and the maintenance randomisation are also published [9,10]. This paper reports only patients contemporaneously randomised between KRdc and Rdc/Tdc as per the statistical analysis plan for the study.

Randomisation and treatment

Patients were randomly assigned in a 2:1:1 ratio between KRdc, Rdc, and Tdc (Fig 1). All randomisations were performed at the Clinical Trials Research Unit (Leeds, UK) using a centralised, automated 24-hour telephone system. Due to the nature of the intervention, patients and their physicians were aware of the treatment allocation. A minimisation algorithm with a random element was used to avoid chance imbalances in 6 variables measured at trial entry: β2 microglobulin (<3.5 mg/l versus 3.5 to <5.5 mg/l versus ≥5.5 mg/l versus or unknown), haemoglobin (<115 g/l versus ≥115 g/l for men; <95 g/l versus ≥95 g/l for women), corrected serum calcium (<2.6 mmol/l versus ≥2.6 mmol/l), serum creatinine (<140 μmol/l versus ≥140 μmol/l), platelets (<150 × 109 cells/l versus ≥150 × 109 cells/l), and centre.

Fig 1. Patient disposition.

Fig 1

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ASCT, autologous stem cell transplantation; CR, complete response; CVD, cyclophosphamide, bortezomib, and dexamethasone; KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; MR, minimal response; PD, progressive disease; PR, partial response; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; SD, stable disease; Tdc, thalidomide, dexamethasone, and cyclophosphamide; VGPR, very good partial response.

Initial induction treatment with KRdc, Rdc, or Tdc was administered, in the absence of toxicity, consent withdrawal, or progression, for a minimum of 4 cycles and to maximum response. Patients in the KRdc group received 28-day cycles of carfilzomib 36 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2); lenalidomide 25 mg PO on days 1–21; dexamethasone 40 mg PO on days 1–4, 8, 9, 15, and 16; and cyclophosphamide 500 mg PO on days 1 and 8. In cycle 1 intravenous hydration was recommended prior to administration of carfilzomib with 250 to 500 ml of normal saline or other appropriate IV fluid. Carfilzomib was dose capped at a body surface area of 2.2 m2. Investigators were advised to routinely evaluate and treat hypertension and monitor patients for cardiac events.

Patients in the Rdc group received 28-day cycles of lenalidomide 25 mg PO on days 1–21; dexamethasone 40 mg PO on days 1–4 and 12–15; and cyclophosphamide 500 mg PO on days 1 and 8. Patients in the Tdc group received 21-day cycles of thalidomide 100 mg (increasing to 200 mg as tolerated) PO on days 1–21; dexamethasone 40 mg PO on days 1–4 and 12–15; and cyclophosphamide 500 mg PO on days 1, 8, and 15. Patients who received Tdc/Rdc underwent response-adapted intensification, with those achieving only minimal or partial response undergoing a randomisation to a proteasome inhibitor (bortezomib)–containing triplet (CVD) or no further therapy. All patients who received Tdc/Rdc with stable or progressive disease received CVD. CVD was administered in 21-day cycles of cyclophosphamide 500 mg PO on days 1 and 8; bortezomib 1.3 mg/m2 SC or IV on days 1, 4, 8, and 11; and dexamethasone 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12.

Peripheral blood stem cell harvest commenced after the patient had completed induction therapy, followed by high-dose melphalan and stem cell return according to local practice but with the intention to deliver melphalan 200 g/m2 (except 140 mg/m2 in those with renal insufficiency, defined as serum creatinine ≥ 200 μmol/l prior to transplant). A maintenance randomisation at 3 months post-ASCT compared lenalidomide (10 mg PO on days 1–21 of a 28-day cycle until disease progression) to observation.

Endpoints and assessments

The co-primary endpoints of the trial were PFS and OS. PFS was defined as the time from randomisation to progressive disease or death from any cause. OS was defined as the time from randomisation to death from any cause or last follow-up. Secondary efficacy endpoints included the percentage of patients in remission (very good partial response [VGPR] or complete response [CR]), overall response, toxicity, and progression-free survival 2 (PFS2), defined as the time from randomisation to the date of second progressive disease, start of third anti-myeloma treatment, or death from any cause.

The therapeutic efficacy was evaluated in the molecular risk subgroups of standard risk, high risk (defined as 1 adverse molecular abnormality), and ultra-high risk (2 or more adverse molecular abnormalities) and was pre-specified by protocol. Adverse molecular abnormalities were defined as gain(1q), del(17p), t(4;14), t(14;16), or t(14;20). Molecular risk profiling for the majority of patients (339/383) was performed centrally using multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time PCR (qRT-PCR) on DNA/RNA extracted from CD138-selected plasma cells from bone marrow biopsies of patients taken prior to treatment commencing. In this approach, qRT-PCR is used to assay the expression of translocation gene partners including t(4;14) MMSET and FGFR3, t(14;16) MAF, and t(14;20) MAFB. MLPA was used to assay copy number by including probesets at sites of the commonly deleted and amplified regions in myeloma, e.g., at genes CKS1B on 1q21.3 and TP53 on 17p13. These techniques have been previously validated and provide equivalent results to interphase fluorescence in situ hybridisation (iFISH) [11–13]. For the remaining patients (44/383), local cytogenetic (FISH) reports were centrally reviewed, and only those with a valid result for all risk markers were included in this analysis.

The presence of minimal residual disease (MRD) was assessed using a validated flow cytometry assay (sensitivity ≤ 0.004%, cutoff 4 × 10−5 bone marrow leucocytes) performed at a single central laboratory on bone marrow aspirates obtained at the end of initial induction and at 100 days after ASCT. A minimum of 500,000 cells were evaluated with 8-color antibody combinations including CD138, CD38, CD45, CD19, CD56, CD27, CD81, and CD117.

Paraprotein (Sebia, France) and serum free light chains (Freelite, The Binding Site, Birmingham, UK) were assessed at least every 2 months for the first 2 years and then at least every 3 months until disease progression. Urine light chain excretion (Sebia, France) was assessed to confirm CR. Response and progressive disease were assessed on the basis of IMWG uniform response criteria [14,15] and reviewed centrally by an expert panel masked to treatment allocation. Adverse events were graded according to the US National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. Adverse reactions were assessed at the start of each treatment cycle. Serious adverse events (SAEs) were reported for all patients from the date of randomisation until 30 days after the date of disease progression except in the case of serious adverse reactions or second primary malignancies, which were collected for the duration of the trial.

Statistical analysis

The primary analysis was performed in the intention-to-treat population, which included all patients who underwent randomisation. The safety population included all patients who received at least 1 dose of the trial treatment. The primary analysis was designed to compare KRdc to the triplet control group, which consisted of patients randomised to receive either Rdc or Tdc. Exploratory analysis was specified to compare KRdc with whichever of the triplets was superior. The primary endpoint of PFS was compared between the treatment groups with the use of a Cox regression model adjusting for the stratification factors. The adjusted treatment effect (hazard ratio) and corresponding 95% confidence interval were estimated with the use of this model. Other time-to-event efficacy endpoints were analysed similarly. The proportional hazards assumption was assessed informally by plotting the hazards over time (i.e., the log cumulative hazard plot) for each treatment group, and formally using the simulation-based method of Lin et al. [16]. Subgroup analysis was pre-specified for the presence or absence of individual adverse cytogenetic abnormalities and cytogenetic risk status. We did a likelihood ratio test for heterogeneity of treatment effect using Cox models identical to those used for the main analysis, with the inclusion of terms for the subgroup in question and the appropriate interaction term. The reported test for heterogeneity for subgroup analysis corresponds to a 1-degree-of-freedom test for 2 category subgroups and a 2-degrees-of-freedom test for 3 category subgroups. Continuous variables were summarised with the use of descriptive statistics, and categorical variables were summarised as numbers and percentages. Time-to-event variables were summarised with the use of the Kaplan–Meier method. We analysed binary endpoints using a logistic regression model adjusting for the stratification factors.

