Multiple Myeloma Renal Impairment Research Articles

Limited Long-Term Benefit of Upfront Autologous Stem Cell Transplant on Survival in Severe Renal Impairment in Multiple Myeloma in Novel Drug Era, a Retrospective Multi-Center Study in China

Background Renal impairment (RI) is a common complication of multiple myeloma (MM) affecting approximately 20%-30% of the patients at diagnosis. The presence of severe RI is associated with an increased risk of early death and poor prognosis in myeloma. The impact of autologous stem cell transplant (ASCT) on outcome in severe RI patients remains controversial. Therefore, we performed a retrospective real-world analysis to clarify the effect of ASCT on the survival of MM patients with severe RI. Methods Clinical data of 337 MM patients with severe RI at diagnosis were collected from three centers in China from April 2004 to January 2020. Severe RI was defined as an increase creatinine ＞177 umol/L (or 2mg/L) or an estimated glomerular filtration rate ≤40 ml/min/1.73 m2 using the simplified modification of diet in renal disease (MDRD) formula. RI caused by other confirmed pathological diagnosis except for tubular nephropathy was excluded. We excluded patients underwent salvage ASCT (6 cases), patients older than 65 years (107 cases), and traditional introduction therapy (2 cases). At last, there were 232 cases for analysis, containing 59 cases received ASCT. All enrolled patients were treated with novel-agent introduction. Patients were divided into the ASCT group and the non-ASCT group. Hematological and renal response were assessed based on the International Myeloma Working Group (IMWG) criteria. Results The median age for all patients at diagnosis was 55 years old (range: 37-65 years old). 37% presented with free light chain myeloma. There were 4 patients underwent double-ASCT in the ASCT group. All dialysis patients in ASCT group were off dialysis after induction therapy. Baseline profiles between ASCT and non-ASCT group were matched in sex, M-protein isotype, ISS stage, and induction therapy. More patients were on dialysis at diagnosis in non-ASCT group (34.7% vs 19.3%, P=0.04). There were 59/159 patients presented unfavorable cytogenetic abnormality (del(17p), t(4;14), t(14;16)), including 40 cases (34.2%) in non-ASCT group and 19 cases (41.3%) in ASCT group (P=0.47). The 1q amplification presented 21.4% in non-ASCT group and 22.2% in ASCT group (P=0.56). In terms of hematological response, at least VGPR accounts for 88.1% in the ASCT group and 50.3% in the non-ASCT group (P<0.001). The overall renal response was significantly higher in the ASCT group than that in the non-ASCT group (94.9% vs 54.3%, P<0.001). There was the similar tendency for at least renal PR between ASCT and non-ASCT groups (88.1% vs 41.3%, P<0.001). The transplant-related mortality (within 3 months after ASCT) was 6.8%. Early mortality within 1 year was 6.7% in the ASCT group and 19.8% in the non-ASCT group (P=0.002). The median follow-up for all patients was 37.6 months (range: 1-157 months) and the median overall survival (OS) was 49.5 months (95% CI：42-57 months). In the ASCT group, the median OS was much longer than ASCT group (57.3 months vs 42.8 months, P =0.052). But there was no difference in PFS between the two groups (36.9 months vs 26.5 , p=0.348). As the log-rank test didn't hold the proportional hazards assumption, it would have low power. We use the two-stage landmark analysis to further determine the effect of ASCT on survival. In landmark analysis, 3-year PFS rate in ASCT group was significantly higher (54.0% vs 41.9%, P=0.024). Within 5-year follow-up, OS was significantly longer in the ASCT group than that in non-ASCT group (OR=0.61, 95%CI: 0.39-0.97, P=0.04). Beyond the 5-year time point, OS was similar between the two groups (OR=1.59, 95%CI: 0.60-4.20, P=0.35). In univariate analysis, at least renal MR, at least hematological VGPR, PLT＞100×109/L, and BMPC ≥60% were correlated with longer OS. In multivariate analysis, at least renal MR (HR=0.61, 95%CI: 0.39-0.96, P=0.031), at least hematological VGPR (HR=0.41, 95%CI: 0.27-0.63, P<0.001), and PLT＞100×109/L (HR=0.43, 95%CI: 0.28-0.66, P<0.001) were independent predictor of OS. Although upfront ASCT could remarkably prolong OS in severe RI myeloma, it was not confirmed in multivariate analysis. Conclusions In the novel agent era, role of upfront ASCT in myeloma with severe RI remains uncertain. In our analysis, it seems the benefit of the OS from novel-drug induction and upfront ASCT was observed in the first 5-year, but the long-term survival benefit was limited. Instead, deep hematological response and renal recovery was strong predictors for OS.

