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) < 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.

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.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 955-955 ◽  
Author(s):  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Agent Based ◽  
Renal Response ◽  
Group A ◽  
Group B ◽  
Novel Agent

Abstract Abstract 955 Renal 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.

Recovery of Renal Function and Independence from Dialysis in Newly Diagnosed and Relapsed Multiple Myeloma Patients - A Single Instituition Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4847-4847
Author(s):  
Girish Ravindranathan ◽  
Tanya Indrakumar ◽  
Sohail Ahmad ◽  
Moez Dungarwalla ◽  
Pamela Kanagasabapathy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Function ◽  
Renal Impairment ◽  
Current Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Female Ratio ◽  
Male To Female ◽  
Relapsed Myeloma

Abstract Background: Renal impairment occurs in up to 30% of patients who present with multiple myeloma and in up tp 50% of patients at some stage of the illness. It is known that renal impairment can be reversed in a significant number of such patients by correction of precipitating factors and rehydration but that 3–12% patients will require dialysis or other major intervention. These patient have a worse prognosis largely due to an excess of early deaths, renal failure being the major cause of death in 14% of myeloma patients and contributing factor in a further 14%. (Drayson et al UK MRC MM trials 1980–2002) We have conducted a study to look into the clinical course and outcome of all patients with renal impairment sufficiently severe to be referred to the regional renal unit in South East England between 2000 and 2007 with either newly diagnosed multiple myeloma (MM) or relapsed disease to try to identify features which predict for better outcomes. Methods: 62 patients with MM and renal failure received treatment in our hospital over the last 8 years. Patients have been assessed for recovery of renal function and dialysis independence in two groups - newly diagnosed (n=47) and relapsed patients (n=15). They were analysed separately as the disease tends to be biologically different at presentation and relapse, and therapeutic options may be different. In addition relatively little data on relapsed myeloma with renal failure is available. Results: 14 patients in the newly diagnosed group and 4 in the relapsed group were deemed unsuitable for an active treatment approach and have been excluded from statistical analysis in this paper but will be analysed separately to try to identify factors which could improve the outcome for this group. The patients with newly diagnosed MM and actively treated had a mean age of 65.3±1.7 years (range 41.9–83.3), male to female ratio of 1.7:1 and a mean peak creatinine at presentation of 684.5±60.9 mmol/l (range 107–1820). Light chain myeloma was overrepresented and was seen in 57.5% of patients (n=19). 12 (36.3%) of 33 the new patients avoided dialysis. 21 required dialysis, of whom 8 patients (38.1%) recovered function to dialysis independence at 6 months. There were only 3 deaths at 6 months follow-up. The mean age of the relapsed patients was 61.8±3.5 years (range 34.9–80.7), male to female ratio of 2.6:1 and a mean peak creatinine at presentation of 824±118.4 mmol/l (range 231–1591). Majority of myeloma was IgA in 36.3% (n = 4). Among the 11 relapsed, 82% (n=9) required dialysis but a significant proportion, 88% (n=8), were dialysis independent at 6 months There was only one death within 6 months of a relapse. Treatments in the 2 groups varied but involved the use of regimes containing high dose steroids in most patients. Conclusions: Our data suggest that renal failure and dialysis dependence can be avoided or is reversible in a large number of newly diagnosed and relapsed myeloma patients. This study of an unselected group of patients receiving current therapy provides an important baseline against which to compare the effect of approaches involving the newer biological agents.

Successful Treatment with Bortezomib in Combination with Bendamustine and Prednisone of Patients with Newly Diagnosed/Untreated Multiple Myeloma and Light Chain Induced Renal Failure

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2938-2938
Author(s):  
Wolfram Pönisch ◽  
Marc Andrea ◽  
Ina Wagner ◽  
Doreen Hammerschmidt ◽  
Ute Kreibich ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Research Funding ◽  
Cross Resistance ◽  
Newly Diagnosed ◽  
Myeloma Protein ◽  
Increased Risk ◽  
Grade 3