Of 2 planned interim analyses, the first, reported here, evaluated PFS when at least 50% of participants had experienced progressive disease or death. To ensure that an overall significance level of 5% was maintained, we used the O’Brien and Fleming alpha-spending function [17] (interim analysis bound 0.5%, final analysis bound 4.7%). The bound for the interim analysis was advisory, with the decision to release results at the recommendation of the Independent Myeloma XI/+ Data Monitoring and Ethics Committee (DMEC) and the Independent Myeloma XI/+ Trial Steering Committee (TSC). The interim analysis was done and presented to the DMEC on 12 June 2018. The DMEC recommended to the TSC that the data be released, and the TSC ratified this decision on 21 June 2018. The final PFS analysis is planned when 703 progression or death events have been reported, and the final OS analysis when 466 deaths have been reported. We estimated that a sample size of 1,044 patients would provide the trial with 80% power to detect a risk of disease progression or death that was 19% lower, and also 80% power to detect a risk of death that was 23% lower, with KRdc compared to the triplet control group. This is under the assumption of exponential survival times, with 2 years of recruitment and 4 years of follow-up, at a 2-sided alpha level of 0.05. All reported p-values are 2-sided and considered significant at an overall significance level of 5%.

Ethics statement

The study was approved by the national ethics review board (National Research Ethics Service, London, UK), the institutional review boards of the participating centres, and the competent regulatory authority (Medicines and Healthcare Products Regulatory Agency, London, UK), and was undertaken according to the Declaration of Helsinki and the principles of Good Clinical Practice as espoused in the UK Medicines for Human Use (Clinical Trials) Regulations 2004. All patients provided written informed consent.

Results

Patients were enrolled between December 2013 and April 2016 at 88 sites in the UK. Overall, 1,056 patients underwent induction randomisation (Fig 1): 526 were allocated to KRdc and 530 to the control group (265 to Rdc and 265 to Tdc). The median follow-up for this analysis is 34.5 months (IQR 27.9 to 41.3), and at the time of analysis all patients had completed their induction therapy. The groups were well matched across baseline variables, with median age 61 years (range 33–75) (Table 1).

Table 1. Baseline characteristics.

Characteristic Primary endpoint comparison Rdc
(n = 265)		 Tdc
(n = 265)
KRdc
(n = 526)		 Control (Tdc/Rdc combined)
(n = 530)
Median age (range)—years 61 (33 to 75) 62 (36 to 74) 62 (36 to 74) 61 (38 to 74)
Age group—n (%)
    ≤65 years 385 (73.2%) 370 (69.8%) 179 (67.5%) 191 (72.1%)
    >65 years 141 (26.8%) 160 (30.2%) 86 (32.5%) 74 (27.9%)
    >70 years 12 (2.3%) 24 (4.5%) 12 (4.5%) 12 (4.5%)
Sex—n (%)
    Male 317 (60.3%) 326 (61.5%) 170 (64.2%) 156 (58.9%)
    Female 209 (39.7%) 204 (38.5%) 95 (35.8%) 109 (41.1%)
Ethnicity—n (%)
    White 494 (93.9%) 482 (90.9%) 243 (91.7%) 239 (90.2%)
    Black (Black Caribbean, Black African, other) 9 (1.7%) 6 (1.1%) 5 (1.9) 1 (0.4%)
    Asian (Indian, Pakistani, Bangladeshi, other) 9 (1.7%) 17 (3.2%) 7 (2.6%) 10 (3.87%)
    Other 8 (1.5%) 2 (0.4%) 1 (0.4%) 1 (0.4%)
    Unknown 6 (1.1%) 23 (4.3%) 9 (3.4%) 14 (5.3%)
WHO performance status—n (%)
    0 225 (42.8%) 224 (42.3%) 101 (38.1%) 123 (46.4%)
    1 194 (36.9%) 182 (34.3%) 98 (37.0%) 86 (32.5%)
    2 58 (11.0%) 63 (11.9%) 30 (11.3%) 33 (12.5%)
    3 20 (3.8%) 26 (4.9%) 17 (6.4%) 9 (3.4%)
    4 1 (0.2%) 2 (0.4%) 1 (0.4%) 1 (0.4%)
    Unknown 28 (5.3%) 31 (5.8%) 18 (6.8%) 13 (4.9%)
ISS stage—n (%)
    I 167 (31.7%) 164 (30.9%) 80 (30.2%) 84 (31.7%)
    II 198 (37.6%) 194 (36.6%) 95 (35.8%) 99 (37.4%)
    III 117 (22.2%) 122 (23.0%) 63 (23.8%) 59 (22.3%)
    Unknown 44 (8.4%) 50 (9.4%) 27 (10.2%) 23 (8.7%)
Immunoglobulin subtype—n (%)
    IgG 299 (56.8) 345 (65.1%) 173 (65.3%) 172 (64.9%)
    IgA 131 (24.9%) 108 (20.4%) 49 (18.5%) 59 (22.3%)
    IgM 4 (0.8%) 3 (0.6%) 1 (0.4%) 2 (0.8%)
    IgD 5 (1.0%) 4 (0.8%) 2 (0.8%) 2 (0.8%)
    Light chain only 81 (15.4%) 66 (12.5%) 38 (14.3%) 28 (10.6%)
    Non-secretor 4 (0.8%) 4 (0.8%) 2 (0.8%) 2 (0.8%)
    Unknown 2 (0.4%) 0 0 0
Median creatinine (range)—μmol/l 82 (40 to 395) 81 (30 to 649) 82 (36 to 446) 80 (30 to 649)
    Unknown—n (%) 2 (0.4%) 2 (0.4%) 1 (0.4%) 1 (0.4%)
Median LDH (range)—IU/l 248 (83 to 1,510) 257 (2 to 1,477) 257 (5 to 1,477) 256 (2 to 774)
    Unknown—n (%) 113 (21.5%) 125 (23.6%) 66 (24.9%) 59 (22.3%)
Molecular risk assessment available—n (%) 204 (38.8%) 179 (33.8%) 85 (32.1%) 94 (35.5%)
Molecular risk—n (% of those available)
    Standard 101 (49.5%) 103 (57.5%) 47 (55.3%) 56 (59.6%)
    High risk† 81 (39.7%) 60 (33.5%) 31 (36.5%) 29 (30.9%)
    Ultra-high risk† 22 (10.8%) 16 (8.9%) 7 (8.2%) 9 (9.6%)
Molecular risk lesions—n (% of those available)
    t(4;14) 28 (13.7%) 22 (11.2%) 11 (12.9%) 11 (11.7%)
    t(14;16) 7 (3.4%) 0 (0%) 0 (0%) 0 (0%)
    t(14;20) 2 (1.0%) 0 (0%) 0 (0%) 0 (0%)
    del(17p) 17 (8.3%) 11 (6.1%) 4 (4.7%) 7 (7.4%)
    gain(1q) 71 (34.8%) 60 (33.5%) 30 (35.3%) 30 (31.9%)
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†High-risk molecular abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), and del(17p). Ultra-high risk was defined as the presence of more than 1 high-risk lesion.

ISS, International Staging System; KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; LDH, lactate dehydrogenase; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; Tdc, thalidomide, dexamethasone, and cyclophosphamide.