Fibroblast Growth Factor23 as a Novel Marker of Renal Impairment in Multiple Myeloma

Fibroblast Growth Factor23 as a Novel Marker of Renal Impairment in Multiple Myeloma

Early Light Chains Removal and Albumin Levels with a Double Filter-Based Extracorporeal Treatment for Acute Myeloma Kidney.

Renal impairment in Multiple Myeloma (MM) represents one of the most important factors that influences patient survival. In fact, before the introduction of modern chemotherapy, less than 25% of patients with acute kidney injury (AKI) and MM who required dialysis recovered sufficient renal function to become independent from dialysis, with a median overall survival of less than 1 year. There are many other factors involved in determining patient survival. In this study we aimed to investigate the role of double filter-based extracorporeal treatment for removal of serum free light chains (sFLC) in acute myeloma kidney (AKI for MM) and to evaluate patient overall survival. All patients received Bortezomib-based chemotherapy and extracorporeal treatment for sFLC removal. For each session 2 dialyzers of the same kind were used. The dialytic dose was not related to the degree of renal function but to the removal of sFLC. The factors that have been found to be significantly associated with lower mortality were reduction of sFLC at day 12 and day 30, >50% reduction of sFLC at day 30, number of sessions and independence from dialysis. Among baseline characteristics, albumin level was statistically associated with the patients’ outcome. Our analysis highlights the importance of the early treatment for removal of sFLC in AKI for MM. These results indicate that the early removal of sFLC can improve patient’s outcome.

多发性骨髓瘤肾损害早期诊断标志物的研究进展

多发性骨髓瘤肾损害早期诊断标志物的研究进展

Serum free light chain level at diagnosis in myeloma cast nephropathy\u2014a multicentre study

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m2 (range 1–34). Six patients (5.8%) had an FLC level <1500 mg/L, which is the International Myeloma Working Group threshold for MCN and two patients were below the International Kidney and Monoclonal Gammopathy working group threshold of 500 mg/L; one was hypercalcaemic, and one had high-normal serum calcium level and had received a non-steroidal anti-inflammatory agent. Sixty-nine (67%) patients required haemodialysis treatment of whom 36 (52.1%) recovered independent renal function. Sixty-six (64%) patients died with a median OS of 2.5 years (95% CI 1.8–3.3). A landmark analysis revealed that independence from dialysis was associated with improved survival at 3-months (P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.

Induction Therapy with Novel Agents and Autologous Stem Cell Transplant Overcomes the Adverse Impact of Renal Impairment in Multiple Myeloma

