Bortezomib-Based Triplets Are Associated with a High Probability of Dialysis Independence and Rapid Renal Recovery in Newly Diagnosed Myeloma Patients with Severe Renal Failure or Those Requiring Dialysis
Authors: Dimopoulos Meletios A. , Kastritis Efstathios , Roussou Maria , Psimenou Erasmia , Gavriatopoulou Maria , Migkou Magdalini , Eleutherakis-Papaiakovou Evangelos , Ziogas Dimitrios , Panagiotidis Ioannis , Fotiou Despoina , Kafantari Eftychia , Giannouli Stavroula , Kontogiannis Sofoklis , Terpos Evangelos 
Published: October 2019

Abstract
Severe renal failure (RF) is a common complication of symptomatic myeloma and in approximately 1-5% of newly diagnosed patients, dialysis may be required. Severe RF is associated with significant morbidity and mortality; these patients are often excluded from clinical trials. Bortezomib/dexamethasone (VD) based regimens have been proposed as the backbone of the treatment of newly diagnosed MM patients who present with severe RF. In addition to VD-based regimens other means are also under investigation, mainly for patients who require dialysis. Such options include high cut-off hemodialysis combined with effective antimyeloma therapy based on VD. In the current analysis, we focused on the outcomes of patients with severe RF and of those requiring dialysis in order to evaluate the activity of VD-based combinations.
Our study included 78 (39M/39F) consecutive patients with severe RF (eGFR <30 ml/min/1.73 m2 per the MDRD formula); 27 (35%) patients required dialysis. All these patients were treated in a single center (Alexandra Hospital, University of Athens, Greece), they received similar supportive care and started bortezomib-based therapy upon diagnosis. IMWG renal response criteria were used: renal complete response (CRrenal) was defined as a sustained increase of baseline eGFR to >60 ml/min/1.73 m2, renal partial response (PRrenal) as an increase of eGFR from <15 to 30-50 ml/min/1.73 m2 and renal minor response (MRrenal) as a sustained improvement of baseline eGFR of <15 ml/min/1.73 m2 to 15-29 ml/min/1.73 m2 or if baseline eGFR was 15-29 ml/min/1.73 m2, improvement to 30-59 ml/min/1.73 m2.
The median age was 66 years (range: 37-88) and 27% were >75 years. The median eGFR was 11 ml/min/1.73 m2 (range: 1- 29 ml/min/1.73 m2); 65% had eGFR<15 ml/min/1.73 m2. The median age of patients who required dialysis was 66 years (range 37-88) and all these patients received dialysis with regular filters. Median level of proteinuria was 1.5 g/24h (range 0.2-12 g/24h) and of involved free light chain (iFLC) was 8,455 mg/l (range 44-201,000 mg/l). All patients received VD-based regimens: 22 (28%) received VD, while 56 (72%) received a triplet [33 (42%) VCD, 15 (19%) VTD, 6 (7%) PAD and 2 (2%) VMP). Among patients requiring dialysis, 70% received a triplet (10 VCD, 8 VTD and one PAD).
At least MRrenal was recorded in 52 (67%) patients within a median of 23 days (range 4-238). CRrenal was documented in 36% of patients and PRrenal in 12% (major renal response rate of 48%). The median time to major renal response was 28 days (range 7-238 days). Fourteen of 27 (51%) patients became dialysis independent; the median time to dialysis independence was 140 days (range 11-474). Three-drug combinations vs VD alone were associated with higher probability of renal responses (72% vs 30%; p=0.006). Among patients who became dialysis independent 5 received VTD, 1 PAD, 5 VCD and 3 VD. A triplet was associated with higher probability of dialysis discontinuation (58% vs 35% for VD).
ROC analysis indicated that iFLC ≥11,550 mg/L was associated with a lower probability of major renal response (14% vs 59%, p=0.002) and longer time to major renal response (>240 to 66 days, p=0.017). In patients requiring dialysis iFLC ≥11,550 mg/L was also associated with lower probability of dialysis discontinuation (37.5% vs 56%) and longer time to dialysis discontinuation (474 vs 93 days).
Other factors associated with major renal response in univariate analysis were age <65 years (p=0.004) and myeloma response (p=0.001). Among patients requiring dialysis, age <65 years (p=0.072), male gender (p=0.037) and myeloma response (p=0.037) were associated with a higher probability of dialysis discontinuation. Early death (<2 months from treatment initiation) occurred in 9 (12%) patients. The median survival for all patients was 44 months. Excluding early deaths, the survival of patients who became dialysis-independent was longer than that of patients who remained on dialysis (90 vs 28 months, p=0.015).
Our study suggests that three drug VD-based combinations are associated with a high probability of renal response and a >50% probability of dialysis discontinuation in MM patients requiring dialysis, without the use of high cut-off filters. Furthermore, patients who became dialysis independent have better overall survival. The levels of FLCs are predictive of the probability and of the time required for renal response, including dialysis independence.

Disclosures
Dimopoulos: Celgene: Honoraria; Onyx: Honoraria; Janssen: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Terpos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Celgene: Honoraria, Other: travel expenses; Novartis: Honoraria.