Efficacy

Disease progression or death occurred in 411 patients (171 of 526 patients [32.5%; 101/526, 19.2%, progression and 70/526, 13.3%, death] in the KRdc group and 240 of 530 patients [45.3%; 151/530, 28.5%, progression and 89/530, 16.8%, death] in the control group). The median PFS is not yet estimable in the KRdc group, compared to a median of 36.2 months in the control group. The hazard ratio for disease progression or death was 0.63 (95% CI 0.51 to 0.76, p < 0.001), corresponding to a 37% lower risk in the KRdc group (Fig 2A). There was no evidence of violation of the assumption of proportional hazards on inspection or using the method of Lin et al. (p = 0.379). The proportion of patients with 3-year PFS estimated by the Kaplan–Meier method was 64.5% (95% CI 59.9% to 69.1%) in the KRdc group and 50.3% (95% CI 45.4% to 55.3%) in the control group.

Fig 2. Progression-free survival.

Fig 2

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(A) Progression-free survival for KRdc compared to the Tdc/Rdc control group. (B) Subgroup analysis of progression-free survival with KRdc compared to the Tdc/Rdc control group. *Performed only for patients with subgroup data available. (C) Progression-free survival for KRdc compared to the Tdc and Rdc groups separately. HiR, high risk; ISS, International Staging System; KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; NE, not estimable; P. (het), p-value from likelihood ratio test for heterogeneity of effect; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; SR, standard risk; Tdc, thalidomide, dexamethasone, and cyclophosphamide; UHiR, ultra-high risk.

The improvement in PFS was seen across all subgroups defined by baseline characteristics, with no significant heterogeneity detected except with respect to age (Fig 2B). For transplant-eligible patients of all ages, KRdc was associated with significantly prolonged PFS compared to the control group, but those aged over 65 appeared to benefit to a greater extent, with a hazard ratio of 0.45 (95% CI 0.31 to 0.65) compared to those 65 or under, where a hazard ratio of 0.70 (95% CI 0.55 to 0.90) was seen (phet = 0.035). Improved PFS was seen in all molecular risk groups, with no significant heterogeneity between groups (standard risk: hazard ratio 0.62, 95% CI 0.39 to 0.98, median PFS KRdc not estimable [NR] versus control 37 months; high risk: 0.68, 95% CI 0.40 to 1.14, median PFS KRdc NR versus control 37 months; ultra-high risk: 0.50, 95% CI 0.20 to 1.25, median PFS KRdc 36 months versus control 20 months; phet = 0.7841) (Fig 2B and Fig A in S1 Text). The results were consistent within each of the groups with the individual risk lesions t(4;14) and del(17p) (Fig 2B and Fig B in S1 Text). An exploratory analysis to compare all 3 induction regimens demonstrates prolonged PFS associated with KRdc compared to both Rdc and Tdc induction when analysed separately (Fig 2C).

Deeper response rates were seen at the end of induction in patients treated with KRdc compared to the control group, with an odds ratio for achieving at least VGPR of 4.35 (95% CI 3.19–5.94, p < 0.001). At the end of induction, 82.3% of patients in the KRdc group achieved VGPR or better compared to 58.9% in the control group (Table 2). A higher proportion of patients in the KRdc group (74.9%) were able to undergo ASCT compared to those in the control group (63.8%). Post-ASCT VGPR or better was achieved in 91.9% of patients in the KRdc group compared to 79.3% in the control group.

Table 2. Response rates.

Timepoint and response Primary comparison Rdc Tdc
KRdc Control (Tdc/Rdc)
At end of initial induction n = 526 n = 530 n = 265 n = 265
    CR 93 (17.7%) 37 (7.0%) 19 (7.1%) 18 (6.8%)
    nCR 203 (38.6) 142 (26.8%) 90 (34.0) 52 (19.6%)
    VGPR 137 (26.0%) 133 (25.1%) 63 (23.8%) 70 (26.4%)
    ≥VGPR 433 (82.3%) 312 (58.9%) 172 (64.9%) 140 (52.8%)
    PR 43 (8.2%) 154 (29.1%) 66 (24.9%) 88 (33.2%)
    MR 3 (0.6%) 18 (3.4%) 7 (2.6%) 11 (4.2%)
    SD 1 (0.2%) 3 (0.6%) 0 (0.0%) 3 (1.1%)
    PD 6 (1.1%) 12 (2.3%) 5 (1.9%) 7 (2.6%)
    Early death* 6 (1.1%) 5 (0.9%) 2 (0.8%) 3 (1.1%)
    Missing 34 (6.7%) 26 (4.9%) 13 (4.9%) 13 (4.9%)
At 100 days post-ASCT$ n = 394 n = 338 n = 179 n = 159
    CR 122 (31.0%) 81 (24.0%) 41 (22.9%) 40 (25.2%)
    nCR 152 (38.6%) 107 (31.7%) 60 (33.5%) 47 (29.6%)
    VGPR 88 (22.3%) 80 (23.7%) 46 (25.7%) 34 (21.4%)
    ≥VGPR 362 (91.9%) 268 (79.3%) 147 (82.1%) 121 (76.1%)
    PR 23 (5.8%) 54 (16.0%) 26 (14.5%) 28 (17.9%)
    MR 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
    SD 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
    PD 2 (0.5%) 6 (1.8%) 4 (2.2%) 2 (1.3%)
    Early death# 1 (0.3%) 1 (0.6%) 0 (0.0%) 1 (0.6%)
    Missing 6 (1.5%) 9 (2.7%) 2 (1.1%) 7 (4.4%)
MRD-negative status
At end of initial induction n = 164 n = 157 n = 83 n = 74
    MRD negative 90 (54.9%) 20 (12.7%) 18 (21.7%) 8 (10.8%)
At day 100 after ASCT n = 202 n = 160 n = 79 n = 81
    MRD negative 152 (75.2%) 80 (50.0%) 40 (50.6%) 40 (49.4%)
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Data given as n (percent).

*All-cause death within 60 days of randomisation.

$Reported of these undergoing ASCT.

#All-cause death within 100 days of high-dose melphalan dose.

ASCT, autologous stem cell transplantation; CR, complete response; KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; MR, minimal response; MRD, minimal residual disease; nCR, complete response without bone marrow confirmation; PD, progressive disease; PR, partial response; SD, stable disease; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; Tdc, thalidomide, dexamethasone, and cyclophosphamide; VGPR, very good partial response.

At the end of induction, MRD negativity (MRD−) was achieved in more patients in the KRdc group (55% [90/164]) than in the control group (17% [26/157]; 11% [8/74] with Tdc, 22% [18/83] with Rdc). PFS for MRD− patients was improved compared to MRD+ patients (percent PFS at 3 years from MRD assessment, MRD− 78.7% versus MRD+ 51.9%). Interestingly, there were differences in outcome within the MRD− group, with patients receiving KRdc doing better (percent PFS at 3 years from MRD assessment, KRdc MRD− 81.8% versus control MRD− 68.1% [Tdc 62.5% and Rdc 70.6%]). In the MRD+ group the outcomes were similar (percent PFS at 3 years from MRD assessment, KRdc MRD+ 49.9% versus control MRD+ 52.8% [Tdc 61.8% and Rdc 40.7%]). At 100 days after ASCT, the rate of MRD− had improved in all groups, but remained higher in the KRdc group (75% [152/202]) than in the control group (50% [80/160]; 51% [40/79] with Tdc, 49% [40/81] with Rdc). The achievement of MRD− status after ASCT was also associated with improved outcomes.

OS data were immature at the time of analysis, with follow-up continuing. Data for PFS2, a key secondary endpoint, showed a significantly improved outcome for patients receiving KRdc. Second disease progression or death had occurred in 191 patients (85 of 526 patients [16.2%] in the KRdc group and 106 of 530 patients [20.0%] in the control group). The proportion of patients with 3-year PFS2 was 81.8% (95% CI 78.0% to 85.6%) in the KRdc group compared to 75.1% (95% CI 70.7% to 79.6%) in the control group. (Fig 3A). The hazard ratio for disease progression or death was 0.75 (95% CI 0.56 to 0.99, p = 0.0451), corresponding to a 25% lower risk in the KRdc group compared to the Tdc/Rdc control group. An exploratory analysis to compare all 3 induction regimens demonstrates prolonged PFS2 associated with KRdc compared to Tdc but not Rdc, when analysed separately (Fig 3B).

