Complete Renal Response Research Articles

The Role of Novel Agents on Reversibility of Renal Impairment in Newly Diagnosed Patients with Multiple Myeloma; a Single Center Experience on 112 Patients,

Abstract 3961Renal impairment (RI) is a frequent complication of multiple myeloma (MM). Proteasome inhibitors and immunomodulatory drugs (IMiDs) are used as frontline therapy for MM but their effect on renal function recovery has not been clearly defined. To address this issue we studied 112 patients with newly diagnosed MM and RI who were treated in the Department of Clinical Therapeutics of the University of Athens, over the last decade. RI was defined as an estimated glomelural filtration rate (eGFR) ≤60 ml/min, using the simplified MDRD formula. Patients were divided into three groups; group T included 53 patients who received thalidomide-based regimens (with dexamethasone alone, with dexamethasone and melphalan or cyclophosphamide, or with VAD); group B included 30 patients who received bortezomib-based regimens (with dexamethasone alone, with dexamethasone and thalidomide or with cyclophosphamide) and group L included 29 patients who received lenalidomide-based regimens (with dexamethasone or with melphalan and prednisone). Lenalidomide dose was adjusted for the degree of RI according to current recommendations. Renal complete response (CRrenal) was defined as a sustained increase of baseline eGFR to >60 ml/min, renal partial response (PRrenal) as an increase of eGFR from <15 to 30–50 ml/min and renal minor response (MRrenal) as sustained improvement of baseline eGFR of <15 ml/min to 15–29 ml/min, or, if baseline eGFR was 15–29 ml/min, improvement to 30–59 ml/min. Patients in groups T and L were older than those of group B (p=0.0001). Anemia (Hb <10 g/dl) was more frequent in patients of group L (p=0.007). There were no significant differences in the severity of RI, or other clinical and laboratory parameters among the three groups. An improvement of renal function, recorded as MRrenal or better, was achieved more frequently in patients treated with bortezomib-(83%) or thalidomide-based regimens (77%) than in patients treated with lenalidomide-based regimens (55%, p=0.033). We subsequently focused our analysis in major renal responses (at least PRrenal) since this endpoint is clinically more relevant. CRrenal was achieved in 53% of patients in group T, in 70% in group B and in 34% in group L (p=0.014), while CRrenal+PRrenal rates were 55%, 80% and 38% for groups T, B and L, respectively (p=0.004). eGFR <30 ml/min was associated with a significantly lower probability of at least PRrenal (p=0.016). In multivariate analysis bortezomib-based regimens (OR: 8.8, 95% CI: 2–37, p=0.003) and thalidomide-based regimens (OR: 2.85, 95% CI: 1.01–8, p=0.046) were associated with higher probability at least PRrenal than lenalidomide-based regimens. Other factors that were independently associated with higher probability of at least PRrenal, were baseline eGFR >30 ml/min (OR: 4.85, 95% CI: 1.9–12.5, p=0.001) and age ≤65 years (OR: 3.8, 95% CI: 1.07–13.5, p=0.038). The median time to first renal response was longer for patients of group L compared to those of group T (5.5 months vs. 1.5 months, p=0.038) and it was significantly shorter for patients of group B (0.85 months, p=0.001). The median time to major renal response was 1.1 months for bortezomib-based and 2.7 months for thalidomide-based regimens, and exceeds 6 months for lenalidomide-based regimens (p=0.002). In multivariate analysis bortezomib-based regimens (OR: 3.12, 95% CI: 1.35–7.2, p=0.008) and baseline eGFR >30 ml/min (OR: 1.93, 95% CI: 1.13–3.3, p=0.015) were independently associated with a shorter time to ≥PRrenal. Myeloma response to treatment was 61%, 83% and 83% for the three treatment groups, respectively and was associated with any renal response (≥MRrenal; p=0.008) and with a major renal response (CRrenal+PRrenal; p=0.001). Among 8 patients who required dialysis (group T 4 patients, group B 4 patients), 4 patients (2 in each group) became independent of this procedure. This is the first analysis which compared the role of the three novel agents in MM patients presenting with RI. Our data indicate that novel agent-based regimens can improve renal function in the majority of patients with RI. However, bortezomib- and thalidomide-based regimens are more efficacious than lenalidomide-based regimens in this setting. Furthermore, bortezomib-based regimens act more rapidly than IMiD-based regimens even in patients with severe RI. We conclude that bortezomib-based regimens are the preferred therapy for newly diagnosed myeloma patients with RI. Disclosures:Dimopoulos:Janssen-Cilag: Honoraria; Celgene: Honoraria; Millenium: Honoraria. Terpos:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Renal Insufficiency and Failure

