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R. Wester et al.
response before and after high-dose melphalan/autolo- gous stem cell transplantation (HDM/ASCT) is associated with improvement in progression-free survival (PFS) and overall survival (OS).1-5 Therefore, it is important to select the appropriate induction and consolidation therapy in order to achieve a maximum response after ASCT and to maintain or even increase this response during consolida- tion therapy and thereafter.
Standard induction treatment consists of triple therapy including a proteasome inhibitor, and/or an immunomod- ulatory drug and dexamethasone. The combination of bortezomib, thalidomide and dexamethasone (VTD) has been extensively investigated in transplant-eligible patients with NDMM.6-8 However, treatment with borte- zomib is associated with higher rates of polyneuropathy (PN) and a consequent discontinuation of treatment.7,8 It is important to use a regimen that is highly effective and safe in patients with NDMM. This could improve treat- ment adherence and subsequently outcome after induc- tion and consolidation therapy.
Carfilzomib is a selective proteasome inhibitor with irreversible binding to the constitutive proteasome and immunoproteasome. It is approved in the United States and in Europe as a single-agent for the treatment of patients with relapsed and/or refractory MM (RRMM). Carfilzomib is approved at a dose of 27 mg/m2 in combi- nation with lenalidomide and dexamethasone in RRMM based on the data from the ASPIRE trial showing a supe- rior PFS of median 26.3 months versus 17.4 months when patients were treated with lenalidomide/dexamethasone.9 Carfilzomib is also approved at a dose of 56 mg/m2 in combination with dex- amethasone, based on data from the ENDEAVOR trial showing a superior PFS over bortezomib/dexamethasone of median 18.7 months versus 9.4 months (P<0.0001).10 Previous trials showed that the incidence of PN with carfilzomib is lower compared to bortezomib.9-11
Carfilzomib has not yet been approved for treatment in NDMM in Europe. Recent trials in patients with NDMM, using different treatment regimens, showed high response rates.12-15 A phase I/II trial of patients with NDMM treated with carfilzomib at a maximum dose of 36 mg/m2 combined with lenalidomide and low-dose dexamethasone showed a very good partial response (VGPR) rate of 81%. PFS at 24 months was 92%.12
We previously initiated a Phase II dose-escalation trial of carfilzomib combined with thalidomide and dexam- ethasone. The combination of a proteasome inhibitor and an immunomodulating agent has a proven synergystic effect.6 Moreover, thalidomide is an effective and afford- able drug available in many countries.
In NDMM, there is no consensus as to the optimum dose level of carfilzomib, implicating the need for dose- finding trials. The goal of this trial was to investigate the efficacy of this combination at various dose levels of carfilzomib in NDMM. Results of the first three cohorts of this Carthadex trial were published in 2015.11 Overall response rate (ORR) after induction therapy was 90% with a VGPR rate of 68%. PFS at 36 months was 72%. The combination of carfilzomib, thalidomide and dexam- ethasone (KTd) was well tolerated.11 Four different dose levels were included in this trial based on the hypothesis that a higher dose level induces a higher response rate.12,16 We report herein the results of our dose escalation cohorts with a long follow up. This is the first study using
KTd for both induction and consolidation therapy and comparing different dose levels.
Methods
Patients
Transplant-eligible patients with NDMM, aged 18-65 years, were eligible for enrollment. Patients were required to have a World Health Organization (WHO) performance status of 0-3; WHO 3 was allowed only when caused by MM and not by co-morbid conditions.
Patients were ineligible if they had grade 3/4 polyneuropathy (PN) or grade 2 painful PN, severe cardiac dysfunction (New York Heart Association class II-IV), known intolerance of thalidomide, systemic amyloid light-chain amyloidosis, non- secretory MM, Waldenström macroglobulinemia or IgM MM, creatinine clearance <15 mL/min, absolute neutrophil count <1.0x109/L, platelets <75x109/L, hemoglobin <4.9 mmol/L, active malignancy during the past five years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma.
This independent investigator-initiated multi-institutional study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and the European Clinical Trial Directive as implemented under Dutch law. The protocol was approved by institutional review boards and ethics com- mittees. All patients gave informed consent.
Study design and treatment
This single-arm, open-label, phase II trial was conducted at eight hematology centers. Patients were treated with four cycles KTd of a 28-day cycle for induction therapy. Carfilzomib was administered in a 30-minute infusion. The dose in the first dos- ing cohort was 20 mg/m2 on days 1 and 2 and was escalated to adoseof27mg/m2 ondays8,9,15and16ofcycle1andon days 1, 2, 8, 9, 15 and 16 of cycles 2-4. Thalidomide 200 mg was given orally on days 1 through 28 and dexamethasone 40 mg was given orally on days 1, 8, 15 and 22. Induction therapy was followed by stem cell harvest after cyclophosphamide priming (2-4 mg/m2 i.v.) and daily 10 mg/kg granulocyte colony-stimulat- ing factor. Hereafter, patients received high-dose melphalan (HDM, 200 mg/m2) and ASCT followed by consolidation treat- ment with four cycles of KTd in the same schedule and dose as induction treatment except that the dose of thalidomide was 50 mg instead of 200 mg. The dose of carfilzomib was escalated to 20/36 mg/m2, 20/45 mg/m2 and 20/56 mg/m2 in cohorts 2, 3 and 4, respectively. Under the study protocol, patients were required to maintain adequate hydration. In addition, patients were treat- ed prophylactically with antibiotics (ciprofloxacin or another fluoroquinolone) and with antiviral medication (acyclovir or a similar anti varicella agent). All patients received antithrombotic prophylaxis with aspirin in case of low thrombotic risk or with low-molecular-weight heparin in patients with pre-existing thrombotic risk factors.17
The primary end point of the study was response after induc- tion therapy and overall response, specifically complete response (CR) and VGPR. Secondary end points were efficacy and safety, maximum tolerated dose (MTD), dose limiting toxi- cities (DLT), PFS and overall survival (OS). PFS was defined as time from registration to progression or death, whichever came first. OS was calculated from registration to death from any cause; patients still alive at last contact were censored.
This study was registered as #NTR2422 at http://www.trialreg- ister.nl.
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haematologica | 2019; 104(11)