Fig 3. Progression-free survival 2.

Fig 3

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(A) Progression-free survival 2 for the KRdc group compared to the Tdc/Rdc control group. Note that medians and confidence intervals were inestimable. (B) Progression-free survival 2 for the KRdc group compared to the Tdc and Rdc control groups separately. Note that medians and confidence intervals were inestimable. KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; Tdc, thalidomide, dexamethasone, and cyclophosphamide.

Safety

Induction treatment was planned for a minimum of 4 cycles and to continue to maximum response. The median number of treatment cycles received was 4 (range 1 to 12) in the KRdc group and 6 (1 to 15) in the control group (Rdc median 5, Tdc median 6). The use of a dose modification schedule in the event of adverse events allowed the vast majority of patients to complete at least 4 cycles of induction therapy. Patients not completing 4 cycles numbered 50 (9.5%) in the KRdc group and 43 (8.1%) in the Tdc/Rdc control group (Rdc 20, Tdc 23). The most common reasons cited for stopping induction therapy early were clinician choice (KRdc 22 patients, Tdc/Rdc control 26 patients [Rdc 12, Tdc 14]) or unacceptable toxicity (KRdc 20 patients, Tdc/Rdc control 14 patients [Rdc 4, Tdc 11]); more than 1 reason could be cited per withdrawal. Overall, the majority of patients stopped induction therapy because they had reached maximum response as per protocol. For patients completing 4 or more cycles, maximum response was cited as the reason for stopping in 430/526 (81.7%) in the KRdc group and 413/530 (77.9%) in the Tdc/Rdc control group (Rdc 216, Tdc 197). Clinician choice was cited in 37/526 (7.0%) in the KRdc group and 61/530 (11.5%) in the Tdc/Rdc control group (Rdc 24, Tdc 37). Unacceptable toxicity was cited in 25/526 (4.8%) in the KRdc group and 26/530 (4.9%) in the Tdc/Rdc control group (Rdc 7, Tdc 19).

Adverse reactions of any grade that were reported in more than 10% of patients in any treatment group, grade 3–4 reactions reported in more than 5% of patients in any treatment group, and all grade 5 reactions are shown in Table 3. The most common adverse reactions were haematological. Grade 3 or 4 neutropenia occurred in 16.4% KRdc, 22.3% Rdc, and 12.8% Tdc patients; anaemia in 10.2% KRdc, 5.8% Rdc, and 4.7% Tdc patients; and thrombocytopenia in 8.4% KRdc, 2.3% Rdc, and 1.2% Tdc patients. There was no apparent increase in peripheral sensory neuropathy from the addition of carfilzomib to Rdc. Grade 5 adverse events were reported during induction in 3 patients receiving KRdc and 4 patients receiving Tdc/Rdc control treatment. Thromboembolic events occurred at slightly higher rates in patients receiving KRdc compared to Rdc. Thromboembolic events within the study have been examined in more detail in another paper [18]. The incidence of SAEs was 69.5% in those receiving KRdc and 55.3% in those receiving Tdc/Rdc control treatment. The majority of SAEs in all groups were due to infections or infestations.

Table 3. Adverse reactions.

Adverse reaction KRdc (n = 511) Rdc (n = 257) Tdc (n = 261)
Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Haematological
Anaemia 354 (69.3%) 51 (10.0%) 1 (0.2%) 0 185 (70.9%) 14 (5.4%) 1 (0.4%) 0 174 (67.7%) 12 (4.7%) 0 0
Neutrophil count decrease 172 (33.7%) 59 (11.5%) 25 (4.9%) 0 76 (29.1%) 40 (15.3%) 18 (6.9%) 0 72 (28.0%) 18 (7.0%) 14 (5.4%) 1 (0.4%)
Platelet count decrease 213 (41.7%) 27 (5.3%) 16 (3.1%) 0 80 (30.7%) 6 (2.3%) 0 0 35 (13.6%) 3 (1.2%) 0 0
Infections
Cellulitis 4 (0.8%) 5 (1.0%) 0 1 (0.2%)* 1 (0.4%) 1 (0.4%) 0 0 0 1 (0.4%) 0 0
Lung infection 31 (6.1%) 50 (9.8%) 3 (0.6%) 1 (0.2%) 25 (9.6%) 18 (6.9%) 1 (0.4%) 0 18 (7.0%) 20 (7.8%) 2 (0.8%) 1 (0.4%)
Sepsis 1 (0.2%) 10 (2.0%) 14 (2.7%) 1 (0.2%) 0 7 (2.7%) 3 (1.1%) 2 (0.8%) 0 5 (1.9%) 2 (0.8%) 0
Gastrointestinal
Constipation 208 (40.7%) 1 (0.2%) 0 0 114 (43.7%) 2 (0.8%) 0 0 158 (61.5%) 1 (0.4%) 1 (0.4%) 0
Diarrhoea 136 (26.6%) 15 (2.9%) 0 0 64 (24.5%) 4 (1.5%) 0 0 50 (19.5%) 5 (1.9%) 0 0
Nausea 94 (18.4%) 4 (0.8%) 0 0 45 (17.2%) 5 (1.9%) 0 0 65 (25.3%) 1 (0.4%) 0 0
Gastrointestinal—other 3 (0.6%) 2 (0.4%) 0 0 1 (0.4%) 0 0 1 (0.4%)* 4 (1.6%) 2 (0.8%) 0 0
Neurological
Peripheral motor neuropathy 40 (7.8%) 2 (0.4%) 1 (0.2%) 0 21 (8.0%) 1 (0.4%) 0 0 26 (10.1%) 1 (0.4%) 0 0
Peripheral sensory neuropathy 104 (20.4%) 0 1 (0.2%) 0 58 (22.2%) 1 (0.4%) 0 0 124 (48.2%) 3 (1.2%) 0 0
Tremor 29 (5.7%) 0 0 0 30 (11.5%) 1 (0.4%) 0 0 58 (22.6%) 0 0 0
Other
Back pain 47 (9.2%) 4 (0.8%) 0 0 41 (15.7%) 2 (0.8%) 0 0 32 (12.5%) 7 (2.7%) 0 0
Cough 53 (10.4%) 7 (1.4%) 0 0 17 (6.5%) 2 (0.8%) 0 0 23 (8.9%) 2 (0.8%) 0 0
Dyspnoea 71 (13.9%) 5 (1.0%) 0 1 (0.2%) 18 (6.9%) 7 (2.7%) 0 0 40 (15.6%) 4 (1.6%) 0 0
Fatigue/lethargy 204 (39.9%) 5 (1.0%) 0 0 153 (58.6%) 96 (36.8%) 5 (1.9%) 0 124 (48.2%) 3 (1.2%) 0 0
Fever 85 (16.6%) 26 (5.1%) 0 0 31 (11.9%) 4 (1.5%) 1 (0.4%) 0 23 (8.9%) 9 (3.5%) 1 (0.4%) 0
Oedema limbs 60 (11.7%) 2 (0.4%) 0 0 32 (12.3%) 0 0 0 48 (18.7%) 0 0 0
Pain—other 40 (7.8%) 3 (0.6%) 0 0 26 (10.0%) 3 (1.1%) 0 0 16 (6.2%) 6 (2.3%) 0 0
Pulmonary embolism 1 (0.2%) 11 (2.2%) 3 (0.6%) 0 2 (0.8%) 8 (3.1%) 2 (0.8%) 0 0 12 (4.7%) 2 (0.8%) 0
Rash 116 (22.7%) 29 (5.7%) 3 (0.6%) 0 45 (17.2%) 6 (2.3%) 0 0 32 (12.5%) 5 (1.9%) 0 0
ARs of special interest
Infusion reaction 13 (2.5%) 3 (0.6%) 1 (0.2%) 0 4 (1.5%) 0 0 0 2 (0.8%) 0 0 0
Hypotension 21 (4.1%) 2 (0.4%) 3 (0.6%) 0 12 (4.6%) 2 (0.8%) 0 0 13 (5.1%) 2 (0.8%) 0 0
Other thrombosis/embolism 8 (1.6%) 0 4 (0.8%) 0 1 (0.4%) 1 (0.4%) 0 0 1 (0.4%) 2 (0.8%) 0 0
Deep vein thrombosis 30 (5.9%) 6 (1.2%) 0 0 10 (3.8%) 2 (0.8%) 1 (0.4%) 0 17 (6.6%) 4 (1.6%) 0 0
Heart failure 1 (0.2%) 4 (0.8%) 0 0 0 0 0 0 0 0 0 0
Hypertension 1 (0.2%) 2 (0.4%) 0 0 2 (0.8%) 0 0 0 0 1 (0.4%) 0 0
Pulmonary oedema 2 (0.4%) 2 (0.4%) 0 0 0 0 0 0 0 0 0 0
Myocardial infarction 0 1 (0.2%) 1 (0.2%) 0 0 0 0 0 0 0 0 0
Acute coronary syndrome 1 (0.2%) 0 0 0 0 0 0 0 0 0 0 0
Cardiac disorders—other 0 3 (0.6%) 1 (0.2%) 0 2 (0.8%) 1 (0.4%) 0 0 2 (0.8%) 1 (0.4%) 0 0
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The safety population included all patients who received at least 1 dose of the trial treatment. Adverse reactions of any grade that were reported in >10% of patients in any treatment group, grade 3–5 in >5% of patients in any treatment group, or grade 5 in any treatment group are listed, along with other adverse events of special interest.