We investigated the impact of renal impairment (RI) on the outcome in multiple myeloma (MM) patients following induction and autologous stem cell transplantation (ASCT). Among 349 patients who received a first ASCT for MM, 86 (24.6%) had RI at diagnosis, defined as estimation of glomerular filtration rate (eGFR) <40 mL/min/1.73 m2 according to the modification of diet in renal disease (MDRD) formula. Post induction reversal of renal function occurred in 68 (79%) patients including complete renal response in 37.2%. Two hundred and fifty-one patients had received novel agents for induction; posttransplant complete response (CR) rates were 71.4% for patients with renal impairment (RI) versus 67.2% in those without RI, p = 0.23. The quality of stem cell collection and days to engraftment were similar except that patients with RI required higher transfusion numbers of packed red cells (p < 0.002) and platelets (p < 0.007). The median overall survival (OS) was 96 months (95% confidence interval [CI] 72.80–119.20) for patients with eGFR ≥40 mL/min, n = 195) versus 62 months (95% CI 28.7–95.3) for 56 patients with RI (eGFR <40 mL/min), p = 0.15. The 5-year OS was 64.6% versus 54.4%, respectively. The median progression-free survival (PFS) was 52 months (95% CI 36.3–67.7) for patients with eGFR ≥40 mL/min versus “not reached” for those with eGFR <40 mL/min p = 0.87; and the 5-year PFS was 48.1% versus 51%, respectively. We conclude that induction with novel agents results in reversal of renal dysfunction in the majority of patients. Consolidation with Hemopoietic Stem Cell Transplantation (HSCT) overcomes the adverse impact of RI on survival.

Prevalence and Predictors of Renal Impairment Among Patients with Multiple Myeloma (MM): An Analysis of Oncology Clinic Electronic Health Records Linked to Commercial Claims in the United States

BackgroundAlthough incurable, MM is responsive to treatment, and the prognosis of MM patients has improved dramatically over the past two decades. This has led to increased recognition of the importance of effective long-term management of the classic clinicopathological features of MM. Renal impairment (RI) is a defining hallmark of active myeloma. While it is known that RI is associated with poor survival and can complicate drug dosing and limit treatment options, patterns of renal function and risk factors of RI in MM are poorly characterized. This study seeks to characterize the natural history and risk factors of RI in MM using a unique real-world dataset that links patient-level electronic health records (EHR) to healthcare insurance claims.MethodsThe Oncology Services Comprehensive Electronic Records (OSCER) database contains EHR data from community and hospital-affiliated oncology clinics in the U.S. The MarketScan (MS) database contains healthcare claims information from large employers, managed care organizations, Medicare, and Medicaid programs. This study used a subset of MM patients with overlapping data from OSCER and MS, allowing the analysis of EHR-based serum creatinine and claims-based comorbidity data in the same patient.Patients ≥ 18 with a MM diagnosis between 2011 and February 28, 2016 in an OSCER clinic; had at least 6 months of continuous MS benefits coverage; no MM diagnosis in MS in the 3 months prior to OSCER MM diagnosis; and no evidence of another malignancy prior to MM diagnosis were included in the study. Index date was the date of OSCER MM diagnosis and patients were followed up until February 28, 2017. Baseline (BL) patient characteristics and potential risk factors of RI, including demographics, BMI, ECOG, ISS stage, and comorbidities (e.g., hypertension, diabetes, hypercalcemia, etc.) were assessed in the 6 months prior to index. Intravenous bisphosphonate (IV BP) use was assessed during follow-up. Renal function was assessed using the MDRD eGFR method or CKD stage diagnosis codes, with RI defined in this study as eGFR < 60 or stage 3+ CKD. BL eGFR was assessed using the serum creatinine measurement closest to the index in the interval 1 month before and 1 month after index.The prevalence of RI in the year following diagnosis was calculated based on the average number of at-risk patients during this period. Change in renal function for up to 4 years post-diagnosis was assessed by BL renal function and was characterized based on the worst recorded estimate of renal function during this period. A multivariate Cox model was used to assess the impact of BL risk factors and IV BP use during follow-up on progression to RI in patients without RI at BL (eGFR ≥ 60 and CKD diagnosis). Follow-up IV BP use (dose count) was treated as a time-dependent variable.ResultsThe median number of eGFR values recorded per patient during follow-up was 18 (range: 7-36). Among newly diagnosed MM patients (n = 625), 69% (95% CI: 65-73%) experienced ≥ 1 episodes of eGFR < 60 ml/min or stage 3+ CKD diagnosis (RI) within 1 year of diagnosis, with 16% (13-20%) experiencing an episode of eGFR 15-29 or stage 4 CKD and 15% (11-18%) experiencing an episode of eGFR < 15 or stage 5 CKD.Among patients without RI at diagnosis (n = 281), 37% (31-43%) subsequently experienced at least one episode of RI during follow-up (Figure 1). In addition, 26% (20-32%) of patients with BL eGFR 30-59 or stage 3 CKD experienced progression to an episode of eGFR < 30 or stage 4+ CKD, and 31% (20-42%) of patients with BL eGFR 15-29 or stage 4 CKD progressed to an episode of eGFR < 15 or stage 5 CKD.In our multivariate Cox model, use of the IV BP zoledronic acid (ZA) during follow-up; ECOG; baseline eGFR; known predisposing conditions, including autoimmune diseases, vascular conditions, and infections of the kidney were found to be associated with higher risk for experiencing an episode of RI in patients with high BL renal function (Figure 2). In our sample, 12 doses of ZA was associated with a 2.4-fold (1.2-4.8) increase in risk of RI. A baseline ECOG of 1 vs. 0 was also associated with a 2.4-fold (1.1-5.2) increase in risk of RI.ConclusionsUsing a unique EHR-insurance claims linked data source, we found that two-thirds of patients experienced at least one episode of renal impairment within the first year of MM diagnosis. Repeated exposure to zoledronic acid and poor performance status may increase the risk of RI in patients without renal impairment at diagnosis. DisclosuresBlock:Amgen, Inc.: Consultancy. Fu:Amgen: Employment, Equity Ownership. Wade:Wade Outcomes Research and Consulting: Employment, Equity Ownership. Jaramillo:Amgen, Inc.: Consultancy; SimulStat: Employment. Bhatta:Amgen, Inc.: Employment, Equity Ownership. Raskin:Amgen, Inc.: Employment, Equity Ownership. Hernandez:Amgen, Inc.: Employment, Equity Ownership.