Abstract Abstract 2938 Introduction: Renal impairment is one of the most severe complications of Multiple Myeloma (MM) at diagnosis. 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 up to 25%. The window of opportunity to reverse renal impairment is rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as Bendamustine have turned out to be effective, rapid action drugs in the treatment of MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks of DNA, and shows only partial cross resistance with other alkylating drugs. Methods: Between June 2006 and May 2011, 18 patients (median age 69; range 43 – 86 years) with newly diagnosed/untreated MM and renal insufficiency (creatinine clearance < 35 ml/min) were treated with Bendamustine 60 mg/qm day 1 and 2, Prednisone 100 mg on day 1, 2, 4, 8 and 11, and Bortezomib 1.3 mg/qm on day 1, 4, 8 and 11 (BPV). Cycles were repeated every 21 days up to the stage of maximum response or disease progression. MM response was assessed using IMWG criteria modified to include near complete response (nCR) and minimal response (MR). Eight patients were on dialysis at the time of diagnosis. Results: Fifteen patients (83%) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow up of 17 months, PFS at 12 months was 57 % and OS was 61 %. The median number of the BPV-treatment cycles was 2 (1–5) cycles. The myeloma protein decreased rapidly, reaching the best response after the first cycle in 4 patients and after the second cycle in a further 7. Six patients showed a complete remission of the kidney function (creatinine clearance > 60 ml/min) and in seven patients a partial remission (creatinine clearance > 30 ml/min) was attained. Transient grade 3 – 4 neutropenia was reported in one patient, and grade 3 – 4 thrombocytopenia occurred in 6 patients. One patient experienced a new grade 3 polyneuropathy. Summary: These results indicate that the combination of Bortezomib, Bendamustine and Prednisone is effective and tolerated in patients with newly diagnosed/untreated MM and renal failure. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3961-3961
Author(s):  
Meletios A Dimopoulos ◽  
Maria Roussou ◽  
Maria Gkotzamanidou ◽  
Erasmia Psimenou ◽  
Despoina Mparmparoussi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Multivariate Analysis ◽  
Renal Impairment ◽  
Median Time ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Group B

Abstract Abstract 3961 Renal 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.

Improvement in Renal Function and Its Impact on Survival in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3368-3368
Author(s):  
Wilson I Gonsalves ◽  
Nelson Leung ◽  
S. Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
High Risk ◽  
Renal Impairment ◽  
Induction Therapy ◽  
Response To Therapy ◽  
Older Age ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Novel Agent

Abstract Background: Renal impairment is a common feature of multiple myeloma (MM) seen in over a quarter of newly diagnosed patients (pts). Studies have confirmed the presence of renal impairment (RI) as a strong predictor of inferior survival in MM. Some studies have also indicated that reversibility of RI is associated with improved survival. However, it is not clear if normalization of renal function improves the outcome to that expected for MM pts without RI at diagnosis. Methods: We evaluated 1,135 consecutive pts with newly diagnosed MM seen at the Mayo Clinic, Rochester between December 2002 and January 2011. Renal function was assessed by the estimated creatinine clearance (CrCl) which was calculated by the modified MDRD formula. We examined these pts for improvement in renal function based on their CrCl at diagnosis and their highest CrCl during their disease course. RI was defined as having a CrCl of < 60. Pts were categorized based on their renal function at diagnosis and response to therapy: Group 1- CrCl >60 at diagnosis, Group 2- CrCl <60 at diagnosis but improved to >60 after therapy and Group 3- CrCl <60 at diagnosis and remained <60 after therapy. The degree of restoration of renal function was evaluated according to the IMWG criteria. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: The median age at diagnosis was 65 years (range; 22 - 93) and 682 (60%) were male. The median follow up for the entire group from diagnosis was 73 mos (95% CI; 69 - 77). At diagnosis, 123 (11%) pts had a CrCl < 30, 322 (28%) had a CrCl of 30-59 and 690 (61%) had a CrCl >60. Most pts (N=754, 67%) received novel agent induction (NAI) therapy. The median PCLI was 0.7 (range: 0 – 22) and 91 (21%) pts had high-risk cytogenetics by FISH. The median OS for the pts with CrCl at diagnosis of < 30, 30-59 and >60 were 41 mos, 60 mos and not reached respectively (P < 0.001). Of the 445 patients with RI, the median absolute creatinine and CrCl at diagnosis were 1.6 mg/dL (range: 1 – 11) and 44 (range: 4 – 59) respectively. Among pts with RI, any improvement in CrCl was seen in 295 (66%) with median time to highest CrCl of 5 months and 228 (51%) had complete reversal of their RI. The median OS for pts with RI at diagnosis receiving and not receiving NAI therapy was not reached (NR) vs. 46 mos (P < 0.001). The median OS for Groups 1, 2 and 3 were NR, 60 and 49 mos respectively (Figure 1, P < 0.001). At a 6 month landmark analysis, the median OS for Groups 1, 2 and 3 were NR, 67 and 62 mos respectively (P < 0.001). The complete renal response and no renal response rates for pts with RI at diagnosis receiving and not receiving NAI induction therapy was (57% vs. 44%, P=0.004) and (29% vs. 39%, P=0.04) respectively. In a univariable analysis, presence of RI at diagnosis, no NAI therapy, older age, ISS stage 3, high-risk FISH, elevated PCLI, diagnosis prior to 2007 and increased LDH were found to predict for worse OS; however only older age (P<0.001), high-risk FISH (P=0.037) and lack of NAI therapy (P=0.023) retained their negative prognostic significance in a multivariable analysis. Conclusion: MM pts with RI treated with novel agent induction therapy demonstrate improved responses in their renal function and OS. The results also demonstrate improved outcome for pts with improvement in renal function, but it remains inferior to pts with normal renal function at diagnosis. These results have implications for early treatment strategies for pts at risk of developing renal insufficiency. Figure 1: OS based on improvement in CrCl upon receiving treatment Figure 1:. OS based on improvement in CrCl upon receiving treatment Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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.

