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

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.

Current approaches to management of newly diagnosed multiple myeloma

“…The Myeloma XI+ trial randomized patients to receive KRdc or control (Rdc or Tdc) followed by ASCT, and then a second randomization between lenalidomide maintenance and observation 94 . KRdc was associated with a significantly better PFS as compared to control (NR vs. 36.2 months, HR = 0.63, p < .01).…”

“…The Myeloma XI+ trial randomized patients to receive KRdc or control (Rdc or Tdc) followed by ASCT, and then a second randomization between lenalidomide maintenance and observation. 94 Isatuximab, bortezomib, lenalidomide, dexamethasone (Isa-VRd)…”

Current Treatment Approaches to Newly Diagnosed Multiple Myeloma

“…The UK study group introduced a different quadruplet with the combination of KRd with cyclophosphamide in induction. In a large trial including >1,000 patients, in the patient group receiving KRCd a ≥ VGPR rate of 82% with a MRD negativity rate of 55% was reported translating in a significant superior PFS compared to the standard immunomodulatory-cyclophosphamide triplet induction [17]. With elotuzumab, another monoclonal antibody targeting SLAM-F7 is available for the treatment of MM and has been approved in combination treatments in relapsed disease.…”

In search of the optimal proteosome inhibitor. How, when and for whom?

“…1 , 6 , 7 ENDEAVOR and other trials with even higher carfilzomib doses, given at 70 mg/m 2 weekly rather than biweekly, demonstrate that the efficacy of carfilzomib is dose-dependent, but that the incidence of cardiac events must be kept low. 2 , 6 , 7 , 9 , 10 The role of continuous versus fixed-duration therapy is also important, explaining differences in outcome among different trials. Since continuous treatment may affect quality of life, MUK five ’s fixed duration rather than continuous treatment was probably designed with this in mind, but might have been planned differently today in the light of other experiences ( Table 1 ).…”

“… 11 The phase III Myeloma XI+ trial is assessing KRd with cyclophosphamide (KRdc) as compared to Rdc/Tdc (lenalidomide-dexamethasone-cyclophosphamide/ thalidomide-dexamethasone-cyclophosphamide) in 1,056 transplant-eligible NDMM patients with impressive rates of very good partial response or better of 82% and 59%, respectively. 10 Whether this will translate into better survival and excellent therapy endurance remains to be seen. The future of MM therapies seems bright and exciting, further advances are still to come and the UK study group continues to contribute to this.…”