The Scope of Kidney Affection in Monoclonal Gammopathies at All Levels of Clinical Significance.

Multiple myeloma (MM) is one of the most important clonal malignant plasma cell disorders and renal involvement is associated with poor prognosis. Although there are several reasons for renal impairment in MM, the main cause is the toxic effects of monoclonal proteins. Although cast nephropathy is the best known and unchallenged diagnosis for hematologists and pathologists, the renal effects of monoclonal gammopathy can be various. Monoclonal gammopathy of renal significance was proposed by the International Kidney and Monoclonal Gammopathy Research Group for renal lesions in monoclonal gammopathy in recent years. Renal lesions in monoclonal gammopathy can be grouped as follows: light chain (cast) nephropathy, acute tubular injury/necrosis, tubulointerstitial nephritis, amyloidosis, monoclonal Ig deposition diseases, immunotactoid glomerulopathy, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, C3 glomerulopathy with monoclonal gammopathy, and crystal-storing histiocytosis, considering the previous and new terminology. In this study, renal involvement of monoclonal gammopathies, in terms of previous and new terminology, was reviewed.

Screening of Serum Peptidome-Based Biomarker for Multiple Myeloma Renal Impairment

To screen serum peptide associated with renal impairment in patients with multiple myeloma(MM) and search early biomarker of MM renal impairment. The weak cation exchange magnetic bead combined with matrix assisted laser desorption/ionization time of flight mass spectrometry was used to compare and analyze serum peptidome of MM with or without renal impairment. There were 18 peptide peaks with statistical significance in the molecular weight range from 700 to 10 000 Da(P<0.05), among them 7 peptides were upregulated and 11 were downregulated. The Quick Classifier diagnostic model composed of 3 peptides, which can strongly distinguish MM patients with or without renal impairment by means of Embedded Software. Its sensitivity and specificity were 97.14% and 94.12%, respectively. Peptides with molecular weight of 3908.85 Da and 3216.06 Da were significantly upregulated in MM patients with renal impairment, while the peptide with molecular weight of 2990.08 Da was significantly downregulated in MM patients with renal impairment. Peptides associated with MM renal impairment obtained by serum peptidome technology can provide a new clue for early assessment and diagnosis of clinical MM renal impairment.

