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Renal failure in multiple myeloma: A medical emergency
Abstract and Figures
Up to 50% of newly diagnosed plasma cell myeloma (PCM) patients can present with renal insufficiency, 20% with severe renal impairment and 10% requiring dialysis. PCM patients account for 2% of the dialysis population, adding 5000 new patients each year worldwide. Dialysis-dependent PCM patients have a 2.77 higher risk of death compared with other dialysis-dependent patients without this diagnosis. Renal failure and especially dialysis dependency is an independent poor prognostic factor in PCM, with the majority unable to achieve dialysis independence. Renal failure in PCM is a medical emergency with the need for rapid accurate diagnosis and prompt institution of supportive care and PCM-directed therapy, because reversal of renal impairment and recovery from dialysis dependency can occur in up to half the patients early in the course of disease and can lead to enormous survival benefits. Recently, the serum free light chain (SFLC) assay and serum β-2-microglobulin free heavy chain (SFHC) assay have been used to rapidly diagnose PCM in renal failure and provide prognostic information in the setting of renal failure where the Durie-Salmon and International Staging Systems do not. A renal biopsy early in the course of renal impairment can provide diagnostic and prognostic information. A new generation of dialyzers with larger pores than routine dialyzers can be used with extended hemodialysis to remove SFLC more efficiently than plasmapheresis, allowing for greater renal recovery. Novel chemotherapy agents such as bortezomib are associated with an improved renal response and have moved to the front line of therapy. Successful use of high-dose therapy and autologous hematopoietic cell transplantation (HCT) in PCM with renal failure and even dialysis dependency has been associated with late renal recovery and also allowed for the subsequent use of renal transplantation to provide even greater survival benefits. Combined non-myeloablative allogeneic HCT with renal transplant in PCM patients with end-stage renal disease on dialysis is now being studied in prospective trials.
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... Renal failure is one of the most common and most serious complications of MM that is associated with high mortality [41,[69][70][71][72]. Renal impairment has been reported in 30-50% of patients with newly diagnosed MM, while renal failure occurs in 20-30% of MM patients. Additionally, renal impairment develops in 50% of patients with MM during the course of the disease, and approximately 5-10% of MM patients having renal failure at diagnosis are dialysis-dependent [34, 36, 37, [73][74][75]. Causes of renal dysfunction/failure in patients with MM include: light chain-induced proximal tubular damage, cast nephropathy, interstitial nephritis, dehydration, hypercalcemia, hyperuricemia, amyloid deposition, plasma cell infiltration, hyperviscosity, various infections, nephrotoxic drugs, and contrast media [36,37,72,76]. The modalities of treatment of renal dysfunction/failure in MM patients include: hydration, treatment of infectious complications, withholding nephrotoxic drugs and contrast media, renal replacement therapy such as hemodialysis, removal of serumfree light chains by plasma exchange, use of high cut-off dialyzers, administration of anti-myeloma chemotherapy, HSCT for patients with controlled disease, and renal transplantation [37,71,[75][76][77]. ...
... Causes of renal dysfunction/failure in patients with MM include: light chain-induced proximal tubular damage, cast nephropathy, interstitial nephritis, dehydration, hypercalcemia, hyperuricemia, amyloid deposition, plasma cell infiltration, hyperviscosity, various infections, nephrotoxic drugs, and contrast media [36,37,72,76]. The modalities of treatment of renal dysfunction/failure in MM patients include: hydration, treatment of infectious complications, withholding nephrotoxic drugs and contrast media, renal replacement therapy such as hemodialysis, removal of serumfree light chains by plasma exchange, use of high cut-off dialyzers, administration of anti-myeloma chemotherapy, HSCT for patients with controlled disease, and renal transplantation [37,71,[75][76][77]. ...
... In patients with MM having dialysis-dependent renal failure, the use of induction therapy with novel agents and high cut-off dialyzers has resulted in an improvement of renal function due to the removal of large quantities of serumfree light chains [37, 75,77]. Factors associated with a high probability of dialysis independence in patients with newly diagnosed MM having dialysis-dependent renal failure include: shorter duration of kidney disease, achieving at least very good partial response (VGPR), low beta 2 microglobulin at diagnosis, and low level of free light chains at diagnosis [70]. ...
