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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3682-3682 ◽  
Author(s):  
Heinz Ludwig ◽  
Zdenek Adam ◽  
Roman Hajek ◽  
Richard Greil ◽  
Felix Keil ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Light Chain ◽  
Tumor Response ◽  
Safety Analysis ◽  
Tumor Control ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Grade 3 ◽  
Intent To Treat

Abstract Acute light chain induced renal failure (ARF) is a severe complication of progressive MM, leading to permanent renal dysfunction and dependence on chronic hemodialysis in a substantial proportion of patients (pts). Reversal of kidney failure can only be achieved by fast and substantial suppression of pathogenic light-chains with effective anti-MM therapy. Bortezomib in combination with doxorubicin and dexamethasone has been shown to be highly effective in newly diagnosed pts. In addition, bortezomib is well tolerated in pts with reduced glomerular filtration rate (GFR) and its half life is independent of renal function. In this study we aimed to evaluate the efficacy of the BDD regimen in restoring renal function and in achieving tumor control in pts with light chain-induced renal failure. Up to now 67 of 70 planned pts have been enrolled. Documentation is available for 55 pts for intent to treat analysis and for 47 evaluable for renal and tumor response (age: median 66 years, range 41–79 years, ISS stage I: 2%, II: 13%, III: 85%. 37 (79%) of pts presented with de novo MM, and 10 (21%) with progressive disease; baseline median GFR 19.8 ml/min (range 3.7–49.9ml/min). ARF was defined in newly diagnosed pts as reduction of GFR to <50ml/min due to MM nephropathy, and in previously treated pts with signs of tumor progression and a GFR of ≥60ml/min within the last 4 weeks before enrolment as a reduction of GFR by >25% to <50ml/min. 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. 47 pts have completed at least 2 cycles and are evaluable for response as yet. 23 pts achieved CR/nCR (50%), 3 (6%) VGPR, 6 (13%) PR and 5 (11%) MR (CR-MR: 90%). Median time to response was 108 days. Median GFR increased from 19.8 ml/min (range: 3.7 – 49.9 ml/min) to 46.1ml/min (range 6.7 – 106 ml/min). Improvement of GFR correlated weakly with tumor response. In 26 pts with CR/nCR/VGPR, median GFR increased to 62 ml/min (10–106 ml/min). Best median GFR was 25 ml/min (11 – 106 ml/min) in 11 pts with PR/MR, and 22 ml/min (7 – 51 ml/min) in 10 pts with SD/PD. When renal response was defined either as complete (CRrenal: GFR≥60 ml/min), partial (PRrenal: increase from GFR <15 ml/min to 30–59 ml/min), or minor (MRrenal: increase in GFR either from < 15 ml/min to 15–29 ml/min or from 15–29 ml/min to 30–59 ml/min), a total of 15 (32%), and 14 (30%) pts achieved a CRrenal, or a PR/MRrenal, respectively, yielding an ORRrenal in 29 (62%) of pts (Table 1). Three of 8 dialysis dependent pts became dialysis independent. Table 1 Stage of renal failure at baseline (GFR) Number of pts Best renal response (number of pts, percentage) CRrenal PRrenal MRrenal Stage III 30–59ml/min 11 6 (55%) - - Stage IV 15–29ml/min 23 8 (35%) 8 (35%) - Stage V <15ml/min 13 1 (8%) 3 (23%) 3 (23%) Overall survival (OS) was 72% @ 2 years in the intent to treat and 78% @ 2 years in the evaluable population. OS was 76% @ 2 years in pts without CRrenal, and 86% in pts with CRrenal. Leucopenia, thrombopenia, and anemia of grade 3&4 were seen in 15%, 6% and 6%, respectively. Other common grade 3&4 toxicities were infection (4%), nausea/vomiting (6%), weakness/fatigue (11%) and polyneuropathy (8%). In conclusion, the BDD regimen resulted in high tumor (CR/VGPR 56%, ORR: 90%) and renal response rates (CRrenal 32%, ORRrenal 62%). 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.

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.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3862-3862 ◽  
Author(s):  
Heinz Ludwig ◽  
Zdenek Adam ◽  
Roman Hajek ◽  
Richard Greil ◽  
Elena Tóthová ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Renal Impairment ◽  
Light Chain ◽  
Tumor Response ◽  
Safety Analysis ◽  
Renal Response ◽  
Previously Treated ◽  
Grade 3 ◽  
Intent To Treat

Abstract Abstract 3862 Poster Board III-798 Acute 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.

