Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone

Abstract Introduction: Bortezomib (VELCADE®), a novel proteasome inhibitor, is currently approved for treatment of multiple myeloma (MM) patients in first relapse in the US and EU. At presentation, up to 50% of patients with MM have decreased creatinine clearance, and 20–30% have concomitant renal failure. Although bortezomib has been reported to be safe and effective in patients with renal insufficiency and creatinine clearance as low as 14 mL/min, there is currently little information on its use in patients with advanced renal failure requiring hemodialysis. We conducted a multicenter, retrospective review to investigate the safety and efficacy of bortezomib in renal failure patients requiring hemodialysis. Patients and Methods: Patients were identified by the treating physicians at the participating centers. MM patients with advanced renal failure with or without hemodialysis support who were treated with bortezomib or a bortezomib containing regimen were eligible. Patients had to be ≥ 18 years. Demographic data, dose of bortezomib, response (by EBMT criteria) and duration of response as well as available toxicity data were to be collected for a maximum of 30 patients. Results: Thus far, all data are available for 15 MM patients. The median age was 59 years (range 51–78) and 60% were male. The MM type was IgG in 7 patients, light chain disease in 5, IgA in 2, and IgD in 1. The MM subtype was kappa in 6 patients, lambda in 3, and not specified in 6. All patients had relapsed after a median of 2 prior therapies (range 1–5). All had advanced renal failure while 11 patients were receiving hemodialysis at the time of bortezomib administration. Bortezomib was given after hemodialysis in 10 patients; the timing was not specified in 1. One patient was not evaluable for response. Of the 14 evaluable patients, 2 (14%) achieved a complete response (CR), 1 (7%) had a near CR (nCR) and 2 (14%) had a partial response (PR) for an overall response rate of 36%. Five patients (36%) had stable disease and 4 (27%) had progressive disease. The response durations for the 2 patients achieving CR were 12+ and 17+ months, and for the patient with nCR was 9+ months. The duration of response for those with PR were 2 and 12+ months. One patient died due to progressive disease. One patient (7%) discontinued due to neuropathic pain at cycle 4, and 2 patients (14%) had doses held due to peripheral neuropathy, both at cycle 4. Bortezomib was otherwise generally well tolerated. One patient scheduled for hemodialysis achieved a CR with normalization of renal function without needing dialysis. Conclusion: Although there is no pharmacokinetic (PK) data available and the number of patients studied is relatively small, the information gathered from this study suggests that bortezomib can be given safely to patients with renal failure on hemodialysis who may benefit from this therapy. A formal prospective study with PK is warranted in this patient population to establish a comprehensive safety and efficacy profile and this is ongoing under the auspices of the NCI.

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

Blood ◽

10.1182/blood.v110.11.2739.2739 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2739-2739 ◽

Cited By ~ 2

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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Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study

Blood ◽

10.1182/blood-2006-09-046409 ◽

2006 ◽

Vol 109 (6) ◽

pp. 2604-2606 ◽

Cited By ~ 181

Author(s):

Asher A. Chanan-Khan ◽

Jonathan L. Kaufman ◽

Jayesh Mehta ◽

Paul G. Richardson ◽

Kena C. Miller ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Overall Response Rate ◽

Complete Response ◽

Significant Activity ◽

Retrospective Case ◽

Response Data ◽

Advanced Renal Failure ◽

Poor Outcomes ◽

The Impact

Abstract Patients with multiple myeloma (MM) frequently present with concomitant renal dysfunction, and those requiring dialysis have particularly poor outcomes. Bortezomib is a reversible proteasome inhibitor with significant activity in MM. This retrospective case analysis evaluated the feasibility and activity of bortezomib-based therapy in MM patients (n = 24) requiring dialysis support for advanced renal failure. All but 1 patient were undergoing dialysis at the time of therapy. Patients received bortezomib alone or bortezomib-based combination therapy. Among 20 patients with available response data, overall response rate (complete response [CR] + partial response) was 75%, with 30% CR + near CR. One patient was spared dialysis, and 3 other patients became independent of dialysis following bortezomib-based treatment. These encouraging results suggest that bortezomib or bortezomib-based regimens can be used in MM patients requiring dialysis, with manageable toxicities. Further studies will more formally evaluate the impact of bortezomib-based regimens in this patient population.

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Favorable kidney recovery by extracorporeal light chain removal and anti-myeloma treatments in patients with newly diagnosed multiple myeloma and acute renal failure

Saudi Journal of Kidney Diseases and Transplantation ◽

10.4103/1319-2442.308370 ◽

2020 ◽

Vol 31 (6) ◽

pp. 1445

Author(s):

Pasquale Niscola ◽

Giorgio Silvestrini ◽

Paola Tatangelo ◽

Laura Scaramucci ◽

Germana Sfara ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Acute Renal Failure ◽

Light Chain ◽

Newly Diagnosed

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Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents

Haematologica ◽

10.3324/haematol.10759 ◽

2007 ◽

Vol 92 (4) ◽

pp. 546-549 ◽

Cited By ~ 122

Author(s):

E. Kastritis ◽

A. Anagnostopoulos ◽

M. Roussou ◽

D. Gika ◽

C. Matsouka ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Novel Agents ◽

High Dose ◽

Newly Diagnosed ◽

High Dose Dexamethasone ◽

The Impact

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Bortezomib in treatment of a newly diagnosed multiple myeloma patient with renal failure

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2009.00603 ◽

2009 ◽

Vol 29 (5) ◽

pp. 603-604

Author(s):

Lie-Ping GUO ◽

Fan ZHOU ◽

Sheng-Ling YANG ◽

Wei WEI ◽

Yi-Zi ZHANG ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Newly Diagnosed ◽

Myeloma Patient ◽

Multiple Myeloma Patient

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

Blood ◽

10.1182/blood.v110.11.4847.4847 ◽

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.

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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 ◽

10.1182/blood.v118.21.2938.2938 ◽

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.

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