Renal impairment is a common complication of multiple myeloma. Chronic renal failure is classified according to glomerular filtration rate as estimated by the MDRD (modification of diet in renal disease) formula, while RIFLE (risk, injury, failure, loss and end-stage renal disease) and AKIN (acute renal injury network) criteria may be used for the definition of the severity of acute renal injury. Novel criteria based on estimated glomerular filtration rate measurements are proposed for the definition of the reversibility of renal impairment. Renal complete response (CRrenal) is defined as sustained (i.e., lasting at least 2 months) improvement of creatinine clearance (CRCL) from under 50 mL/min at baseline to 60 mL/min or above. Renal partial response (PRrenal) is defined as sustained improvement of CRCL from under 15 mL/min at baseline to 30 to 59 mL/min. Renal minor response (MRrenal) is defined as sustained improvement of the baseline CRCL of under 15 mL/min to 15 to 29 mL/min or, if baseline CRCL was 15 to 29 mL/min, improvement to 30 to 59 mL/min. Bortezomib with high-dose dexamethasone is considered the treatment of choice for myeloma patients with renal impairment and improves renal function in most patients. Although there is limited experience with thalidomide, this agent can be administered at the standard dosage to patients with renal failure. Lenalidomide, when administered at reduced doses according to renal function, is effective and can reverse renal impairment in a subset of myeloma patients.

Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment

Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility. Fifty consecutive patients with relapsed/refractory MM received LenDex in 28-d cycles. Median lines of previous therapies were 2 (range: 1-6). Lenalidomide was administered on days 1-21 according to creatinine clearance (CrCl), while dexamethasone was given at a dose of 40 mg on days 1-4 and 15-18 for the first four cycles and only on days 1-4 thereafter. Twelve patients (24%) had RI at baseline, defined as CrCl < 50 mL/min. Most patients were pretreated with either thalidomide or bortezomib and > 50% of them were refractory to both drugs. At least partial response was documented in 60.5% and 58% of patients with and without RI. Median progression-free survival (PFS) and overall survival (OS) for all patients was 9 and 16 months, respectively. RI was not associated with an inferior PFS or OS. There were no differences in the incidence of adverse events among patients with and without RI. Three of 12 patients with RI (25%) achieved complete renal response and two (16%) achieved minor renal response with LenDex. We conclude that LenDex is an active treatment even in heavily pretreated MM. With dosing of lenalidomide according to renal function, LenDex can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, LenDex may improve the renal function in approximately 40% of patients with RI.

Anti-CD20 therapy in patients with refractory systemic lupus erythematosus: a longitudinal analysis of 52 Hispanic patients