Tumor Cell-Derived Microvesicles Induced Not Epithelial-Mesenchymal Transition but Apoptosis in Human Proximal Tubular (HK-2) Cells: Implications for Renal Impairment in Multiple Myeloma.

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target.

Haemorheological considerations in the pathophysiology of renal impairment in multiple myeloma: Implications for therapy

Haemorheological considerations in the pathophysiology of renal impairment in multiple myeloma: Implications for therapy

Renal impairment in multiple myeloma: A single center experience.

To determine the features of the different forms of kidney diseases associated with multiple myeloma (MM), we retrospectively studied 144 patients with kidney injury and MM at our institute from 1974 to 2014. The mean age of the patients was 60.1 years and the male:female ratio was 1.25. Renal disease was concomitant with the discovery of MM in 92% of cases. The mean follow-up of our patients was 2.1 years. Initial renal insufficiency was found in 131 (91%) patients. Cast nephropathy of the distal tubule was found in 110 (26%) patients, renal amyloidosis in 16 (11.1%), and light chain deposition disease in five (3.47%). Twelve (8.3%) patients had chronic glomerular nephropathy. Twenty-six patients reached end-stage renal failure within 13.4 months. Renal survival was 30.45 months. Predictive factors for improvement of renal function undergoing chemotherapy included serum creatinine <250 µmol/L, proteinuria <1 g/24 h, and the non-use of renal replacement therapy. Multiple pathogenic mechanisms can contribute to kidney injury in myeloma patients. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes.

Neutrophil Gelatinase--Associated Lipocalin and Cystatin C Are Sensitive Markers of Renal Injury in Patients With Multiple Myeloma.

Renal impairment is a common complication of patients with multiple myeloma (MM). We aimed to evaluate the clinical significance of 2 newly discovered biomarkers of renal injury, cystatin C (CysC), a protein reflecting glomerular filtration rate, and neutrophil gelatinase-associated lipocalin (NGAL), a protein reflecting tubular injuries. We studied 64 patients with newly diagnosed myeloma: 16 with asymptomatic (smoldering) MM and 48 with symptomatic myeloma; 8 patients with monoclonal gammopathy of undetermined significance (MGUS); and 20 healthy control subjects. Along with common blood and urine chemistry determinations, measurements of CysC, NGAL, β2-microglobulin, high-sensitivity C-reactive protein, and interleukin 6 were performed. We found that only patients with symptomatic MM had increased levels of CysC compared to controls (P < .01); that serum NGAL levels were elevated in all patients compared to controls P < .001; that NGAL strongly correlated with both estimation of glomerular filtration rate (eGFR) (CysC) and eGFR (Modification of Diet in Renal Disease [MDRD] formula) (r = 0.616, P < .0001; and r = -0.371, P < .01, respectively); that CysC showed strong correlation with eGFR (r = -0.782, P < .001) and with the International Scoring System (ISS) (more pronounced in patients with ISS-3); and that receiver operating characteristic curve analysis showed that NGAL values of > 50.5 μg/L have a 80.8% sensitivity and 86.4% specificity for eGFR < 60 mL/min (area under the curve = 0.764). These findings suggest that both NGAL and CysC are very sensitive markers that reflect renal impairment in newly diagnosed patients with MM. The high levels of NGAL in asymptomatic patients and in MGUS patients support the hypothesis of the presence of renal damage in these patients early in the course of their disease and may reveal NGAL to be an early marker that predicts the presence of renal impairment in MM.