Rapid Reduction of Light-Chains and Proteinuria in Multiple Myeloma (MM) Patients with Light Chain Induced Acute Renal Failure Treated with Lenalidomide and Dexamethasone

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5114-5114
Author(s):  
Heinz Ludwig ◽  
Josef Thaler ◽  
Jan Koren ◽  
Ludek Pour ◽  
Ercan Müldür ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Median Time ◽  
Light Chain ◽  
De Novo ◽  
Light Chains ◽  
High Risk Population ◽  
Renal Response ◽  
Increased Risk ◽  
Grade 3

Abstract Abstract 5114 Introduction: Light chain-induced renal failure (LC-ARF) is a severe complication of MM associated with increased risk of infections, dependency on chronic hemodialysis and shortened survival. Reversibility of renal impairment depends on the degree of renal damage, the duration of renal failure and the quality of response to anti-myeloma therapy. In this phase II trial we assess the efficacy of lenalidomide-dexamethasone in reducing pathogenic light chains and restoring renal function. In addition, we analyze the kinetics of treatment response in patients with LC-ARF. Patients and Methods: 24 patients with LC-ARF as formerly defined (JCO 2010) have been enrolled so far. Age (median): 65.5 years (range: 46–78 years), Gender: male/female: 12/12. All patients presented with ISS stage III. 20 (83.3%) had de novo MM and 4 (16.7%) previously treated, but relapsing disease. Median GFR was 19.9 ml/min (range 6.1 – 37.2 ml/min). ECOG performance was 0 in 6, I-II in 14 and III-IV in 4 patients, respectively. One patient died before first study medication, 3 patients died within the first cycle and 2 patients dropped out early (< 2 cycles). Lenalidomide was given from d 1–21 with dose adaptation according to GFR. Dexamethasone 40 mg was administered on d 1–4, 9–12, 17–20 during cycle 1; thereafter 1x/week. Cycles were repeated q 4 weeks. Results: Presently, 17 patients are evaluable for response (completed ≥2 cycles and fully documented). The median number of cycles is 9 (range 2–9). CR was achieved in 5 (31.3%), nCR in 4 (25%), VGPR in 2 (12.5%) and PR in 5 (25%) patients, respectively, yielding an ORR (CR+nCR+VGPR+PR) of 94% for the evaluable and 69.6% for the ITT population. Median time to best tumor response was 132 days. The greatest proportional reduction in 24 hour urinary excretion (86%) in responding patients occurred within the first 4 weeks of therapy, with only little further improvement beyond that time (figure 1). Renal response was assessed as formerly defined (JCO 2010). 3 patients achieved CRrenal, 3 PRrenal and 5 MRrenal, yielding an ORRrenal in 11 patients (64.7% of the evaluable and 47.8% of the ITT population). Median time to best renal response was 83 days. 3 of 10 dialysis dependent patients became dialysis independent. Median GFR of evaluable patients increased from 15.2 (range 6.1 – 35.1 ml/min) at baseline to a median best GFR of 28.3 ml/min (range 11.3 – 101.1 ml/min) (p<0.0075). The greatest increase in median GFR was noted in the 5 patients with CR (26.7 to 60.9 ml/min, p<0.024) while in those with nCR/VGPR/PR a less pronounced improvement in GFR (10.6 to 22.4 ml/min, p<0.025) was observed Tolerance: Full documentation of adverse events is presently available in 23 patients. Four patients died, 1 (4.3%) each due to infection and cardiac arrest and 2 (8.7%) with unknown causes of death (sudden death). Grade 3/4 anemia, thrombopenia and leucopenia, were seen in 11 (47.8%), 7 (30.4%), and 3 (13%) patients, respectively. Other common grade 3/4 toxicities were infection/sepsis in 9 (39.1%), and cardiac dysfunction in 5 (21.7%) patients, respectively. Exanthema and fatigue were seen in 2 patients (8.7%), and pulmonary embolism and macula edema in 1 patient each (4.3%). Conclusions: LD showed significant anti-myeloma activity with an overall response rate of 94% in the evaluable and of 69.9% in the ITT population. The greatest proportional decrease in 24 hour proteinuria (86%) was obtained already within the first 4 weeks of therapy while renal recovery occurred with delay only. Improvement in renal function was obtained in 65% of the evaluable and in 48% of the ITT population. Toxicity of the LD regimen with the lenalidomide dose adjusted to GFR was as expected in this high risk population. Updated results will be presented. Disclosures: Ludwig: Celgene: Research Funding, Speakers Bureau.