Over the past two decades, treatment of multiple myeloma (MM) has advanced dramatically. However, despite the introduction of several lines of novel therapeutics, autologous hematopoietic stem cell transplantation (HSCT) followed by maintenance therapy is the current standard of care in transplant eligible patients. Autologous HSCT can be performed with or without cryopreservation with equivalent short-term and long-term outcomes. In patients with MM, performance of autologous HSCT at outpatient setting is safe, feasible and has a number of advantages such as saving hospital beds and reducing treatment costs. Autologous HSCT can be safely performed in patients with MM having renal dysfunction or failure although particular attention should be made to the timing of administering medications and stem cells with respect to hemodialysis and dose reduction of specific medications according to creatinine clearance. Tandem autologous HSCT is of value in younger patients with adverse cytogenetics and extramedullary disease. Allogeneic HSCT is the only potentially curative therapeutic modality in MM, but it can only be performed in a small fraction of highly selected patients due to the relatively high treatment-related morbidity and mortality. Despite its valuable role in the treatment of MM, autologous HSCT has its own short-term as well as long-term complications.
... The nephrotoxicity of the LCs is determined by the degree of their self-aggregation and the decreased lysosomal degradation in the proximal tubular cells; therefore, their nephrotoxic potential is not always dependent on their concentration [17]. Common non-LC-related causes of RI in MM include hypercalcemia (the second most common cause of RF in MM after cast nephropathy), infections, hypovolemia (often associated with hypercalcemia), use of nephrotoxic drugs, use of contrast media, and renal amyloidosis [13,14]. ...
... Almost all cases of myeloma kidney present with RF, and about two-thirds of the cases develop proteinuria [12]. Other manifestations of MM cast nephropathy are nephrogenic diabetes insipidus and rarely acquired adult Fanconi syndrome [13]. Normally, the excess serum free light chain (SFLC) gets filtered through the glomerulus and, on reaching the proximal tubule of the nephron, binds to the multiligand receptors including cubilin and megalin; after that, the formed complex gets endocytosed by the clathrin-dependent endosomal-lysosomal pathway in the proximal tubule cells [22][23][24]. ...
... In addition, the overwhelmed endocytosis of LCs activates various proinflammatory cytokines and, through different mediators, causes interstitial fibrosis [26]. All these changes are seen on renal biopsy as a triad of injury in the proximal tubules, hard waxy casts in the distal tubules and interstitial inflammation and fibrosis ( Figure 1) [13]. Myeloma cast nephropathy is associated with an exceptionally poor prognosis for both renal and overall survival (OS) [12]. ...
Multiple myeloma (MM) is the second most common hematologic malignancy that involves monoclonal immunoglobulin (Ig)-producing plasma cells. Due to its multifaceted clinical manifestations and complications, it draws attention to various medical specialties like neurology, nephrology, orthopedics, cardiology, etc. Renal failure (RF) is one of the most common and most serious complications of MM that can be caused either by excess immunoglobulins that are nephrotoxic or some other causes like hypercalcemia, infection, etc. In this review article, we have discussed the pathogenesis of RF in MM, described the different diagnostic tools to diagnose RF in MM, and explained different treatment modalities to treat RF in MM, including certain general measures (i.e., hydration, withholding any nephrotoxic agents), renal replacement therapy, serum free light chain (SFLC) removal by plasma exchange and high cut-off dialyzer (HCO-HD), chemotherapy, hematopoietic stem cell transplantation (HSCT), and renal transplantation.
... Interestingly, treatment with ketoconazole and fluconazole is used in Cushing's syndrome in order to reduce the high glucocorticoid hormone levels associated with this pathology [81]. In this context, renal failure is critical because concomitant treatment with anticancer agents in these patients becomes more toxic for individuals with lower renal clearance [84]. The effect of hormonal imbalance generated by adrenal insufficiency conditions the individual to an immunosuppressed state, mainly affecting populations of cytotoxic T lymphocytes such as the natural killer cells, which directly corroborates the impairment of antitumor immunity [85]. ...