*Patients whose cause of death included “sepsis” in addition to the cause in this row.

AR, adverse reaction; KRdc, carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide; Rdc, lenalidomide, dexamethasone, and cyclophosphamide; Tdc, thalidomide, dexamethasone, and cyclophosphamide.

Cardiac events were closely examined (Table 3). Grade 3 or 4 cardiac failure was reported in 4 patients (0.8%) in the KRdc group and no patients in the Tdc/Rdc control group, and pulmonary oedema in 2 (0.4%) patients in the KRdc group and no patients in the triplet control group. Grade 3 or 4 hypertension was reported in 2 patients (0.4%) in the KRdc group and 1 patient (0.2%) in the Tdc/Rdc control group.

Exploratory analysis using optimal risk-adapted control group

To address whether the improvement in outcome with KRdc identified was attributable to the efficacy of the combination or was influenced by the control group that could, in the current treatment landscape, be considered suboptimal, we explored data from the risk-adapted randomisation step of the trial. Patients who achieved a suboptimal response (minimal or partial response) to triplet Tdc/Rdc induction were randomised between sequential triplet therapy with a proteasome inhibitor (CVD) or no further therapy prior to transplant. We have previously reported that CVD intensification was associated with improved outcome [9]. In order to remove this potential bias from the current analysis, we compared outcomes excluding those patients in the triplet control group who had achieved a partial or minimal response to initial induction and been randomised to the suboptimal approach of no further therapy prior to transplant. Results remained consistent with the intention-to-treat comparison (Fig C in S1 Text). The hazard ratio for the risk of progression or death was 0.64 (95% CI 0.52 to 0.78, p < 0.001), corresponding to a 36% lower risk in the KRdc group compared to the optimal risk-adapted control group.

Discussion

This is a large phase III study of a lenalidomide and carfilzomib combination regimen for newly diagnosed myeloma, with the results highlighting the efficacy and safety of this combination in previously untreated patients, supporting prior early phase studies [19,20]. The use of KRdc in this setting is associated with a significant improvement in PFS in comparison to a combination comprising either Tdc or Rdc, reducing the risk of progression or death by 37%. Recipients of KRdc induction were 4.35 times more likely to achieve at least a VGPR after a median of only 4 cycles of therapy, highlighting the rapidity of disease control. Responses of at least CR without bone marrow confirmation were seen in 56% with KRdc versus 34% with Tdc/Rdc pre-transplant, and 70% and 56% post-transplant, respectively, consistent with the benefit of the KRdc combination. Around 30% of cases had material available for assessment of MRD status; post-ASCT high rates of MRD negativity were attained, and importantly MRD− was associated with significantly longer PFS. This pattern of results, with a slightly higher rate of MRD− than of CR, is typical of myeloma studies reported recently; for example, IFM-2009 [21] reported CR rates of 59% and MRD− rates of 79% following ASCT. These differences reflect both the half-life of immunoglobulins and the availability of bone marrow confirmation of CR, a requirement of the definition.

Even within the group of patients achieving MRD negativity at a level of sensitivity of 0.004% (cutoff 4 × 10−5 bone marrow leucocytes), there were differences in outcome, with the KRdc-treated group having significantly better PFS compared to those receiving Tdc/Rdc triplets. The cause for this difference is unknown, but we postulate there were deeper responses in the KRdc-treated group compared to the control group that translated to improved PFS.

We demonstrate that patients with high- and ultra-high-risk disease benefit from the use of KRdc, with no heterogeneity in the impact of the KRdc combination compared to standard-risk patients. This finding is encouraging, showing activity in patients with t(4;14) and del(17p), subgroups in whom there has been a lack of progress over the last decade [22]. Importantly, exposure to proteasome inhibitor and immunomodulatory agent combinations has been reported to be beneficial for these subgroups of patients [23], and potentially the greater activity of carfilzomib compared to bortezomib is associated with these excellent results. The superiority of carfilzomib compared to bortezomib was demonstrated in patients with relapsed disease in the ENDEAVOR study [5]. The superiority of carfilzomib is not, however, supported by data from the recently reported ENDURANCE study [24], which examined the combination of carfilzomib with lenalidomide and dexamethasone (without cyclophosphamide) as induction treatment for newly diagnosed myeloma patients. This study did not identify a difference in outcome between patients receiving KRd or bortezomib, lenalidomide, and dexamethasone (VRd), but it was not carried out in the same population as Myeloma XI+, excluding patients with high-risk disease and those destined for stem cell transplantation. For transplant-eligible patients of all risk subgroups, the phase II FORTE study [25] has reported preliminary data suggesting the KRd combination can achieve deeper responses than the combination of carfilzomib, cyclophosphamide, and dexamethasone, but full results are awaited.

An exploratory analysis demonstrated that KRdc was associated with prolonged PFS compared to both Rdc and Tdc when analysed separately. Any comparison between Rdc and Tdc is not powered within this contemporaneously recruited cohort, but from the preceding Myeloma XI trial, Rdc was associated with prolonged PFS, PFS2, and OS compared to Tdc [8]. KRdc was associated with significantly prolonged PFS2 compared to the pre-planned Tdc/Rdc triplet control group comparator. On exploratory analysis, KRdc was associated with prolonged PFS2 compared with Tdc, but not Rdc. However, the follow-up remains immature for this endpoint, which will be re-examined, along with OS, at final analysis.

The KRdc combination was well tolerated in the present study, with a low incidence of peripheral neuropathy. Interestingly, there was also less neutropenia in the KRdc group, possibly due to the fewer cycles required to achieve maximum response (median 4 versus 5 cycles) and the associated rapid, deep responses with improved bone marrow function. In relapsed patients in the ENDEAVOR study [5,26], grade 3 or higher cardiac failure were seen in 22/462 (4.8%) carfilzomib-treated patients compared to only 8/456 (1.8%) patients in the control group. In the newly diagnosed myeloma setting investigated here, the overall incidence of cardiac adverse events was low, which may be related to the different dose of carfilzomib used in our study (36 mg/m2 versus 56 mg/m2) or the absence of the impact of prior therapy. The exclusion of patients with a significant history of cardiac disease was at the discretion of the investigators and so may have affected this finding. The treatment was delivered in community as well as academic hospitals, with no significant difficulties encountered.