Lenalidomide and Dexamethasone for Acute Light Chain-Induced Renal Failure: Final Results of a Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3484-3484
Author(s):  
Heinz Ludwig ◽  
Elisabeth Rauch ◽  
Thomas Kuehr ◽  
Adam Zdenek ◽  
Adalbert Weissmann ◽  
...  
Keyword(s):  
Renal Failure ◽  
Serum Creatinine ◽  
Light Chain ◽  
Phase Ii Study ◽  
Renal Response ◽  
Cast Nephropathy ◽  
Protocol Population ◽  
Best Response ◽  
Grade 3 ◽  
Intent To Treat

Abstract Background: Acute renal failure (ARF) is a frequent complication of multiple myeloma (MM) and most frequently due to clonotypic light chains (LC) causing cast nephropathy, which is associated with fast deterioration of renal function, increased risk for infections and shortened survival. Here we present the final results of a phase II study employing lenalidomide-dexamethasone as treatment for patients with acute light-chain induced ARF. Patients and methods: 35 patients with LC-induced ARF have been enrolled. Cast nephropathy was confirmed in all 15 patients who had a renal biopsy. Patients with previously unknown MM must have presented with eGFR < 50ml/min and serum creatinine ³2.0mg/dL, and those with previously established diagnosis must have had documented eGFR ³ 60ml/min and serum creatinine ≤1.2mg/dL within 6 weeks before deterioration of eGFR to < 50ml/min and of serum creatinine to ≥ 2mg/dL due to LC-induced kidney injury. Nine cycles of Lenalidomide, day 1-21, q28 days, with dose adaptation according to eGFR (eGFR 30 – 50ml/min: 10 mg daily, eGFR < 30ml/min without requiring dialysis: 15mg q 48 hrs., eGFR < 30ml/min requiring dialysis: 5 mg daily following each dialysis) and dexamethasone (Dex), 40 mg, day 1-4, 9-12 and 17-21 during the first cycle and thereafter 40 mg once weekly were planned. Renal response was defined as previously described (Dimopoulos et al, Clin Lymphoma Myeloma. 2009, Ludwig et al. JCO 2010). Results: Patient's median age was: 66 (45-87), 28 patients had newly diagnosed and 7 previously established MM. 5.7% had ISS stage II, 94.3% stage III. 18 patients had light chain myeloma, 14 IgG, and 3 IgA isotype. Adverse cytogenetics t (4; 14) ± del17q ± 1q21 were detected in 14/29 patients. 4/35 patients died and 5 discontinued therapy (3 due to AEs, 1 due to PD, and 1 due to withdrawal of consent) within the first 2 cycles, leaving 26 patients for per protocol (PP) analysis. Median follow up was 17.7 months. Responses were seen in 25/35 (71.4%) patients; 7 (20%) had CR, 3 (8.6%) VGPR, 14 (40%) PR, and 1 (2.9%) MR. Median time to first and to best myeloma response was 28, and 92 days, respectively. Median baseline concentration of involved FLC was 5.465mg/L (range: 147–42.700mg/L) and 8350mg/L (range: 234– 35.500mg/L) in patients reaching ≥PR and ≤MR, respectively, and decreased significantly to a median of 95.75mg/L (range: 11.3–5.630mg/L, p <0.001) in the former, but not in the latter group. Renal response was observed in 16 (45.7%) of 35 patients (CRrenal, 5(14.2%), PRrenal, 7(20%), MRrenal, 5(14%)). Median time to renal and to best renal response was 28 and 157 days, respectively. Median eGFR increased significantly in patients with ≥ PR from 17.1ml/min at baseline to 39.1ml/min at best response (p<0.001), and from 23.7ml/min to 26.0ml/min in patients with ≤ MR (p=0.469) (figure 1A). Median PFS and OS were 5.5 and 21.8 months in the ITT and 12.1 and 31.4 months, respectively, in the PP group (figure 1B). Grade 3/4 anemia was seen in 43%, thrombocytopenia in 23% and neutropenia in 15% patients. Other non-haematologic AEs consisted mainly of grade 3-4/5 infection in 38%/9%, and of grade 3-4/5 cardiac toxicity in 11%/9% patients. Grade 3 diarrhea and vomiting/emesis were noted in 1 patient each. Conclusion: Lenalidomide (with dose adapted to eGFR) plus initial high dose Dex during the first cycle and low dose Dex during subsequent cycles resulted in rapid reduction of involved LC within 28 days in patients with ≥ PR. Overall, 71.4% of patients had a myeloma and 45.7% a renal response. Median eGFR increased significantly in patients with ≥ PR from 17.1ml/min at baseline to 39.1ml/min. Elderly patients experienced more toxicity and had more treatment discontinuations. Figure 1A. Median eGFR in patients with CR-PR and MR-NR at baseline and at best response. Figure 1A. Median eGFR in patients with CR-PR and MR-NR at baseline and at best response. Figure 1B. PFS and OS in the intent to treat and per protocol population. Figure 1B. PFS and OS in the intent to treat and per protocol population. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1725-1725 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Flora Zagouri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Function ◽  
Partial Response ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Light Chain ◽  
Management Problem ◽  
Newly Diagnosed ◽  
Renal Response