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.

scholarly journals Randomized Trial Comparing Pomalidomide, Bortezomib, and Dexamethasone (PVd) Versus Bortezomib and Dexamethasone（Vd） in NDMM with Renal Impairment（RI）

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1660-1660
Author(s):  
Jian Hou
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Group Performance ◽  
Conflicts Of Interest ◽  
Eastern Cooperative Oncology Group ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Renal Response

Abstract Background: RI is one of the most common complications of multiple myeloma (MM). The incidence of RI at diagnosis ranges from 20% to 50%, Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI, and the addition of a third drug to Vd seems to be beneficial，but not for sure. Pomalidomide is extensively metabolized by liver, with only approximately 2% of active substance eliminated in the urine, which suggests that RI may not affect pomalidomide exposure in a clinically relevant manner. The MM013(phase 2, NCT02045017) trial confirmed that Pomalidomide could be safely used in RRMM with RI and achieved good response in MM and Renal function. The OPTIMISMM (phase 3, NCT01734928) trial Subgroup analysis reported efficacy and safety of PVd vs Vd at first relapse by renal function (creatinine clearance [CrCl] &lt; 60 vs ≥ 60 mL/min) before. The ORR significantly improved with PVd vs Vd regardless of renal status (P &lt; .001 for both renal groups): 91.4% vs 53.6% (≥ VGPR,54.3% vs 21.4%) in the CrCl &lt; 60 mL/min group and 89.5% vs 55.2% (≥ VGPR, 64.5% vs 23.0%) in the CrCl ≥ 60 mL/min group. Since RVd is the standard treatment for NDMM patients, We believe that standard dose Pomalidomide plus Vd will be very promising for NDMM patients with RI Study Design/ Methods: This is a multicenter, prospective, randomized phase 2 study designed to evaluate the efficacy and safety of PVd Versus Vd in Patients With NDMM and Renal Impairment（RI）. Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had no prior antimyeloma regimen. The definition of RI is based on reduced creatinine clearance (15 mL/min≤CrCl＜60 mL/min) without indication for hemodialysis, which have to be the result of myeloma. Key exclusion criteria included previous course of chemotherapy; uncontrolled malignant disorder, infection, or peripheral neuropathy, patients on dialysis will be excluded too. Approximately 79 patients will be randomized 2:1(Figure 1) to Arm A (PVd) or Arm B (Vd), both Arms will have induction therapy for 4 cycles. In Arm A, patients will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of each cycle. Dexamethasone 20mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (21-day cycles); In Arm B, patients will receive the same bortezomib and dexamethasone as Arm A. The primary endpoint is ≥VGPR, the secondary endpoints are MRD(-) rate,renal response,Immune function,Renal tubular function, and safety. Myeloma response and renal response will be assessed by the International Myeloma Working Group criteria after each cycle. Eficacy analyses will be performed on the intent-to-treat population; Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 8 sites in China. Disclosure：Research Sponsor : CHIATAI TIANQING PHARMACEUTICAL GROUP. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Pomalidomide which was approved in RRMM will be used in NDMM with RI

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.

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