Invasive fungal infections (IFI) are responsible for a large number of annual deaths. Most cases are closely related to patients in a state of immunosuppression, as is the case of patients undergoing chemotherapy. Cancer patients are severely affected by the worrisome proportions that an IFI can take during cancer progression, especially in an already immunologically and metabolically impaired patient. There is scarce knowledge about strategies to mitigate cancer progression in these cases, beyond conventional treatment with antifungal drugs with a narrow therapeutic range. However, in recent years, ample evidence has surfaced describing the possible interferences that IFI may have both on the progression of pre-existing cancers and in the induction of newly transformed cells. The leading gambit for modulation of tumor progression comes from the ability of fungal virulence factors to modulate the host's immune system, since they are found in considerable concentrations in the tumor microenvironment during infection. In this context, cryptococcosis is of particular concern, since the main virulence factor of the pathogenic yeast is its polysaccharide capsule, which carries constituents with high immunomodulatory properties and cytotoxic potential. Therefore, we open a discussion on what has already been described regarding the progression of cryptococcosis in the context of cancer progression, and the possible implications that fungal glycan structures may take in both cancer development and progression.
... Sudden renal impairment (acute kidney injury) is a type of disorder which is relatively common feature of multiple myeloma (MM) and it should be treated as a medical emergency. 1 Renal diseases in multiple myeloma may responsible for various factors. In minor cases, the renal function can be recovered easily with infusion solution and serum calcium level correction but sometime the condition may become worse such as acute kidney injury and progressive CKD. 2 Due to invention of modern anti-myeloma therapy, the survival rate of myeloma patients with renal impairment has significantly improved. ...
Multiple myeloma (MM) is a type of cancer occurs due to malignant plasma cell that affects with various clinical manifestations including renal impairment, anemia, bone disease and infection. The most common renal presentation of multiple myeloma is myeloma cast nephropathy. We described a case of multiple myeloma along with renal impairment in a 62-year old male patient. His serum B2-Microglobulin was 19.18 mg/L, which is much higher than reference value. His serum creatinine was 2.58 mg/dL. After continuing medication, the patient’s renal function was restored. This case is being reported for clinical knowledge dissemination and building clinical insight. CBMJ 2023 January: Vol. 12 No. 01 P: 111-114
... L'incidenza annuale stimata in Europa è di circa 3-4 nuovi casi su 100.000 abitanti;di questi, il 50 % si presenta con un danno renale di entità variabile all'esordio, con un 20% di danno renale grave (creatinina sierica >2 mg/dl). Il 10% dei pazienti con manifestazioni renali necessita di trattamento sostitutivo emodialitico già al momento della diagnosi [4]. L'insorgenza della patologia è rara nei giovani adulti e l'età media alla diagnosi è di circa 66 anni [5]. ...
... Substantial FLCs (nephrotoxic proteins) accumulated in the proximal tubular epithelium are responsible for most tubulointerstitial injuries. Monoclonal light chains in renal tubules stimulate the production of some proinflammatory cytokines, including macrophage chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), which subsequently, rapidly leads to renal tubulointerstitial fibrosis [11,12]. Light chain proteins can also cause glomerular function impairment when deposited on the glomerular basement membrane (GBM) and mesangial area [13]. ...
Objectives: Bone destruction and renal impairment are two frequent complications of multiple myeloma (MM). Cystatin C, an extracellular cysteine proteinase inhibitor, is encoded by the housekeeping gene CST3 and associated with human tumors. The role of cystatin C in multiple myeloma has been revealed recently. The purpose of this study was to explore the role of cystatin C as a proteasome inhibitor in multiple myeloma. Methods: A comprehensive literature review was conducted through Pubmed to summarize the published evidence on cystatin C in multiple myeloma. English literature sources since 1999 were searched, using the terms cystatin C, multiple myeloma. Results: cystatin C is a sensitive indicator for the diagnosis of myeloma nephropathy and has a dual role in myeloma bone disease. Also, cystatin C reflects tumor burden and is strongly associated with prognosis in patients with multiple myeloma. Conclusion: Cystatin C have great diagnostic and prognostic value in multiple myeloma. It can provide a new treatment direction for MM by designing and searching for antagonists of cystatin C or cysteine protease agonists using cystatin C as a therapeutic target.