Abstract 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) &lt; 50 mL/min. Median CrCl was 23 mL/min (range 6 to 48), 34 (74%) had a CrCl&lt;30 ml/min and 9 patients required renal dialysis. Sixteen patients (35%) had light chain only myeloma, elevated LDH&gt;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 &gt;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: &lt;30 mL/min, stage III 30–59 mL/min) but with a post treatment CrCl &lt; 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 &lt;30 ml/min (47% vs. 33% for ClCr 330 ml/min, p=0.410), age&gt;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.

Combined Bendamustine, Prednisone and Bortezomib (BPV) In Patients With Relapsed Or Refractory Multiple Myeloma and Light Chain Induced Renal Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3203-3203 ◽  
Author(s):  
Wolfram Pönisch ◽  
Barbara Moll ◽  
Dietger Niederwieser
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Dysfunction ◽  
Light Chain ◽  
Severe Side Effect ◽  
Renal Response ◽  
Group A ◽  
Severe Renal Dysfunction ◽  
Grade 3 ◽  
Group B

Abstract Introduction Serious renal failure represents a main complication of Multiple Myeloma (MM). An estimated 25% to 50% of patients are affected during the course of their disease. These patients are at increased risk for infections and have a significantly worse prognosis. Small phase I/II studies suggest that treatment with chemotherapy and/or new substances results in recovery of renal function in more than 25%. The window of opportunity for reversal of renal impairment is rather small making an immediate and highly active treatment strategy mandatory. Bortezomib and bendamustine have turned out to be quickly acting and effective drugs in the treatment of MM. Methods Between March 2005 and March 2013, 36 patients (median age 64; range 32-81 years) with relapsed/refractory MM and light chain induced renal failure (creatinine clearance <60ml/min) were treated with bendamustine 60mg/qm on day 1 and 2, bortezomib 1.3mg/qm on day 1, 4, 8 and 11, and prednisone 100mg on day 1, 2, 4, 8 and 11. Cycles were repeated every 21 days. Patients were divided into two groups: group A (n=20) consisted of patients with moderate or severe renal dysfunction (eGFR 15-59ml/min) and group B (n=16) of patients with renal failure/dialysis (eGFR <15ml/min). Results The median number of the BPV-treatment was 2 (1-7) cycles. 24 patients (67%) responded after at least one cycle of chemotherapy with 3 CR, 3 nCR, 6 VGPR, and 12 PR. Six patients had MR, 2 patients stable disease and 4 patients had a progress. With a median follow up of 22 months of the surviving patients, median PFS and OS for patients with moderate or severe renal dysfunction (group A) were 10 months and 25 months, respectively. Outcome for these patients was significantly better compared to patients with renal failure/dialysis (group B) with a median PFS and OS of 3 months and 7 months, respectively (p<0.02). Eleven patients showed a CRrenal, 5 patients a PRrenal and 15 patients a MRrenal. Median time to first renal response and best renal response were 21 days and 42 days, respectively. The most common severe side effect was grade 3-4 thrombocytopenia in 81% of the patients. Grade 3-4 neutropenia was observed in 50% of the patients. Moderate to severe infections were seen in 13 patients. Summary These results indicate that the combination of bortezomib, bendamustine and prednisone is effective and well tolerated in patients with relapsed/refractory MM and light chain induced renal failure. Disclosures: No relevant conflicts of interest to declare.