The objective of this study was to investigate the efficacy and safety of anti-CD20 treatment in Hispanic patients with refractory systemic lupus erythematosus and to determine whether baseline parameters predict disease flare. Fifty-two patients with systemic lupus erythematosus, 13 with active lupus nephritis, eight with thrombocytopenia, three with leukocytopenia, 25 with severe musculoskeletal involvement and three with skin involvement) refractory to conventional therapy were treated with anti-CD20 treatment (rituximab; MabThera, Roche) plus ongoing immunosuppressive treatment. Disease activity was assessed monthly using the SLEDAI validated for the Mexican population with a follow-up period of 6 months. At 6 months of follow-up, significant clinical improvements were detected, with a reduction in the global SLEDAI validated for the Mexican population score. Five of the 13 patients with lupus nephritis (38.4%) had a complete renal response and five (38.4%) had a partial response. Rituximab was also effective in patients with autoimmune thrombocytopenia, inducing a significant increase in platelet counts (p = 0.012). Nineteen of 25 patients with severe musculoskeletal involvement had remission of arthritis. Only one of the three patients with skin involvement had no lesions at 6 months. Rituximab treatment also allowed a reduction of the oral prednisone dose in the majority of patients. No baseline predictors of flare were found. Treatment was discontinued after the first infusion in two patients due to serum sickness and in another due to pulmonary infection. In conclusion, the addition of rituximab to conventional immunosuppressive therapy may be an effective strategy for lupus nephritis, autoimmune thrombocytopenia and inflammatory polyarthritis in patients with refractory systemic lupus erythematosus.

Reversibility of Renal Failure in Newly Diagnosed Patients with Multiple Myeloma and the Role of Novel Agents.

Abstract 955Renal impairment (RI) is a common complication of multiple myeloma (MM) and is associated with increased mortality. High dose dexamethasone-based regimens have been extensively used for the initial management of patients with MM presenting with RI. Recently, novel agent-based regimens have been introduced in the frontline management of MM. The purpose of our analysis was to assess the effect of novel agent-based regimens on the rate of RI improvement and compare their efficacy with conventional chemotherapy (CC) plus dexamethasone (Dexa) in newly diagnosed MM patients. Over the last decade, 82 patients with newly diagnosed MM and RI, defined as creatinine clearance (CrCI) <50ml/min, received frontline treatment in our Center. Patients were divided into three groups: group A: 28 patients who received CC plus Dexa-based regimens (VAD, VAD-like regimens, melphalan plus Dexa); group B: 38 patients who received IMiDs-based regimens (thalidomide or lenalidomide with high dose Dexa and/or cyclophosphamide or melphalan) and group C: 16 patients who received bortezomib-based regimens with Dexa. Renal complete response (RCR) was defined as a sustained increase of baseline CrCI to >60ml/min. Renal partial response (RPR) was defined as an increase of CrCI from<15 to 30-50ml/min. Renal minor response (RMR) was defined as sustained improvement of baseline CrCI of<15ml/min to 15-29 ml/min, or, if baseline CrCI was 15-29 ml/min, improvement to 30-59 ml/min. Patients in group B were older than those of groups A and C (p=0.01) while more patient in group C had light chain only MM than in groups A and B (p=0.04). There were no significant differences in the severity of RI, Bence Jones proteinuria, hypercalcemia or ISS stage among the three groups. Improvement of renal function, recorded as RMR or better, was achieved more frequently in patients treated with novel agents (group B: 87% and in group C: 94%) than in patients treated with CC plus Dexa-based regimens (64%, p=0.024). Among 9 patients who required renal dialysis 3 became independent of this procedure after treatment. We subsequently focused our analysis in major renal responses (RPR or RCR), because this endpoint is clinically more relevant. RCR was achieved in 43% of patients in group A, in 50% in group B and in 69% of patients in group C (p=0.2) and RCR+RPR rates were 50% and 57% and 81% for groups A, B and C respectively (p=0.1). Creatinine clearance <30 ml/min was associated with a significantly lower probability of RCR or RPR only in patients treated with CC plus Dexa- or with IMiDs-based regimens (p<0.01), but not in patients treated with bortezomib (p=0.529). The probability of RPR+RCR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (p=0.619). In multivariate analysis bortezomib–based regimens (p=0.02, OR: 7, 95% CI 1.5-25) and CrCl>30 ml/min (p=0.002, OR: 6.1, 95% CI 2.5-22.5) were independently associated with a higher probability of RCR+RPR. The median time to RPR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (2.2 months for Group A, 1.5 months for Group B, p=0.587) but it was significantly shorter for Group C (0.7 months, p=0.017). Other factors associated with a shorter time to ≥RPR included CrCl>30 ml/min (p=0.039) and age<75 (p=0.089). In multivariate analysis bortezomib–based regimens (p=0.004, OR: 3 95% CI 1.6-6.7) and CrCl>30 ml/min (p=0.006, OR: 2.5 95% CI 1.3-4.5) were independently associated with a shorter time to ≥RPR. In landmark analysis (time was one month in order to reduce bias due to early deaths), rapid improvement of renal function (≤1 month) was associated with a trend for a longer survival compared to patients who achieved renal response later (>1 month) (47 vs. 21 months, p=0.19). Myeloma response to treatment was 58%, 68% and 79% for the three treatment groups respectively and was associated with renal response (p=0.024), though less strongly with a major renal response (p=0.061). Our data indicate that novel agent-based regimens can improve renal function in most patients; furthermore bortezomib-based regimens improve renal function to a higher degree and significantly more rapidly than CC plus Dexa-based or IMiD-based regimens even in patients with severe renal impairment. We conclude that bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients who present with renal impairment. Disclosures:Dimopoulos:JANSSEN-CILAG: Honoraria; CELGENE: Honoraria.