... However, in our data 36.5% patients with IgG MM and 68.8% patients with IgA MM in the renal involvement group presented with renal failure, indicating that the development of renal failure is not dependent solely on the concentration of light chains. Wirk B et al. [24] reported that patients with large amounts of serum free light chains can have normal renal function, and patients with small concentrations of serum free light chains can present with renal failure. IgD and IgE overproduction is rare in MM. ...
Background . Renal involvement is a common complication of multiple myeloma (MM). However, most studies have focused on renal failure in MM, and little information is available about the other renal manifestations in MM and their association with immunophenotypes and renal pathology. Methods . We retrospectively analyzed the clinical, laboratory and pathology data of 283 MM patients treated in Sichuan Provincial People’s Hospital, West China, between January 1990 and May 2017. The patients were divided into a renal involvement group (n = 200) and a non-renal involvement group (n = 83). Results. In the renal involvement group, 90 (45.0%) patients were diagnosed with MM in the Nephrology department, and isolated proteinuria, renal failure and nephrotic syndrome were detected in 90(45.0%), 94 (47.0%) and 58 (29.0%) patients, respectively. 135 patients with renal involvement underwent immunofixation electrophoresis, and IgG, IgA, IgD, IgE, pure light chain and nonsecretory MM were detected in 52 (38.5%), 32 (23.7%), 1 (0.7%), 1 (0.7%), 45(33.3%) and 4 (3.0%) patients, respectively. 47 patients without renal involvement also underwent immunofixation electrophoresis, and IgG and IgA MM were found in 24 (51.0%) and 18 (38.3%) patients, respectively. Severe anemia and hypertension, hypercalcemia and pure light chain were more frequent in patients with renal involvement (P
... However, in our data 36.5% patients with IgG MM and 68.8% patients with IgA MM in the renal involvement group presented with renal failure, indicating that the development of renal failure is not dependent solely on the concentration of light chains. Wirk B et al. [24] reported that patients with large amounts of serum free light chains can have normal renal function, and patients with small concentrations of serum free light chains can present with renal failure. IgD and IgE overproduction is rare in MM. ...
Background Renal involvement is a common complication of multiple myeloma (MM). However, most studies have focused on renal failure in MM, and little information is available about the other renal manifestations in MM and their association with immunophenotypes and renal pathology. Methods We retrospectively analyzed the clinical, laboratory and pathology data of 283 MM patients treated in Sichuan Provincial People’s Hospital, West China, between January 1990 and May 2017. The patients were divided into a renal involvement group (n = 200) and a non-renal involvement group (n = 83). Results In the renal involvement group, 90 (45.0%) patients were diagnosed with MM in the Nephrology department, and isolated proteinuria, renal failure and nephrotic syndrome were detected in 90(45.0%), 94 (47.0%) and 53 (27.0%) patients, respectively. 135 patients with renal involvement underwent immunofixation electrophoresis, and IgG, IgA, IgD, IgE, pure light chain and nonsecretory MM were detected in 52 (38.5%), 32 (23.7%), 1 (0.7%), 1 (0.7%), 45(33.3%) and 4 (3.0%) patients, respectively. 47 patients without renal involvement also underwent immunofixation electrophoresis, and IgG and IgA MM were found in 24 (51.0%) and 18 (38.3%) patients, respectively. Severe anemia and hypertension, hypercalcemia and pure light chain disease were more frequent in patients with renal involvement (P
Background
Acute Kidney Injury (AKI) in patients with multiple myeloma (MM) requiring renal replacement treatment (RRT) is associated with high morbidity and mortality. Early reduction of serum free light chains (FLC) using both targeted therapy against MM and intensive hemodialysis (IHD) may improve renal outcomes. We evaluated the effectiveness of two different RRT techniques on renal recovery in a MM patient population: standard dialysis procedure versus IHD with either PMMA or hemodiafiltration with endogenous reinfusion (HFR).