Significant Activity of Lenalidomide-Dexamethasone in Multiple Myeloma (MM) Patients with Light Chain Induced Acute Renal Failure (LC-ARF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4031-4031
Author(s):  
Heinz Ludwig ◽  
Elisabeth Rauch ◽  
Thomas Kuhr ◽  
Adalbert Weissman ◽  
Daniel Heintel ◽  
...  
Keyword(s):  
Renal Failure ◽  
Clin Oncol ◽  
Median Time ◽  
Light Chain ◽  
Oral Candidiasis ◽  
Renal Tubules ◽  
Significant Activity ◽  
Renal Response ◽  
Grade 3 ◽  
Renal Responses

Abstract Abstract 4031 Introduction: Excessive production of free light chains with affinity for uromodulin results in protein aggregates and toxic injury of distal renal tubules. The ensuing renal failure is a significant risk factor for infections, dependency on chronic hemodialysis and reduced survival. Management of this emergency includes rapid confirmation of the diagnosis and prompt installment of effective anti-myeloma therapy. Here, we assess the efficacy of lenalidomide-dexamethasone for treatment of patients with LC-ARF. Patients and Methods: 32 patients with LC-ARF as formerly defined (J. Clin. Oncol. 2010 20; 28(30):4635-41) have been enrolled so far. Age (median): 66 years (range: 46–87 years), Gender: male/female: 17/15. All patients presented with ISS stage III. 26 (81.3%) had de novo MM and 6 (18.8%) previously treated, but relapsing disease. Median GFR was 19.9 ml/min (range 6.1 – 37.2 ml/min). ECOG performance status was 0 in 9, I-II in 18 and III-IV in 5 patients, respectively. Lenalidomide was given from d 1–21 with dose adaptation according to GFR as suggested in the prescribing information. Dexamethasone 40 mg was administered on d 1–4, 9–12, 17–20 during cycle 1; thereafter 1x/week. Cycles were repeated q 4 weeks. Results: Presently, 23 patients are evaluable for response (completed ≥2 cycles and fully documented). The median follow-up is 7.7 months, median number of cycles is 9 (range 2–9). CR was achieved in 5 (21.7%), nCR in 1 (4%), VGPR in 2 (8%) and PR in 13 (52%) patients, MR in 1 (3%), respectively, yielding an ORR (CR+nCR+VGPR+PR) of 91.3% for evaluable patients and 65.6% for the ITT population. Median time to first myeloma response was 28 (range 27–63 days) and to best response was 113 days (34–304 days). The cumulative incidence of all patients with myeloma and renal responses are shown in figure 1. Median PFS and OS were 13.8 and 31.2 months respectively in the evaluable patients and 7.4 and 31.2 months in the ITT population. Renal response was assessed as formerly defined (J Clin Oncol. 2010 20; 28(30):4635-41). 4 patients achieved CRrenal, 8 PRrenal and 3 MRrenal, yielding an ORRrenal in 15 patients (65.2% of the evaluable and 46.9% of the ITT population). Median time to first renal response was 28 (range: 27–34) days, and to best renal response 119 days (34–304 days). 5 of 13 dialysis dependent patients became dialysis independent. Median GFR of evaluable patients increased from 15.2 (range 6.1 – 35.1 ml/min) at baseline to a median best GFR of 31.4 ml/min (range 11.3 – 103.2 ml/min). In the 5 patients with CR a significant increase in GFR (median 26.7 to 60.9 ml/min) and in the 16 patients with nCR/VGPR/PR an increase from 13.5 to 30.1 ml/min was observed. Full documentation of adverse events is presently available in 32 patients. 5 patients died within the first 2 months, 2 (8.7%) each due to infection and cardiac arrest and 1 (4.3%) with apoplexia. Grade 3/4 anemia, thrombopenia and leucopenia, were seen in 17 (53.1%), 9 (28.1%), and 5 (15.6%) patients, respectively. Other common grade 3/4 toxicities were infection/sepsis in 13 (40.6%), and cardiac dysfunction in 8 (25%) patients, respectively. Exanthema G3 was seen in 3 patients (9.3%), pulmonary embolism, macula edema and multiple stroke syndrome in 1 (3.1%), potassium deficiency G3/4 in 5 (15.6%), and oral candidiasis in 2 patients (6.3%) each. Conclusions: LD showed significant anti-myeloma activity with an overall myeloma response rate (CR-PR) of 91.3% in the evaluable of 65.5% in the ITT cohort. Renal responses (CRrenal-PRrenal) were observed in 65.2% and 46.9% patients, respectively. Time to first myeloma and first renal response was fast (28 days each). The LD regimen with the lenalidomide dose adjusted to GFR was well tolerated. Updated results will be presented. Disclosures: Ludwig: Janssen Cilag: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria. Off Label Use: Lenalidomide was used of label in combination with dexamethasone in this phase II study in patients with acute light-chain induced renal failure.