Bortezomib-Doxorubicin-Dexamethasone (BDD) in Patients with Acute Light Chain Induced Renal Failure (ARF) in Multiple Myeloma (MM). Final Results of a Phase II Study.

Abstract 3862Poster Board III-798Acute light chain (LC) induced renal failure (ARF) is a severe complication of progressive MM. Reversal of ARF can only be achieved by fast, substantial and continuous suppression of production of pathogenic LCs. Bortezomib is highly effective and well tolerated in myeloma patients (pts) with renal impairment, because its metabolism is independent of renal function. In this study we evaluated the efficacy of Bortezomib in combination with doxorubicin and dexamethasone (BDD) in restoring renal function and in achieving tumor control in pts with LC-induced renal failure. In total, 72 pts have been enrolled; 2 pts did not fulfil inclusion criteria, 2 pts had been excluded because kidney biopsy revealed renal amyloidosis as main cause of renal failure. Hence, 68 pts constituted the intent to treat population and 58 pts were evaluable per protocol (≥2 cycles of therapy). Age: median 65.8; range 41-79 years. Forty-six (79%) pts presented with de novo MM, and 12 (21%) with progressive, previously treated disease; median baseline GFR was 20.0 ml/min (range 3.7-49.5 ml/min). ARF was defined as decrease in GFR to <50ml/min due to LC nephropathy. Previously treated pts were required to have acute deterioration (< 4 weeks before inclusion) of formerly normal renal function (GFR „d60ml/min), and clear signs of progressive disease with increased LC excretion. Treatment regimen: Bortezomib (1.3mg/m2, d 1, 4, 8, 11 until the first safety analysis; thereafter 1.0mg/m2, d 1, 4, 8, 11), doxorubicin (9mg/m2, d 1, 4, 8, 11 until first safety analysis; thereafter 9mg/m2, d 1 and 4) and dexamethasone 40mg (d 1, 4, 8, 11). Cycles were repeated every 21 days. Renal response was defined as complete (CRrenal, with GFR ≥60 ml/min), partial (PRrenal with GFR increase >100%, from <15 ml/min to 30-<60 ml/min), or minor (MRrenal with GFR increase >50%, either from <15 ml/min to 15-<30 ml/min or from 15-<30 ml/min to 30-<60 ml/min). Twenty-six of 58 evaluable pts achieved CR/nCR (45%), 10 (17%) VGPR, 9 (16%) PR and 4 (7%) MR (CR-MR: 85%). Median time to best tumor response was 88 days. Twenty-one (36%) pts achieved CRrenal, and 19 (33%) pts PR/MRrenal, respectively, yielding an ORRrenal of 69%. Three of the 9 dialysis dependent pts became dialysis independent. Median GFR increased from 20.0 ml/min (range: 3.7 – 50.2 ml/min) to 48.4 ml/min (range 6.7 – 135.5 ml/min). Improvement of GFR correlated weakly with tumor response. The median of best GFR increased to 60.0 ml/min (14.7-131.3 ml/min) in the 36 pts with CR/nCR/VGPR, to 38.9 ml/min (14.7 – 135.5 ml/min) in the 13 pts with PR/MR, and to 16.8 ml/min (6.7 – 57.9 ml/min) in 9 the pts with SD/PD, respectively. Overall survival (OS) was 72% @ 1 and 60% @ 2 years in the intent to treat and 84% @ 1 and 70% @ 2 years in the evaluable population. OS was similar in pts with and without complete renal response (p= 0.9267). Univariate analysis revealed a significant association between both, treatment status (previously treated vs. not previously treated), and LDH with survival (p<0.0003, and p<0.0232, respectively), while in multivariate analysis (Cox regression) treatment status only was found to correlate with survival (p=0.0211). Leukopenia, thrombopenia, and anemia of grade 3&4 were seen in 12%, 14% and 48%, respectively. Other common grade 3&4 toxicities were weakness/fatigue (12%) and polyneuropathy (10%), infection (7%), herpes reactivation (7%) and nausea/vomiting (5%). In conclusion, the BDD regimen resulted in high tumor (CR/nCR/VGPR: 62%, ORR: 85%) and renal response rates (CRrenal 36%, ORRrenal 69%). Improvement of renal function was more often seen in pts with significant tumor response and CRrenal was more likely in pts with less severe renal impairment. Treatment was well tolerated after dose adjustment. Disclosures:Ludwig:Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Hajek:Janssen-Cilag: Honoraria.

Lenalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma; Dosing of Lenalidomide According to Renal Function and Effect On Renal Impairment.

Abstract 3871Poster Board III-807Lenalidomide and dexamethasone (RD) is an active regimen for the management of relapsed and/or refractory multiple myeloma (MM). Over the last 2 years consecutive patients with pre-existing peripheral neuropathy grade ≥ 2 were treated with RD, regardless of their performance status and renal function. Patients with disease refractory to thalidomide, bortezomib and dexamethasone (i.e. progressive disease during treatment or within 60 days of treatment completion) were also included. Lenalidomide was administered on days 1 to 21 according to creatinine clearance (CrCl): 25 mg/day for CrCl >50 ml/min, 10mg/day for CrCl 30-50 ml/min, 15 mg every other day for CrCl 15-30 ml/min and for patients on dialysis, 15 mg three times per week on the day after dialysis. Dexamethasone was administered at a dose of 40mg PO on days 1 to 4 and 15 to 18 for the first 4 cycles and only on days 1 to 4 thereafter. RD was repeated every 28 days till disease progression or unacceptable toxicity. All patients received DVT prophylaxis with aspirin 100 mg/day unless there were already on coumadin or LMWH for pre-existing DVT or for other indications, usually atrial fibrillation. So far, 46 patients have been included and their characteristics were: median age was 69 years (range 43-87 years); median lines of prior therapy were 3 (range 1-6); prior treatment with thalidomide-containing regimens: 74% of patients (thalidomide-refractory: 68% of patients); prior treatment with bortezomib-containing regimens: 78% of patients (bortezomib-refractory: 56%); dexamethasone-refractory: 61% of patients; performance status ≥2: 33% of patients; LDH >300 IU/dl (normal value >225 IU/dl): 13% of patients; extramedullary involvement: 9% of patients; renal impairment (RI), defined as CrCl <50 ml/min: 28% of patients (range of CrCl: 13-49 ml/min). Thirty-six patients started with lenalidomide dose of 25mg/day and 10 patients with dose adjusted to renal function (10mg/day: 7 patients, 15mg every other day: 2 patients, 15 threetimes a week after dialysis: 1 patient). Response according to IMWG criteria include: CR: 17%, vgPR:5%, PR: 38%, SD: 22%, PD: 18% (PR or better: 60%). At least PR was observed in 43% of thalidomide-refractory patients, in 76% of bortezomib-refractory patients and in 20% of patients with high LDH. At least PR was documented in 60% of patients with RI and in 58% without RI. Median time to progression was 9 months and median overall survival was 16 months. Main toxicities include: neutropenia (grade 3/4): 26%; thrombocytopenia (grade 3/4): 11%; other toxicities (any grade): fatigue 50%, infections 28%, constipation 17%, diarrhea 15% and skin toxicity 11%. DVT prophylaxis with aspirin was administered to 39 patients (84%) and no patient developed DVT. Dose-reductions of lenalidomide were necessary in 46% of patients. There were no statistical differences in the incidence of adverse events in patients with normal or abnormal renal function. More specifically grade 3/4 thrombocytopenia and neutropenia occurred in 10% versus 11% (p=0.92) and 31% versus 10% (p=0.190) of patients with normal and abnormal renal function, respectively. The effect of treatment on RI reversal was also evaluated: 2 patients achieved complete renal response (i.e. baseline CrCl <50 ml/min improving to ≥60 ml/min) and 2 patients achieved minor renal response (baseline CrCl <15 ml/min improving to 15-29 ml/min or baseline CrCl 15-29 ml/min improving to 30-59 ml/min).Thus, in 4 of 10 patients with RI, treatment with RD resulted in improvement of renal function. We conclude that RD is an active treatment in patients with relapsed/refractory MM, even in patients with more heavily pretreated disease that those in the original report (Dimopoulos et al, N Engl J Med 2007;357:2123). RD is active in thalidomide and bortezomib refractory patients. With dosing of lenalidomide according to renal function, RD can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, RD may improve the renal function in a subset of patients with RI. Disclosures:Dimopoulos:CELGENE: Honoraria.