Methods
Multicentric retrospective study with severe AKI related to MM, between 2011 and 2018. Twenty-five consecutive patients with AKI secondary of MM requiring RRT were included. Patients that underwent IHD received 6 dialysis sessions per week during the first 14 days (PMMA vs HFR). All patients were diagnosed with de novo MM or first relapsed MM. Primary outcome was renal recovery defined as dialysis-free at six months follow-up.
Results
A total of 25 patients were included. Seventeen patients received IHD and 8 standard dialysis. All patients were treated with targeted therapy, 84% bortezomib-based. Of the 25 patients included, fourteen (56%) became dialysis independent. We observed a higher proportion of patients who received IHD in the group who recovered kidney function compared to those who remained in HD (92.9% vs 36.4%, p:0.007). In our study, the use of IHD to remove FLC had a statistically significant association with renal recovery compared to standard dialysis group (p = 0.024).
Conclusion
Early reduction of FLC with IHD as an adjuvant treatment along with MM targeted therapy may exert a positive impact on renal recovery.
Renal failure is a serious complication of multiple myeloma, and up to 50% of patients with this most frequent haematological malignancy may develop some form of renal impairment. The aetiology of renal damage is multifactorial, but increased production of free light chains that are filtered into the urine is crucial for the development of renal failure and could be associated with distal tubule involvement (myeloma kidney, light chain cast nephropathy) or with fully developed Fanconi syndrome in proximal tubule damage (proximal tubulopathy, light chain proximal tubulopathy). Glomerular damage most often manifests as AL amyloidosis or light chain deposition disease; both cause severe nephrotic syndrome. Early and adequate chemotherapy in association with symptomatic treatment can lead to rapid reduction of serum light chain concentration which is necessary to prevent development of renal failure. At present, effective therapeutic procedures can be used for this purpose, where especially a triple combination of treatment containing one of the proteasome inhibitors (bortezomib, carfilzomib or ixazomib) is able to elicit a haematological response within a few days. If there is a good haematological response to treatment, up to 50% of patients with renal failure will restore their renal function. Renal function repair can be accelerated by removing light chains from serum by dialysis with high-cutoff membrane (HCO-HD). Using this procedure can increase the chance of dialysis independence in more than 60% of patients with renal failure. Data from previously published studies on HCO-HD (MYRE or EuLITE study) have not yielded as optimistic results as originally expected, however, HCO-HD could be beneficial for some subgroup of patients with renal failure in myeloma kidney. Despite the fact that overall prognosis and survival of patients with multiple myeloma have dramatically improved, the condition with renal failure in these patients remains serious.
Background: The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors.
Methods: We used an automated immunoassay for FLCs and sera from a population 21–90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal κ and λ FLCs in the sera of patients with monoclonal gammopathies.
Results: Serum κ and λ FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of κ FLC to λ FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26–1.65. The 95% reference interval for κ FLC was 3.3–19.4 mg/L, and that for λ FLC was 5.7–26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease.
Conclusions: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.
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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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.
Tubular NF-κB and AP-1 activation in human proteinuric renal disease.Background
Nuclear factor-κB (NF-κB) and activated protein-1 (AP-1) are transcription factors that regulate many genes involved in the progression of renal disease. Recent data have shown that NF-κB is activated in tubules and glomeruli in various experimental models of renal injury. In vitro studies also suggest that proteinuria could be an important NF-κB activator. We therefore approached the idea that NF-κB may be an indicator of renal damage progression.Methods
