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.
Treatment of AL amyloidosis is based on the elimination of the plasma cell clone that produces the amyloidogenic light chains. Typically, these are indolent clones and plasma cell burden is low, thus, even low dose, low toxicity, regimens may be very effective. Bortezomib is effective in targeting plasma cells. Several series have also shown that bortezomib either as single agent or in combinations, such as bortezomib with dexamethasone (VD) or with the addition of cyclophosphamide (VCD) induce high rates of hematologic CRs and organ responses. Patients with AL are frail due to multisystemic involvement and data from the treatment of frail patients with myeloma, usually elderly ones, have shown that addition of a third agent to VD does not improve outcomes and may increase toxicity. However, VCD is considered as a "standard" regimen for primary therapy of patients with AL, in most centers, but, it is not clear whether the addition of a third drug (cyclophosphamide) to bortezomib/dexamethasone (VD) further and significantly improves efficacy, given the substantial activity of bortezomib itself. Thus, we compared the outcomes of patients with AL amyloidosis who received (VD) or with VD plus a third agent (VCD). The analysis included 101 consecutive patients with biopsy confirmed AL amyloidosis, all diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. All patients received similar supportive care and were treated in two consecutive periods (up to 2010 received VD and after 2011 received VCD). Median age was 65 years, 70% had cardiac and 71% renal involvement; Mayo stage was -1, -2 & -3 in 20%, 47% & 33% while renal stage was -1, -2 and -3 in 22%, 56% & 22% of the patients respectively. Treatment was VD in 59 (58%) and VCD in 42 (42%) patients. Compared to patients who received VCD, patients who received VD were older (median age 67 vs 60.5 years, p=0.024), were more often Mayo stage 3 (42% vs 29%, p=0.03), had lower eGFR (median 54 vs 86 ml/min/1.73 m2) but had similar distribution in renal stages. Heart, renal and nerve involvement were similar between those who received VD vs VCD (p>0.5 for all). According to our institutional guidelines for patients with AL amyloidosis schedule of bortezomib (twice per week vs weekly) and dexamethasone are adjusted to cardiac risk and presence of neuropathy. Weekly bortezomib was given in 41% of patients who received VD and vs 40% with VCD and the starting dose was 1.3 mg/m2 in 90% and 92.5% respectively. The median dose of dexamethasone for all patients was 160 mg/month, but for patients treated with VD was 240 mg/month and was 144 mg/month for those treated with VCD (p=0.01). Early mortality (<3 months from start of therapy) was 22% for patients treated with VD and 8% for patients treated with VCD, but after adjustment for Mayo stage there was no difference, and was 36% vs 29% in patients with Mayo stage 3 disease. On intent to treat a hematologic response was achieved by 72% (CR:25%, VGPR:17% , PR: 30%) and was 68% for patients treated with VD and 78% for VCD (p=0.26); after adjustment for Mayo stage there was still no difference in response rates. Regarding CR+VGPR, it was 47.5% with VD and 35% with VCD. Notably higher doses of dexamethasone or twice-weekly bortezomib schedule were not associated with significantly higher hematologic response rates or CR+VGPR rates. Organ responses occurred in 35% of patients (cardiac in 26%, renal in 42%). For VD, cardiac response rate was 29% and renal response rate was 43%, while for VCD cardiac response was 21% and renal response was 41% (p>0.5 for all comparisons). Median follow up is 3 years and median overall survival (OS) is 34 months. Median OS of patients treated with VD vs VCD was similar (33 vs 36 months, p=0.45). After adjustment for the dose and schedule of bortezomib and dexamethasone, and Mayo stage, still there was no difference in the OS between patients treated with VD vs VCD and no prognostic effect of higher doses of dexamethasone and twice weekly bortezomib was found. In conclusion, our data indicate that bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of a third agent (cyclophosphamide) does not seem to have a profound effect on efficacy and survival. Our data also indicate the limits of bortezomib-based therapies, and new agents either targeting the plasma cell clone (like monoclonal antiCD38) or targeting the amyloid deposits are needed. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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