The Use of Novel Drugs Can Effectively Improve Response, Delay Relapse and Enhance Overall Survival in Multiple Myeloma Patients with Renal Impairment

Uttervall, Katarina; Duru, Adil Doğanay; Lund, Johan; Liwing, Johan; Gahrton, Gösta; Holmberg, Erik; Aschan, J; Alici, Evren; Nahi, Hareth

doi:10.1371/journal.pone.0101819

Cited by 52 publications

(41 citation statements)

References 26 publications

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“…The survival of patients with RI who were treated with bortezomib-based chemotherapy (60 months) was better than survival of those who received conventional agents (27 months) [20]. Mayo Clinic investigators reported a complete renal response rate in a higher proportion of patients treated with novel agents compared to conventional treatment.…”

Section: The Relationship Between Renal Function and Survival In MMmentioning

confidence: 99%

Current Trends of Renal Impairment in Multiple Myeloma

2015

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Background: Renal impairment (RI) is a common complication of multiple myeloma (MM). Around 50% of patients with MM have RI at presentation, and up to 5% require dialysis treatment. Severe acute kidney injury (AKI) as a cause of RI is a particular challenge as historically the survival of patients who sustain this complication and require dialysis is very poor. However, in this current period, survival is improving and the focus is on optimum use of novel chemotherapies and the evaluation of extra-corporeal therapies for removal of serum immunoglobulin light chains. Summary: RI in patients with MM is commonly associated with excess monoclonal free light chain (FLC) production; myeloma cast nephropathy is the predominant renal pathology in patients presenting with severe RI secondary to AKI. The majority of patients have mild to moderate RI and recover renal function. However, patients with more severe RI, in particular those with a requirement for dialysis, are less likely to recover renal function. Rapid diagnosis and prompt institution of anti-myeloma therapy is an important determinant of renal function recovery, through targeting early and sustained reduction of involved monoclonal FLC. Novel agents are associated with excellent disease response, and bortezomib is now widely used as a first-line agent in the management of MM in patients with severe RI. Extended haemodialysis using high cut-off dialysers is more effective for extracorporeal removal of FLC than plasma exchange, and clinical trials are in process. High-dose chemotherapy with autologous stem cell transplantation does have a role in patients with severe RI but requires careful patient selection. Key Messages: RI is very common in patients with MM, and renal function recovery is associated with improved clinical outcomes. We summarise the epidemiology of MM in the UK, present the impact of RI and renal function recovery on patient outcome, and describe the current management of MM in western countries. Facts from East and West: (1) A serum creatinine level >2 mg/dl has been reported in 16, 21, 24, and 33% of patients with MM in cohort studies from Japan, Europe, China, and Korea, respectively. A creatinine clearance rate <30 ml/min was observed in 30 and 15% of patients in Chinese and Western MM cohorts, respectively. The commonest cause of severe RI in patients with MM is myeloma cast nephropathy. (2) The efficacy of novel treatments (bortezomib, carfilzomib, thalidomide, and lenalidomide) has predominantly been assessed in Western patients. Bortezomib and dexamethasone are the current standard of care for MM and severe RI in the West. Severe RI is not a contraindication to autologous stem cell transplantation (ASCT). Most of the data are from the West; there are case reports from China describing good outcomes with ASCT. The removal of FLC by high-cut-off hemodialysis is under evaluation in randomized controlled trials (RCTs) in the West. Studies in this area are not yet conducted in China. In China, new treatments, such as bortezomib, are more w...

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Section: The Relationship Between Renal Function and Survival In MMmentioning

confidence: 99%

Current Trends of Renal Impairment in Multiple Myeloma

2015

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“…3 Renal impairment in patients with MM is associated with shortened survival, but recovery of renal function during treatment may improve survival in these patients and even achieve similar outcomes in patients with a history of normal renal function. 3,4,7 The past several decades have seen advances in the treatment of MM, and outcomes have improved for patients with varying degrees of renal impairment; 3,8 despite this, most patients will ultimately relapse. 9,10 Control of MM via effective therapy has been shown to improve renal function in a large proportion of patients.…”

Section: Introductionmentioning

confidence: 99%

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

Weisel

Dimopoulos

Moreau³

et al. 2016

Haematologica

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Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 -< 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 -< 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. Analysis of renal impairment in MM-

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“…Previous retrospective studies have indicated that a second ASCT is beneficial at relapse, at least if relapse occurs later than 18 months from initial treatment. 11 However, the development of novel drugs, for example, PI and IMiDs 1,[12][13][14][15] have raised the question if a second ASCT could be replaced by these drugs in second line. [16][17][18] A recent prospective study has shown that HDT followed by ASCT is superior to a cyclophosphamide-based regimen but data are lacking for comparing the novel drugs to ASCT.…”

Section: Introductionmentioning

confidence: 99%

Autologous stem cell transplantation versus novel drugs or conventional chemotherapy for patients with relapsed multiple myeloma after previous ASCT

Grövdal

Nahi

Gahrton

et al. 2015

Bone Marrow Transplant

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High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common first-line treatment for patients with multiple myeloma (MM) under 65 years of age. A second ASCT at first relapse is frequently used but is challenged by the use of novel drugs. We retrospectively studied the outcome of second-line treatment in MM patients from the Nordic countries with relapse after first-line HDT and ASCT. Patients that underwent a second ASCT (n = 111) were compared with patients re-treated with conventional cytotoxic drugs only (n = 91) or with regimens including novel drugs (proteasome inhibitors and/or immunomodulatory drugs) (n = 362) without a second ASCT. For patients receiving a second ASCT median overall survival was 4.0 years compared with 3.3 years (P o 0.001) for the group treated with novel drugs and 2.5 years (P o 0.001) for those receiving conventional cytotoxic drugs only. A second ASCT also resulted in a significantly longer second time to progression and a significantly longer time to next treatment. We conclude that, irrespective of the addition of novel drugs, MM patients in first relapse after ASCT still appear to benefit from a second ASCT. A second ASCT should be considered for all physically fit patients.

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The Use of Novel Drugs Can Effectively Improve Response, Delay Relapse and Enhance Overall Survival in Multiple Myeloma Patients with Renal Impairment

Cited by 52 publications

References 26 publications

Current Trends of Renal Impairment in Multiple Myeloma

Current Trends of Renal Impairment in Multiple Myeloma

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

Autologous stem cell transplantation versus novel drugs or conventional chemotherapy for patients with relapsed multiple myeloma after previous ASCT

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