Paraffin-embedded renal biopsy specimens from 34 patients with intense proteinuria [14 with minimal change disease (MCD) and 20 with idiopathic membranous nephropathy (MN)] and from 7 patients with minimal or no proteinuria (IgA nephropathy) were studied by Southwestern histochemistry for the in situ detection of activated transcription factors NF-κB and AP-1. In addition, by immunohistochemistry, we performed staining for the NF-κB subunits (p50 and p65) and AP-1 subunits (c-fos, c-jun). By immunohistochemistry and/or in situ hybridization, the expression of some chemokines [monocyte chemoattractant protein-1 (MCP-1), RANTES, osteopontin (OPN)] and profibrogenic cytokines [transforming growth factor-β (TGF-β)], whose genes are regulated by NF-κB and/or AP-1, were studied further.ResultsNF-κB was detected mainly in the tubules of proteinuric patients, but rarely in nonproteinuric IgA nephropathy (IgAN) patients. In addition, there was a significant relationship between the intensity of proteinuria and NF-κB activation in MCD (r = 0.64, P = 0.01) and MN patients (r = 0.64, P < 0.01). Unexpectedly, patients with MCD had a significantly higher NF-κB tubular activation than those with MN (P < 0.01). To assess whether there was a different composition of NF-κB protein components, immunostaining was performed for the NF-κB subunits p50 and p65. However, no differences were noted between MCD and MN patients. In those patients, there was a lower tubular activation of AP-1 compared with NF-κB. Moreover, a strong correlation in the expression of both transcription factors was observed only in MN (r = 0.7, P = 0.004). Patients with progressive MN had an overexpression of MCP-1, RANTES, OPN, and TGF-β, mainly in the proximal tubules, while no significant expression was found in MCD patients.Conclusions
On the whole, our results show that a tubular overactivation of NF-κB and AP-1 and a simultaneous up-regulation of certain proinflammatory and profibrogenic genes are markers of progressive renal disease in humans. Increased activation of solely NF-κB and/or AP-1 may merely indicate the response of tubular renal cells to injury.
Renal impairment (RI) is a severe complication throughout the course of multiple myeloma (MM). Bortezomib has been shown to be highly active in MM patients with RI. We designed this retrospective analysis to investigate the safety and efficacy of bortezomib-based therapy in 117 MM patients with RI, 14 cases required dialysis. A total of 603 cycles of bortezomib were administered (median number, five cycles/patient). Ten patients required early discontinuation of bortezomib because of WHO grade IV toxicity. The rate of bortezomib discontinuation in cases with severe, moderate and mild RI was 11%, 5% and 0%, respectively (P = NS). Overall, 91 episodes of WHO grade III/IV toxicity were observed. At least a partial response was documented in 83/113 evaluable patients (73%), including complete response (19%) and near complete response (8%). The overall response rate was similar across RI subgroups. Reversal of RI was documented in 41% of patients after a median of 2.3 months (range 0.4–7.9). In three of 14 patients on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months. The 2-yr estimate of response duration and overall survival was 70% and 51%, respectively. In conclusion, bortezomib-based regimens are safe and effective and should be considered as appropriate treatment options for MM patients with any degree of RI.
The purpose of the present study was to analyse the importance and prognostic value of renal failure in multiple myeloma patients. The frequency and reversibility of renal failure in 775 multiple myeloma patients diagnosed between 1984–86 and 1990–92 in the Nordic countries were studied. Renal failure, defined as plasma creatinine >130μmol/l, was observed in 29% of the cases at the time of diagnosis. During the first year after diagnosis 58% achieved normalisation of p-creatinine, and this was achieved mainly during the first 3 months. Reversibility of renal failure was more frequently observed in patients with moderate renal failure, hypercalcaemia and low Bence-Jones protein excretion. In a multivariate analysis renal failure, high age, stage III disease and hypercalcaemia were independent prognostic factors for survival. Patients who needed dialysis had a poor prognosis, with a median survival of 3.5 months. A 12-months landmark analysis showed that reversibility of renal failure was a more important prognostic factor than response to chemotherapy. It is concluded that renal failure in multiple myeloma is reversible in about half the cases, and reversibility of renal failure improves long-term survival.
Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176·8 μmol/l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29–69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone (n = 51) or chemotherapy plus G-CSF (n = 27), yielding medians of 10 and 16 × 106 CD34+ cells/kg respectively (P = 0·003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL-200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL-140). Thirty-one patients (38%) completed tandem auto-SCT, including 11 on dialysis. Treatment-related mortality (TRM) was 6% and 13% after the first and second auto-SCT. Median times to absolute neutrophil count (ANC) > 0·5 × 109/l and to platelets > 50 × 109/l were 11 and 41 d respectively. Non-haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event-free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL-140 had an acceptable toxicity and appeared equally effective as MEL-200. In the setting of renal failure, the role of auto-SCT early in the disease course and benefits of tandem SCT require further evaluation.