A potential criticism of the Myeloma XI+ study relates to the control arm, where a triplet combination that was a standard of care in prior UK trials and that is in widespread use across the world was used. A comparison of a different immunomodulatory drug and proteasome inhibitor combination (e.g., VRd or bortezomib, thalidomide, and dexamethasone) would also have been of interest because of more recent uptake of such combinations in the EU and US, but this was not the position when the study was initially implemented. Despite this, the outcome for the control arm in this study compares well to other combinations, with a median PFS of 36.2 months. In the IFM 2009 study [21], VRd was associated with a median PFS of 36 versus 50 months for those who underwent ASCT. In the IFM study all patients received lenalidomide maintenance, in contrast to patients in the Myeloma XI+ study, where only 50% received maintenance. In real-world data reported from the Mayo Clinic [27], which included 243 patients who received VRd followed by ASCT, half of whom received maintenance therapy, VRd was associated with a median PFS of 28 months. To further address this question we utilised data from the current trial, where an immunomodulatory-agent triplet was used initially followed by a proteasome triplet for suboptimal responders not achieving at least a VGPR. Using these data we were able to generate optimised outcome data, but even in comparison to this, the use of KRdc was associated with significantly improved outcomes. Another limitation includes the unblinded nature of the therapy randomisation; both the patient and local investigator were aware of the treatment being delivered.

In conclusion, in transplant-eligible, newly diagnosed multiple myeloma patients in the Myeloma XI+ study, a carfilzomib and lenalidomide combination, KRdc, was well tolerated and was associated with an increased percentage of patients achieving at least a VGPR, more MRD-negative responses, and significantly prolonged PFS compared to a immunomodulatory-agent-based triplet induction combination.

Supporting information

S1 Text

Fig A—Progression-free survival by cytogenetic risk. Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) within each cytogenetic risk group. (A) Standard risk, (B) high risk, (C) ultra-high risk. Adverse molecular abnormalities were defined as gain(1q), del(17p), t(4;14), t(14;16), or t(14;20). Efficacy in the subgroups of standard risk, high risk (defined as 1 adverse cytogenetic abnormality) and ultra-high risk (2 or more adverse cytogenetic abnormalities) were pre-specified by protocol. CI, confidence interval; HR, hazard ratio; m, months. Fig B—Progression-free survival for patients with/without t(4;14) and del(17p). Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) for patients with the cytogenetic lesions t(4;14) and del(17p). (A) t(4;14), (B) no t(4;14), (C) del(17p), (D) no del(17p). CI, confidence interval; HR, hazard ratio; m, months. Fig C—Progression-free survival adjusted for CVD randomisation. Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) with patients achieving a suboptimal response to triplet treatment and randomised to no intensification therapy removed. CI, confidence interval; HR, hazard ratio; m, months. Table A—Myeloma XI+ study sites and principal investigators. Text A—CONSORT Checklist. Text B—Myeloma XI+ protocol.

(PDF)

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Acknowledgments

We thank all the patients at centres throughout the UK whose willingness to participate made this study possible. We are grateful to the UK National Cancer Research Institute Haemato-oncology Clinical Studies Group, UK Myeloma Research Alliance, and all principal investigators, sub-investigators, and local centre staff for their dedication and commitment to recruiting patients to the study. We thank the members of the Myeloma XI+ Trial Steering Committee and Data Monitoring and Ethics Committee. The support of the Clinical Trials Research Unit at the University of Leeds was essential to the successful running of the study; we thank all its staff who have contributed, past and present. Central laboratory analysis was performed at the Institute of Immunology and Immunotherapy, University of Birmingham; the Institute of Cancer Research, London; and the Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds. We are very grateful to the laboratory teams for their contribution to the study. We acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research.

Abbreviations

ASCT

autologous stem cell transplantation

CR

complete response

CVD

cyclophosphamide, bortezomib, and dexamethasone

KRd

carfilzomib, lenalidomide, and dexamethasone

KRdc

carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide

MRD

minimal residual disease

NE

not estimable

OS

overall survival

PFS

progression-free survival

PFS2

progression-free survival 2

Rdc

lenalidomide, dexamethasone, and cyclophosphamide

SAE

serious adverse event

Tdc

thalidomide, dexamethasone, and cyclophosphamide

VGPR

very good partial response

VRd

bortezomib, lenalidomide, and dexamethasone

Data Availability

There are legal restrictions on sharing data that contain potentially identifying or sensitive personal information. The restrictions are imposed by The Information Commissioner's Office (https://ico.org.uk/). Data used in the current study will be made available upon request after application to the Myeloma XI data controller and the independent trial steering committee. Any requests for trial data and supporting material (data dictionary, protocol, and statistical analysis plan) should be sent to ctru-dataaccess@leeds.ac.uk. Data requestors will need to sign a data access agreement.

Funding Statement

Primary financial support was from Cancer Research UK (https://www.cancerresearchuk.org/; C1298/A10410 to GJM, FED, GHJ, MTD, NR, WMG). Unrestricted educational grants from Celgene Corporation (https://www.celgene.com/; to GJM, GHJ), Amgen (https://www.amgen.com/; to GJM, GHJ) and Merck Sharp and Dohme (https://www.merck.com/; to GJM, GHJ), and funding from Myeloma UK (https://www.myeloma.org.uk/; to GJM, MFK) supported trial coordination and laboratory studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Richard Turner

4 Mar 2020

Dear Dr Jackson,

Thank you for submitting your manuscript entitled "Carfilzomib, Lenalidomide, Dexamethasone and Cyclophosphamide (KRdc) as Induction Therapy for Transplant Eligible Newly Diagnosed Multiple Myeloma." for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Richard Turner, PhD

Senior editor, PLOS Medicine

rturner@plos.org

Decision Letter 1

Richard Turner

7 Aug 2020

Dear Dr. Jackson,

Thank you very much for submitting your manuscript "Carfilzomib, Lenalidomide, Dexamethasone and Cyclophosphamide (KRdc) as Induction Therapy for Transplant Eligible Newly Diagnosed Multiple Myeloma." (PMEDICINE-D-20-00730R1) for consideration at PLOS Medicine. We do apologize for the delay in sending you a decision.

Your paper was evaluated by the editors and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that addresses the reviewers' and editors' comments fully. You will appreciate that we cannot make a decision about publication until we have seen the revised manuscript and your response, and we expect to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

-----------------------------------------------------------

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Please review PLOS Medicine's data policy (https://journals.plos.org/plosmedicine/s/data-availability) which your paper will need to comply with in the event of publication. For example, a non-author contact would need to be provided for those inquiring about access to study data.

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Comments from the reviewers:

*** Reviewer #1:

Alex McConnachie, Statistical Review

This is a review of the statistical aspects of Jackson et al's paper about the interim results of the Myeloma XI+ trial, comparing progression free survival between patients treated with a 4-drug combination versus one of two 3-drug combinations.

This is a hugely impressive trial, and I am in favour of the decision to seek to publish the results of the study to date. The statistical analyses are generally very good, and my comments are mainly to do with the way that things have been presented.

The co-primary endpoints are PFS and overall survival, though this paper does not report the OS data. This is fine, but reading the abstract, the reader is expecting to see them. The results in the abstract show PFS results, and then moves on to response rates and adverse events, giving the impression that the OS data are being omitted. I think the first part of the abstract, and maybe the paper as a whole (including the title?), could be more up-front about this being a planned interim analysis, focusing on the first of two co-primary outcomes, plus secondary and safety outcomes. This is clearer on reading the statistical methods section, but many readers will not get that far.

