Carfilzomib, Cyclophosphamide and Dexamethasone Is Well Tolerated in Patients with Relapsed/Refractory Multiple Myeloma Who Have Received One Prior Regimen

Introduction. Carfilzomib-containing doublet and triplet regimens demonstrate high response rates both in the relapsed and frontline settings and will soon enter the treatment pathways for multiple myeloma (MM).  While the phase 3 studies, ENDEAVOUR and ASPIRE provide information on combinations with dexamethasone with or without lenalidomide, there are limited data on other combinations, especially with alkylating agents.

Aim. To describe the safety and toxicity of Carfilzomib, cyclophosphamide and dexamethasone in patients at first relapse of MM, based on an interim assessment of the MyelomaUKfive (MUKfive) study.

Methods. MUKfive is a randomised phase 2 study comparing carfilzomib with bortezomib, in triplet combination with cyclophosphamide and dexamethasone for patients who require treatment after one prior regimen, in a 2:1 randomisation, target 300 patients.  Patients receive 6 months of induction treatment with six 28-day cycles of carfilzomib (20/36 mg/m² in stepped up dosing d1, 2, 8, 9, 15, 16 by IV infusion over 30 minutes), oral cyclophosphamide (500 mg d1, 8, 15) and oral dexamethasone (40mg d1, 8, 15, 22) or eight 21-day cycles of bortezomib (1.3mg/m²SC d1, 4, 8, 11) by SC or IV, cyclophosphamide (500 mg d1, 8, 15) and dexamethasone (40mg d1, 8, 15).  The primary endpoint for this part of the study is ≥VGPR rate.  The study opened in 2013, and we have carried out an interim assessment of safety data on the first 69 patients randomised to the Carfilzomib arm, with toxicities graded by CTCAE V4.0.

Results.   Median age was 67.6 years (range 35-85), 62.3% were male, and ISS stage as follows: 32 patients ISS 1, 22 patients ISS 2, 15 patients ISS 3.  Median GFR was 78ml/min (range 30-243) and ECOG performance status as follows: 43 patients PS 0, 20 patients PS 1, 5 patients PS 2, 1 patient missing PS.  Sixty-seven patients received at least one dose of trial treatment and are evaluable for safety. 

In cycle 1, the commonest treatment-related toxicities of any grade (adverse reactions, ARs) were anaemia (89.6%), thrombocytopenia (67.2%) neutropenia (29.9%), nausea (14.9%), diarrhoea (11.9%), vomiting (10.6%), constipation (9%), infections (4.5%) and infusion reactions (4.5%).  During induction treatment (all cycles), the most common ARs of all grades were anaemia (97%), thrombocytopenia (83.6%) neutropenia (58.2%), nausea (47.8%), diarrhoea (37.3%), infections (29.9%) vomiting (22.4%), constipation (22.4%), hypotension (4.5%) and infusion reactions (4.5%).  Haematologic grade ≥3 ARs included anaemia (19.4%), neutropenia (12%), and thrombocytopenia (10.5%), while non-haematological grade ≥3 ARs were infections (20.9%), vomiting (4.5%), nausea (3%), diarrhoea (3%), infusion reactions (3%).  Treatment emergent neuropathy was reported by 18 patients (26.9%), all G1 except for 1 patient (G2).  Three patients had thromboembolic ARs: one each of pulmonary embolism (G3), thrombophlebitis (G2) and brachial vein thrombosis (G1).  

Serious AEs were reported in 29 patients (43.3%). A total of 47 SAEs were reported, of which 31 (66%) were treatment related (28 related to carfilzomib).   Treatment related SAEs included 22 infections (noted above, of which 15 were respiratory infections), 2 gastrointestinal, 1 acute kidney injury (G2) and 1 worsening of renal function (G1), 2 endocrine (1 each of hypo- and hyperglycemia), and 1 hepatobiliary.  Two G3 SUSARs were reported, one cardiomyopathy, one extensive pulmonary embolism. In 87.2% of SAEs, patients had recovered or were improving.  

In cycle 1, 19 patients (28.4%) had at least one dose modification; carfilzomib dose was modified in 14, cyclophosphamide in 7 and dexamethasone in 11.  The majority of these were dose omissions.  Across all cycles, 54 patients (80.6%) had dose modification/s, 47 to carfilzomib, 32 to cyclophosphamide and 40 to dexamethasone.  Of carfilzomib modifications, 53.3% were omissions, while the rest were reductions (24.6%) or delays (22.1%).   Of carfilzomib dose reductions, the majority (72.9%) were due to haematological toxicity.   Five patients (7.2%) stopped treatment due to toxicity after a median of 3 (range 1-4) cycles.  There were no treatment related deaths.

Conclusion.  The triplet regimen carfilzomib, cyclophosphamide and dexamethasone is well tolerated in this patient group, with toxicity profile that is as expected from published data on carfilzomib.

Acknowledgements: This trial a Myeloma UK Clinical Trial Network study