Three Drug Combinations Based on Bortezomib and Dexamethasone (VD) Backbone Improve Renal Function More Efficiently Than VD in Myeloma Patients with Severe Renal Impairment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4769-4769 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Maria Roussou ◽  
Evangelos Terpos ◽  
Erasmia Psimenou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Median Time ◽  
Light Chain ◽  
Early Death ◽  
Drug Combinations ◽  
Renal Recovery ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Significant Difference

Abstract Renal impairment (RI) is a frequent complication of multiple myeloma (MM) and is associated with significant morbidity and risk of early death. Patients with severe RI (eGFR <30 ml/min/1.73 m2) have worse outcome and are frequently excluded from clinical trials. Two or three drug combinations based on the bortezomib and dexamethasone (VD) backbone have been proposed by the IWMG as the treatment of choice for patients who present with RI. In order to evaluate if two or three drug combinations were more efficient in patients who present with severe RI, we studied 56 (28M/28F) consecutive, unselected, newly diagnosed MM patients with severe RI who were treated in our center (University of Athens, Greece). Assessment of the degree of RI was made with the MDRD formula. Severe RI was defined as an eGFR of <30 ml/min/1.73 m2. 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 of patients was 65 years (range: 37-88 years) and 21% of them were >75 years of age. The median eGFR was 11.2 ml/min/1.73 m2 (range: 3.4- 29.2 ml/min/1.73 m2); 64% had eGFR <15 ml/min/1.73 m2, including 16 (28.5%) patients who received dialysis with regular filters. Median level of proteinuria was 1.8 g/24h (range 0.2-12 g/24h) and involved free light chain (FLC) was 4250 mg/l (range 4.4-35,200 mg/l). All patients received VD-based regimens: 23 (41%) received VCD, 18 (32%) received VD, 8 (14%) received VTD, 5 (9%) received PAD, and 2 (4%) patients received VMP. An improvement of renal function (at least MRrenal) was recorded in 39 patients (70%) within a median time of 21 days (range 4-152 days). CRrenal was documented in 43% of patients and PRrenal in 9% (major renal response rate of 52%). Seven of 16 (44%) patients who required dialysis became dialysis independent. The median time to major renal response was 28 days (range 7-152 days). Patients with eGFR ≥15 ml/min/1.73 m2 (p=0.06) and age <65 years (p=0.036) had more rapid renal recovery (≥PRrenal). The type of light chain, presence of hypercalcemia (≥11 mg/dl) and elevated serum LDH (≥250 U/L) were not predictive of the probability of renal response. Using ROC analysis, we identified serum FLCs >12,500 mg/L as a cut-off associated with major renal response: only 16% of patients with FLCs >12,500 mg/L achieved a major renal response vs 59% of the others (p=0.053). Three-drug combinations (VTD, VCD, PAD, VMP) vs VD alone were associated with higher probability of major renal responses (65% vs 26%; p=0.006). Myeloma response to treatment by IMWG criteria was predictive of major renal response (p=0.05) in the univariate analysis. In multivariate analysis, adjusted for age >65 years and need for dialysis, the use of three-drug combinations was independently associated with a higher probability of major renal response (OR: 3.91, 95% CI 1.014-15, p=0.048). There was also a trend towards a shorter time until a major renal response for patients treated with three vs two drugs (35 vs >90 days, p=0.14). There was no significant difference in the probability of major renal response or time to renal response for those who received VTD vs VCD, PAD or VMP, even after adjusting for need of dialysis and age. Among patients who required dialysis, 9 (56%) received a three drug combination (5 VTD, 3 VCD and one PAD); among patients who became independent of dialysis 3 received VTD, 1 PAD and 3 VD. An early death (within <2 months from treatment initiation) occurred in 6 (11%) patients (5 had received VD and only one VTD). The median survival for all patients was 53 months, similar for patients who achieved a major renal response vs those who did not (p=0.413). Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. In conclusion, our data indicate that bortezomib–based regimens can improve renal function in the majority of patients with severe RI. Three drug combinations based on VD are associated with a higher probability of major renal response and with a shorter time to renal recovery and should be offered to all newly diagnosed patients with severe RI. The FLC level could be used as a predictive factor for renal response. Disclosures No relevant conflicts of interest to declare.