The wording in the abstract "…median PFS not reached vs 36.2 months" is not immediately clear. Perhaps a few more words need to be used to explain this a little better, for someone who is only reading the abstract.

The unblinded nature of the trial is not mentioned as a limitation. Should it be?

Particularly as a non-clinical reader, I found the use of abbreviations quite challenging at times throughout the paper. Often they were not spelled out in full on first use, making it difficult to follow.

The primary analysis method of an adjusted Cox model is fine. I presume the proportional hazards assumption was checked, and was met, though this is not mentioned.

A subgroup analysis is presented of the main treatment effect within those who were MRD negative (though I had to look up what MRD means). Is this a sensible analysis, given that MRD status is defined after randomisation (and treatment)? Should the same results from the MRD+ group be reported? Or, should the main analysis be performed with adjustment for MRD status, to assess whether MRD status explains the treatment effect?

The final efficacy result reported is that KRdc showed improved PSF2 compared to CTD, but not CRD, when analysed separately. Given that the KRdc vs. CTD/CRD comparison only just achieved p<0.05, it is almost certain that at least one of KRdc vs. CTD or CRD will not achieve this p-value threshold. Is this observation worthy of a mention, when I doubt that there is any evidence of a difference between CRT and CRD?

Table 2 present response data, but does not show any treatment effect estimates or p-values. These might be helpful here.

Figures 2a and 2b include legends saying that none of the median PSF2 times, nor their confidence limits, were estimable. Is this necessary?

*** Reviewer #2:

The manuscript by Jackson et al describes the first interim analysis of one of the randomisations on the UK Myeloma XI trial. The randomisation compared KRdc against CRD and CTD (2:1:1) with the latter two arms also undergoing a second randomisation in the event of suboptimal response. The design is thus complex with numerous caveats in interpretation of the results and the control arms (CTD or CRD) are not considered standard induction in most countries where proteasome inhibitor-based induction (+/- IMiD) is routine. Nonetheless, this is an important study and needs to be published to a wide audience. The PFS benefit for the KRdc arm is not only statistically significant but is clinically significant as well. The results are likely to be of interest to readers of Plos Medicine.

Major points

* Methods (p6). It is hopefully a typo, but PFS is defined as the time from maintenance randomisation until progression or death. Please confirm if this definition is correct (rather than from induction randomisation). If it is correct, then results really need to be reanalysed with PFS defined according to correct definition. Same as per OS - please define accurately in view of above point.

* Methods (p7). Is it valid to combine CTD and CRD into one comparative group? In describing the primary endpoint analysis, the Protocol (Section 15.3) states that "To compare RCD with CTD, CCRD with RCD/CTD combined or with whichever of these two is superior" which is not exactly what is communicated in the Methods section. In the Study Design and Participant section of this paper it states that PFS and OS were significantly better for CRD compared to CTD. In the Results section an exploratory analysis of PFS in KRdc compared to both CRD and CTD induction when analysed separately is presented but this analysis is not mentioned or defined in the statistical section. Ultimately that data appears reasonable as both analysis types are presented for readers but the rationale to justify why the CRD and CTD arms can be compared into one group as opposed to performing comparisons of three separate arms, and the analysis method for the three group comparison needs to be tidied up in the statistical methods section.

Minor points

* Methods (p5). Why were calcium and platelets chosen as minimisation factors in the randomisation as opposed to albumin which is a key prognostic variable in the ISS? Was the lased on some prior findings from the UK Myeloma group?

* Methods (p5). Is it valid to compare treatment arms with different dose densities and cycle numbers? The dexamethasone dose in the CTD is greater because of the shortened cycle length and the CTD and CTD arms have more cycles, presumably due to worse response rates. This results in treatment arms that are not directly comparable. Nonetheless, at least in terms of response and PFS efficacy, this would bias against the KRdc.

* Methods (p6). What was the definition of renal insufficiency for using MEL200? Please list whether eGRF cut-off or up to investigator discretion

* Methods (p7). Which group of patients had MRD assessments performed? Only patients in CR? All patients?

* Methods (p7). What methods were used for serum FLC and urine light chain excretion?

* Methods (p7). Why were AEs not assessed in the CTD group?

* Results (Supplementary Fig 1). In the consort diagram it is not clear what has happened at various points as the numbers do not add up e.g. 511pts received KRdc but only 474 had response recorded. What happened to the others e.g. death, off study for toxicity etc. Similarly, it would be helpful to have the broad reasons for not proceeding to ASCT listed in this Figure.

* Results (p9). Patients older than 65 had a greater PFS benefit with KRdc. This is somewhat unexpected. Can the authors speculate in the discussion why this might be the case?

* Results. While OS data is not mature, can the authors please provide the number of deaths in each arm.

* Results (p12). The cardiac event rate in the KRdc arm is very low. It seems that exclusion of patients with a history of cardiac disease was largely at investigator discretion. Perhaps this could be mentioned either in the Methods or Discussion as there will be some uncertainty about the extent of exclusion of patients with a history of cardiac disease.

* Results (Table 1). It appears that molecular risk was only known for ~ 35% of patients which is disappointing. It makes the conclusions about the benefit of KRdc in high and ultra-high risk myeloma harder to support e.g. in Supplementary Fig 2, while HRs are consistent with primary analysis, there is in fact no significant difference between arms for any of the cytogenetic risk groups, particularly not the ultra-high-risk group. While this is probably due to small numbers, it could also be because there is no beneficial effect of KRdc in the ultra-high-risk group. In a similar fashion, the conclusion states that there is promising activity in patients with t(4;14) and 17p- patients but no data in the Supplementary appendix is provided to support this (the high-risk curved in Suppl Fig 2 are overwhelmed by 1q patients). Could data on the t(4;14) and 17p- groups be presented in the Supplementary appendix, acknowledging that numbers will be very small?

* Results (Table 2). The post-ASCT response rates appear to be per-protocol and not IIT. Could this be clearly indicated?

*** Reviewer #3:

I congratulate the authors on their thoughtful study design and well-written manuscript. Unfortunately the study's impact will be limited primarily by the inclusion of CTD-treated patients in the control arm, as thalidomide has largely become antiquated due to its inferior efficacy and tolerability issues and is now only rarely used, at least in the United States. Of course this is not the fault of the authors as the study was initiated prior to the de facto retirement of thalidomide. What I found most thought provoking about this study was the signal of high efficacy in the high-risk subgroup. Although the point of the study was to evaluate the value of adding carfilzomib to an IMiD-Cytoxan triplet, the more relevant question that the study raises in my opinion is the value of adding Cytoxan to an IMiD-PI triplet (or even, very ambitiously and probably unwisely, to an IMiD-PI-mAb quad) in patients with high-risk NDMM. The EVOLUTION study attempted to answer the question regarding the value of an IMiD-PI-Cytoxan quad vs triplets and failed to demonstrate a benefit of adding Cytoxan to VRD, however the overall number of subjects was low to the point of precluding any meaningful subgroup analysis. Certainly the Myeloma XI+ high-risk subgroup analysis is not statistically significant but the HR in the 17p- subgroup for example is enough to give one pause.

It is also noteworthy that the high-grade hematologic toxicity in the KRDc arm was lower than what I would have expected. The EVOLUTION investigators chose a Rev dose of 15mg for this reason, thinking that 25mg would be too toxic hematologically in a VRDc quad, and it seems that Myeloma XI+ may have proven otherwise, albeit with a relatively few number of induction cycles.

Although this was not a study of a combined IMiD-PI vs planned sequential IMiD->PI induction approach, the results nonetheless confirm the power of IMiD-PI synergy and suggest that a response-adapted approach that separates IMiD from PI and attempts to deepen response to the former with a switch to the latter is likely not an effective strategy.