Reversibility of Renal Impairment in Patients With Multiple Myeloma Treated With Bortezomib-Based Regimens: Identification of Predictive Factors

PurposeRenal impairment is a frequent complication of multiple myeloma (MM) and is associated with significant morbidity and increased early death rate. Bortezomib is active and well tolerated in patients with MM who present or develop renal impairment. Patients and MethodsWe analyzed 46 consecutive patients who presented with renal impairment in order to evaluate the impact of bortezomib on the improvement of renal function and to identify predictive factors associated with renal response. All patients received bortezomib with dexamethasone with or without other agents. ResultsRenal response was documented in 59% of patients within a median of 11 days (range, 8-41 days). Two of 9 patients who required dialysis became dialysis independent. A complete renal response (CRrenal) was documented in 30% of patients. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Patients with light chain—only myeloma had a higher probability of achieving a renal response, and previously untreated patients had a higher probability for complete resolution of renal impairment, while light chain—only myeloma was independently associated with a shorter time to renal response. The degree of renal impairment was not predictive of the probability for renal response or CRrenal; however, in a subset of patients for whom cystatin C was available, a baseline cystatin C > 2 mg/L or cystatin C calculated estimated glomerular filtration rate < 30 mL/min were associated with a lower probability of CRrenal. ConclusionWe conclude that bortezomib-based regimens may improve renal function in the majority of myeloma patients with renal impairment.

Reversibility of Renal Impairment of Multiple Myeloma Patients Treated with Bortezomib-Based Regimens: Identification of Predictive Factors.