Tumor and Renal Response in Patients with Newly Diagnosed Multiple Mieloma and Renal Failure Treated with Bortezomib and Dexamethasone: Results of a Prospective Phase II Trial from Pethema/GEM

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4776-4776 ◽  
Author(s):  
Laura Rosiñol ◽  
Albert Oriol ◽  
M Jesús Blanchard ◽  
Luis Palomera ◽  
Maria-Victoria Mateos ◽  
...  
Keyword(s):  
Renal Failure ◽  
Board Of Directors ◽  
Overall Response Rate ◽  
Response Rate ◽  
Early Death ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Renal Response ◽  
Grade 3

Abstract Background: Renal failure (RF) is present in about 20% of patients with newly diagnosed multiple myeloma (MM) and is associated with a poor outcome. Bortezomib-based therapy has shown significant activity in patients with RF, including a higher rate of renal recovery when compared with previous regimens. We report the results of a prospective phase II trial for patients with newly diagnosed MM and RF treated with bortezomib and dexamethasone (VD) (RENVEL: www.clinicaltrials.gov NCT 01084837). Aim: The primary end-point was efficacy in terms of response rate and secondary end-points were recovery of RF, PFS and OS. Patients and Methods: Patients with newly diagnosed MM and renal failure from 11 PETHEMA institutions were included. RF was defined as an estimated filtration glomerular rate (eFGR) < 50 ml/min calculated by the MDRD formula. Patients <66 years were treated with 4 cycles of i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 and dexamethasone 40 mg p.o. on days 1-4 and 9-12 every 3 weeks and those with no other comorbidities than RF were planned to received high-dose melphalan followed by stem cell rescue (ASCT group) . Patients ³66 years or younger with comorbidities not candidates to high-dose therapy received up to 8 cycles of VD. Responding patients with no significant toxicities were given 4 additional cycles at the same dose of bortezomib and dexamethasone 40 mg on days 1-4 at 4-weeks intervals (no ASCT group). Myeloma response was assessed by the IMWG criteria and renal response by the criteria recently proposed (Dimopoulos et al, J Clin Oncol 2010;33:4976-4984). Results: Between April 9, 2010 and September 13, 2012, 60 patients (42 M, 18F, median age 72 years) were enrolled. The M-protein type was IgG in 14 patients, IgA in 22, light-chain only (Bence-Jones) in 22 and IgD in 2. 85% of the patients had ISS 3 and 19% had high-risk cytogenetics. The median baseline eFGR was 17 ml/min and 40 patients had severe RF defined as eFGR <30 ml/min. Seventeen patients (28%) required initial renal replacement with dialysis. The overall response rate in the overall series was 75% (29%CR, 27% VGPR, 19% PR, 3% MR, 16% refractory disease, 5% early death, 1% non-evaluable). Eighteen patients (30%) were initially considered candidates to receive ASCT. The overall response rate after 4 induction cycles was 77% (28% CR, 23% VGPR, 28% PR, 5% MR, 16% refractory disease). Seven patients did not proceed to ASCT because of progressive disease (4), renal impairment with poor PS (2) and lost of follow-up (1). The response rate of the 11 patients who underwent to ASCT was CR in 8 patients (73%), VGPR in 1 (9%), PR in 1 (9%) and early death (sepsis) in 1 (9%). Grade 3 toxicity was only observed in 3 patients. No patient developed grade 3-4 neurological toxicity and only 2 patients had grade 2 peripheral neuropathy. Forty-two patients (70%) were not candidates to receive ASCT. The median number of cycles administered was 7.5. The overall response rate was 71% (29% CR, 29% VGPR, 14% PR, 2% MR, 17% refractory disease, 7% early death, 2% non-evaluable). 15 patients discontinued therapy because of bortezomib-related toxicity and seven were discontinued due to infectious complications. One patient developed grade 3 thrombocytopenia and grade 3 extrahematological toxicity was observed in 4 patients (gastrointestinal, asthenia, Wernicke-Korsakoff and rash one patient each). Peripheral neuropathy was observed in 18 patients (grade 2: 13 patients, grade 3: 5 patients). Renal response was achieved in 66% of the patients (29% CR, 14% PR, 23% MR). The median time to renal respose was 1.6 months (0.8-2.7). Therteen patients out of 17 (76%) could have been discontinued from dyalisis. The renal response rate was similar in the two groups. After a median follow-up of 26.7 months, the median PFS in ASCT and no-ASCT groups was 33.3 and 16.3 months, respectively. The estimated OS at 36 months were 82% and 72%, respectively. In both groups the PFS was not significantly different among patients achieving renal response vs. those not achieving renal response. In no-ASCT group the OS was significantly longer in patients achieving renal response compared with patients not achieving renal response (not reached vs. 35.3 months, p=0.03). Conclusions: VD is a highly effective regimen in patients with newly diagnosed multiple myeloma and severe renal failure, resulting in a high quality tumor responser and a renal response rate of 66% including a 76% of dialysis discontinuation. Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. Mateos:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Jiménez:Janssen: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen: Honoraria; Celgene: Honoraria.

Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study

2010 ◽  
Vol 28 (30) ◽  
pp. 4635-4641 ◽  
Author(s):  
Heinz Ludwig ◽  
Zdenek Adam ◽  
Roman Hajek ◽  
Richard Greil ◽  
Elena Tóthová ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Partial Response ◽  
Light Chain ◽  
Tumor Response ◽  
Minor Response ◽  
Renal Response ◽  
Previously Treated Patients ◽  
Previously Treated

Purpose To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain–induced acute renal failure. Patients and Methods Sixty-eight patients with light chain–induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m2 on days 1, 4, 8, and 11), doxorubicin (9 mg/m2 on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m2 and doxorubicin administered on days 1, 4, 8, and 11. Results By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). Conclusion BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

Treatment of Patients with Multiple Myeloma Complicated by Renal Failure with Bortezomib - Based Regimens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2739-2739 ◽  
Author(s):  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Athanasios Anagnostopoulos ◽  
Erasmia Psimenou ◽  
Irini Grapsa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Function ◽  
Serum Creatinine ◽  
Median Time ◽  
Objective Response ◽  
Elevated Serum ◽  
Management Problem ◽  
Newly Diagnosed ◽  
Kinetics Of

Abstract Introduction: Renal failure is a common feature of multiple myeloma and a major management problem. There is limited data regarding the reversibility of renal failure, the kinetics of serum creatinine and the safety of novel agents, such as bortezomib, when administered to newly diagnosed or relapsed/refractory patients with renal failure. The purpose of our analysis was to assess the frequency of renal failure improvement and kinetics of serum creatinine in patients who received bortezomib-based regimens. Patients and methods: We evaluated 20 consecutive patients with newly diagnosed (n=7) or relapsed/refractory (n=13) multiple myeloma and renal failure, defined as a serum creatinine ≥ 2mg/dl. Patients’ median age was 66 years (range 43–88 years). Median serum creatinine was 3.8 mg/dl (range 2–11.9 mg/dl) and median creatinine clearance was 15.3 ml/min (range 6.4–33.3). Other features included hemoglobin <10gr/dl in 12 patients, platelets <100 × 109/l in 3 patients and elevated serum LDH in 9 patients. All patients received bortezomib plus dexamethasone alone or in combination with other agents, such as thalidomide, doxorubicin or melphalan. Reversibility of renal failure was defined as a sustained decrease of serum creatinine to <1.5 mg/dl and renal response was defined as ≥50% decrease of serum creatinine from its peak value. Results: Reversal of renal failure was documented in 35% of all patients and the median time to reversal was 23 days. Moreover, 9 patients (45%) had 50% decrease in serum creatinine and the median time to decrease was 34 days. Some decrease of creatinine was documented in 88% of patients. Among four patients who were on renal dialysis, 2 became independent of this procedure after the second and the third cycle of treatment. The objective response rate was 61% and the median progression free survival for responders was 12 months. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Grade 3–4 neutropenia and thrombocytopenia were seen in 28% and 22% of patients respectively. One patient died of infection and bortezomib had to be discontinued in 4 patients due to grade III neurotoxicity. Conclusions: When bortezomib-based regimens are administered to myeloma patients with renal impairment their toxicity and efficacy are similar to those observed in patients with normal renal function. Moreover, these regimens are associated with rapid improvement of renal function in most patients and with reversal of renal failure in one-third of them.

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