Accordingly, I do think that the Myeloma XI+ trial is worthy of publication in this journal as it will make a meaningful contribution to the existing body of knowledge in the NDMM space. I think the manuscript is high-quality overall but can be improved further:

1) "This is the first phase III randomised study of a carfilzomib and lenalidomide combination induction therapy for TE NDMM patients." Is this completely accurate? What about ENDURANCE and FORTE?

2) Page 11 paragraph 2: The inclusion of reasons for early stoppage of induction therapy in both arms is appreciated. I am assuming that the definition of "early" is before completion of the fourth cycle. I am curious as to the reasons for stopping induction therapy in general (not just stopping therapy early) in both arms. Since median # of induction cycles was two cycles fewer in the KRDc arm and the ≥VGPR rate was higher in this arm, it is most likely that the latter is the explanation for the former, in other words the quad-treated subjects achieved maximal response with fewer cycles compared to those treated with a triplet. However it is also possible that some subjects may have stopped KRDc after the fourth cycle due to toxicity and prior to the achievement of maximal response (aka prior to M-spike plateau in patients who hadn't yet achieved CR). In order for this study to retain maximal significance in the current era (and specifically thinking about the coming IMiD-PI-mAb quad induction era), it would be nice to have a better idea of how tolerable KRDc is beyond four cycles.

3) Page 11 paragraph 3: "Thromboembolic events occurred in similar proportions of patients across the treatment groups." This statement is probably true vis a vis the KRDc arm (9.4% DVT+other thrombosis) vs CRD/CTD control arm (7.5%), but probably not in terms of the KRDc arm vs the CRD arm specifically (5.8%). We know that Thal is quite thrombogenic, and based on data such as the recently presented MSKCC data (Piedra et al, ASH 2019 abstract #1835) we now know that KRD is more thrombogenic than RVD (VTE rate 4x higher in patients on ASA prophylaxis!). In my opinion, the statement of "similar proportions" may give the reader the impression that carfilzomib does not add thrombotic risk to a Revlimid-based regimen when we have a pretty good idea that it does and when the Myeloma XI+ data describe an almost 10% incidence of thrombosis with KRDc. In my opinion, the portion of this manuscript that remains most relevant today is the KRDc vs CRD analysis, which the authors do a nice job of in terms of efficacy, but I would kindly suggest maybe something similarly robust in terms of toxicity as well.

4) Page 13 paragraph 2: If the "potentially greater activity of carfizomib compared to bortezomib" is to be mentioned, I think there probably should be at least a brief discussion of ENDURANCE in the discussion section.

Congratulations again on an overall excellent manuscript.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Richard Turner

26 Oct 2020

Dear Dr. Jackson,

Thank you very much for re-submitting your manuscript "Carfilzomib, Lenalidomide, Dexamethasone and Cyclophosphamide (KRdc) as Induction Therapy for Transplant Eligible Newly Diagnosed Multiple Myeloma Patients: Myeloma XI+, an open-label randomised controlled trial." (PMEDICINE-D-20-00730R2) for consideration at PLOS Medicine.

I have discussed the paper with editorial colleagues and it was also seen again by two reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

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We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving the revised manuscript shortly.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

So as to comply with PLOS Medicine's data policy, please include de-identified patient data for the current analysis, either in the form of supplementary files or at a publicly-accessible repository.

Please remove "methodologically sound" from your data statement.

Please adapt your title so that "(Myeloma XI+)" appears immediately before the colon.

In the "Background" subsection of your abstract, please add a few words to indicate the clinical indication(s) in which carfilzomib is efficacious.

Please mention in the abstract where the trial was done.

Please quote dates of start and end of participant recruitment in the abstract.

In the "Conclusions" subsection of your abstract and other relevant points in the text, please rephrase "deeper responses", adding a few words to make the meaning clear.

The introduction section of the main text is currently very short, and we suggest adding a few additional sentences of introduction about the disease in question and current treatment options.

In the first paragraph of your discussion section and at the end of the main text, please adapt the phrasing to note that the combination therapy "was" (well tolerated in the present study).

Throughout the text, please remove spaces from within the square brackets containing reference call-outs (e.g., " ... early phase studies [19,20].").

Please remove the information on data sharing from the end of the main text. This information will appear in the article metadata in the event of publication, via entries in the submission form.

In your reference list, please ensure that journal names are abbreviated consistently (e.g., "N Engl J Med.").

We were unable to find a completed CONSORT checklist with your submission - please include this as a supplementary document with your resubmission, referred to in the methods section of your main text (e.g., "See S1_CONSORT_Checklist").

In the completed checklist, please ensure that individual items are referred to by section (e.g., "Methods") and paragraph number rather than by page or line numbers, as the latter generally change in the event of publication.

Similarly, we were unable to find the trial protocol. Please include this as a supplementary document with your resubmission, referred to in the methods section.

Comments from Reviewers:

*** Reviewer #1:

Alex McConnachie, Statistical Review

I thank the authors for their consideration of my original points. I am satisfied with their responses.

I understand the desire to not replicate results between the text and the tables, but I still prefer to see treatment effect estimates presented systematically in tabular form (i.e. added to Table 2). However, this is not a critical point.

*** Reviewer #2:

Thank you for addressing the comments. I have no further suggestions. I think the manuscript reads well.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Richard Turner

23 Nov 2020

Dear Prof Jackson,

On behalf of my colleagues and the academic editor, Dr. Peter N Mollee, I am delighted to inform you that your manuscript entitled "Carfilzomib, Lenalidomide, Dexamethasone and Cyclophosphamide (KRdc) as Induction Therapy for Transplant Eligible Newly Diagnosed Multiple Myeloma Patients (Myeloma XI+): interim analysis of an open-label randomised controlled trial." (PMEDICINE-D-20-00730R3) has been accepted for publication in PLOS Medicine.

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Text

    Fig A—Progression-free survival by cytogenetic risk. Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) within each cytogenetic risk group. (A) Standard risk, (B) high risk, (C) ultra-high risk. Adverse molecular abnormalities were defined as gain(1q), del(17p), t(4;14), t(14;16), or t(14;20). Efficacy in the subgroups of standard risk, high risk (defined as 1 adverse cytogenetic abnormality) and ultra-high risk (2 or more adverse cytogenetic abnormalities) were pre-specified by protocol. CI, confidence interval; HR, hazard ratio; m, months. Fig B—Progression-free survival for patients with/without t(4;14) and del(17p). Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) for patients with the cytogenetic lesions t(4;14) and del(17p). (A) t(4;14), (B) no t(4;14), (C) del(17p), (D) no del(17p). CI, confidence interval; HR, hazard ratio; m, months. Fig C—Progression-free survival adjusted for CVD randomisation. Progression-free survival (PFS) for carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) compared to the triplet control group (Rdc/Tdc) with patients achieving a suboptimal response to triplet treatment and randomised to no intensification therapy removed. CI, confidence interval; HR, hazard ratio; m, months. Table A—Myeloma XI+ study sites and principal investigators. Text A—CONSORT Checklist. Text B—Myeloma XI+ protocol.

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    Attachment

    Submitted filename: KRdc responses 080920.docx

    Click here for additional data file. (36.4KB, docx)

    Data Availability Statement

    There are legal restrictions on sharing data that contain potentially identifying or sensitive personal information. The restrictions are imposed by The Information Commissioner's Office (https://ico.org.uk/). Data used in the current study will be made available upon request after application to the Myeloma XI data controller and the independent trial steering committee. Any requests for trial data and supporting material (data dictionary, protocol, and statistical analysis plan) should be sent to ctru-dataaccess@leeds.ac.uk. Data requestors will need to sign a data access agreement.

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