Renal impairment (RI) is a frequent complication of multiple myeloma (MM) and a major management problem. Previous studies have shown that bortezomib is active and well tolerated in MM patients with RI and can be associated with improvement of renal function. The purpose of our analysis was to identify factors that may predict for renal impairment reversal in patients treated with bortezomib-based regimens. Over the last 5 years, 149 either newly diagnosed or relapsed/refractory MM patients received bortezomib-based regimens in our center. Our analysis is based on 46 consecutive patients with newly diagnosed (n=10) or relapsed/refractory (n=36) MM who presented with RI defined as creatinine clearance (CrCl) < 50 mL/min. Median CrCl was 23 mL/min (range 6 to 48), 34 (74%) had a CrCl<30 ml/min and 9 patients required renal dialysis. Sixteen patients (35%) had light chain only myeloma, elevated LDH>300 IU/L was found in 24%, more than 2 gr/day of Bence Jones protein in 20 (44%) and kappa to lambda free light chain ratio was ≥8 or ≤0.125 in 25%. Patients received bortezomib (B) at standard dose and schedule, plus dexamethasone (D) (16 patients, 35%), or BD in combination with other agents such as thalidomide, doxorubicin or melphalan (30 patients, 65%). Renal complete response (RCR) was defined as a sustained increase of CrCl to >60 mL/min after treatment. Renal partial response (RPR) was defined as an increase of CrCl by 50% and with improvement of renal function by at least one stage (stage IV: <30 mL/min, stage III 30–59 mL/min) but with a post treatment CrCl < 60 mL/min. RCR was documented in 22% of patients and RPR in 22% of patients. Thus, renal response (RCR + RPR) occurred in 20 patients (44%). The median time to renal response was 11 days (range 8 to 41). Among 9 patients who required dialysis 2 patients became independent of this procedure after the second cycle of treatment. The objective response rate (at least partial response) of the myeloma was 63%. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Previously untreated patients (80% vs 33% for pretreated patients, p=0.012) and those with light chain only myeloma (69% vs 30%, p=0.012) had a higher probability to achieve renal response. Response of MM to treatment was also associated with higher rate of renal response (55% vs. 24% for non-responders, p=0.037). Creatinine clearance <30 ml/min (47% vs. 33% for ClCr 330 ml/min, p=0.410), age>75 years (p=0.309), corrected serum calcium ≥10,5 mg/dl (p=0.428), Bence Jones proteinuria ≥2g/day (p=0.167) or type of bortezomib regimen (BD or BD plus other agents, p=0.222) did not significantly affect the probability of renal response. Seventeen percent of patients presenting with RI died within the first 3 months after initiation of treatment. Patients with renal response had a trend for longer survival compared to those who did not achieve a renal response (79% vs 54% alive at 1 year, p=0.150). We conclude that when bortezomib-based regimens are administered to MM patients with RI, they are associated with a clinically meaningful renal response in 44% of them. Renal response is very rapid and occurred within 2 months in all patients. Previously untreated patients and those with light chain only myeloma may have a higher probability of renal response. Moreover, patients who achieved at least a partial response of their myeloma reversed RI more frequently than non-responders. Our data were derived from an unselected patient population with severe renal failure in more than two-thirds and with 20% of patients on dialysis. They provide further evidence that bortezomib-based regimens have a unique role in patients with RI.

Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: An open-labeled pilot study

Tacrolimus is a relatively new calcineurin inhibitor that has been increasingly used in transplant medicine. The objective of the current work is to report our preliminary experience with tacrolimus in the treatment of diffuse proliferative glomerulonephritis in systemic lupus erythematosus (SLE). Nine consecutive patients who fulfilled the American College of Rheumatology criteria for SLE and with biopsy-proven diffuse proliferative glomerulonephritis were recruited for an open-labeled trial with prednisolone and oral tacrolimus (0.1 mg/kg/day for 2 months, followed by 0.06 mg/kg/day). Prospective data on renal response and serologic lupus activity were collected. The efficacy and safety of this regimen was reported. Baseline characteristics of the patients were: mean age 33.3 +/- 12 years, women to men ratio 2:1, serum creatinine 94.2 +/- 46 micromol/L, daily proteinuria 4.56 +/- 2.4 g, seven (78%) patients were nephrotic, three (33%) were hypertensive, and four (44%) had elevated serum creatinine at the time of renal biopsy. At 6 months of therapy, complete and partial renal response was achieved in six (67%) and two (22%) patients, respectively. Significant improvement in proteinuria, hemoglobin, serum albumin, and C3 levels was observed in comparison with baseline values, starting at the second month. Tacrolimus was generally well tolerated, except for two patients who developed transient hyperglycemia. Infective complications, amenorrhea, hypertrichosis, gingivitis, new-onset hypertension, and significant increase in serum creatinine were not reported. Tacrolimus is an effective option for induction treatment of SLE-diffuse proliferative glomerulonephritis. Further trials are necessary to determine the optimal dosage and duration of therapy, and its efficacy in comparison to standard regimens.

Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis.

To study the incidence, predictors, and outcome of renal flares after successful cyclophosphamide (CYC) treatment for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE). Between 1988 and 2001, patients with biopsy-proven SLE DPGN who were treated initially with prednisone and CYC were studied. Those who responded to CYC were followed up for the occurrence of renal flares. The cumulative risk, predictors, and outcome of renal flares were evaluated. We studied 189 patients (167 women; and 22 men) with SLE DPGN. All were initially treated with prednisone and CYC (49% orally; 51% by intravenous pulse). At the last dose of CYC, 103 patients (55%) and 52 patients (28%) had achieved complete and partial renal responses, respectively. Azathioprine (AZA) was given as maintenance therapy in 117 patients (75%). After a mean followup of 96.5 months, 59 patients (38%) experienced renal flares (42% nephritic; 58% proteinuric). The median time to relapse was 32 months. The cumulative risk of renal flare was 28% at 36 months and 44% at 60 months. Independent predictors of nephritic flares were persistently low C3 levels after CYC treatment and absence of AZA maintenance therapy. At the last clinic visit, 16 patients (10.3%) had developed doubling of the serum creatinine level (cumulative risk of creatinine doubling 7.4% at 5 years after renal biopsy and 14.3% at 10 years). Ten patients (6.5%) developed end-stage renal disease (ESRD). Renal survival rates at 5 and 10 years were 94.9% and 87.5%, respectively. Increasing histologic chronicity scores, failure to achieve complete response, persistent hypertension after CYC treatment, and nephritic renal flares were unfavorable factors for doubling of the serum creatinine level and for ESRD by univariate analysis. The occurrence of nephritic flares was the only predictor of creatinine doubling by Cox regression analysis. In patients with SLE DPGN, renal flares are common despite initial responses to CYC. Nephritic renal flares are associated with a decline in renal function. Maintenance therapy with AZA reduces, but does not completely prevent, renal flares. More effective maintenance treatment for SLE DPGN after an initial response to CYC should be evaluated.

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis.

Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes. We conducted a retrospective cohort study to test whether genetic polymorphisms of these enzymes are associated with the toxicity of, and clinical response to, cyclophosphamide in patients with lupus nephritis. Sixty-two patients with proliferative lupus nephritis treated with cyclophosphamide were genotyped for common variant alleles of CYP2B6, 2C19, 2C9, and 3A5. We examined the association between these genotypes and the following clinical end points: development of premature ovarian failure, end-stage renal disease (ESRD), doubling of serum creatinine level, and achievement of complete renal response. The observed frequencies of the variant alleles CYP2B6*5, CYP2C19*2, CYP2C9*2, and CYP3A5*3 were 12.1%, 25.0%, 4.0%, and 75.8%, respectively. Patients who were either heterozygous or homozygous for CYP2C19*2 had a significantly lower risk of developing premature ovarian failure (relative risk 0.10; 95% confidence interval 0.02-0.52), after adjustment for age and total number of cyclophosphamide pulses received. In a survival analysis, patients homozygous for CYP2B6*5 (n = 3) or CYP2C19*2 (n = 4) had a higher probability of reaching ESRD (P = 0.0005) and of doubling the creatinine level (P = 0.0005) as well as a trend toward a lower probability of achieving a complete renal response (P = 0.051). Determination of selected cytochrome P450 enzyme genotypes may be valuable for predicting the risk of premature ovarian failure in lupus nephritis patients treated with cyclophosphamide. The association of these genotypes with renal response needs further validation.