Renal impairment in multiple myeloma and related disorders

Renal impairment in multiple myeloma and related disorders

Renal impairment in multiple myeloma: Presenting features in different departments

In order to analyze the cai]ses of delayed diagnosis and raise the level of early diagnosis of atypical multiple myeloma (MM), the differences of presenting features between the patients presented to nephrologists and those presented to hematologists were compared. MM patients in our hospital were studied retrospectively. Those who referred renal impairment were divided into two groups: group I presented to nephrologists prior to MM diagnosis (n=29) and group II presented to hematologists directly (n=62). The age, sex, initial symptoms, haematological and biochemical parameters, the phenotype of paraprotein, bone marrow biopsy and cytology were undertaken and analyzed. The results showed that the median time between the initial symptoms and diagnosis in the patients of group I was longer than that in group II (P<0.001); patients in group I had significantly lower incidence of bone pain (P<0.01) and worse renal function (P<0.05) on presentation. There were lower level of myeloma cells (P<0.05), lower incidence of hypergammaglobulinemia (P<0.05), lower positive rate of monoclonal immunoglobulin (M protein) (P<0.05) and M protein level (P<0.05) in the patients of group I than those in group II. The ratio of monoclonal to lambda monoclonal proteins in a population was 1:3.67 in patients of group I, whereas 1:0.90 in patients of group II (P<0.01). Moreover, patients with λ type had a higher degree of renal insufficiency than those with κ type (P<0.05). It was suggested that the median time between the initial symptoms and diagnosis in the patients presented to nephrologists was longer than that in those presented to hematologists; the patients presented to nephrologists had the lower incidence of bone pain, lower level of myeloma cells and M protein, which made early diagnosis more difficult; more patients presented to nephrologists had the majority of λ light chain type, moreover, patients with λ light chain type had a higher incidence of renal insufficiency.

Renal Impairment in Multiple Myeloma: Time Is of the Essence

TO THE EDITOR: The recently published consensus statement fromtheInternationalMyelomaWorkingGroup 1 onthemanagement of renal impairment in patients with multiple myeloma provides a much needed overview of the topic. Unfortunately, however, the consensus statement fails to emphasis two key concepts: first, time to treatment, and second, consideration of the severity of renal impairment. As stated in the article, 1 when patients with multiple myeloma presentwithasevereacutekidneyinjury,itismostcommonlyaresult of cast nephropathy, often with a preceding trigger. This tubulointerstitial disorder is a direct consequence of the high monoclonal free lightchain(FLC)levelspresentinthepatient’ssera.Immunoglobulin FLCs, as a result of their low molecular weight, are freely filtered through the glomerulus. They are then reabsorbed in the proximal tubule through endocytosis, which is mediated by the tandem receptorsmegalinandcubilinthatarelocalizedontheapicalbrushborder. FLCs are then additionally processed in the endolysosomal compartment of the proximal tubular cell, where they are degraded by lysosomal enzymes, namely cathepsin B. 2

Use of Lenalidomide May Surmount the Adverse Prognosis Induced by Renal Impairment In Patients (pts) with Relapsed/Refractory Multiple Myeloma (MM)

AbstractAbstract 3042 Introduction:Current goals in MM treatment are to achieve prolonged remission- and treatment-free-intervals and to transform the disease into an indolent course. Renal impairment is a dreaded complication in MM and has formerly been associated with decreased progression free- (PFS) and overall-survival (OS) - at least with standard-MM-agents. Lenalidomide is an effective novel substance, recently suggested to overcome the adverse prognostic impact of renal impairment in MM to a similar extent as other agents, therefore the current study was undertaken to further evaluate the impact of lenalidomide treatment on PFS and OS of MM pts with varying degrees of renal impairment. Methods:Forty-five consecutive MM pts received lenalidomide with dose modification according to current guidelines in G1-4 treatment groups (G1: lenalidomide 25mg+dexamethasone (dex) 40mg [n=19]; G2: lenalidomide 25mg+low-dose dex [n=10]; G3: lenalidomide 10mg [n=11]; G4: lenalidomide 10–15mg plus chemotherapy [n=5]) in our department between 2006 and 2010. Serum creatinine and eGFR were determined before lenalidomide treatment and after 1, 3 and 6 months. Renal function was defined via NKDOQI guidelines and response according to EBMT. Results:The median pt age was 66 years (range: 44–78), with predominantly stage II/III disease according to Durie-Salmon (97%) and ISS (71%). Pretreatment before lenalidomide initiation was substantial: ≥2 previous therapy lines had been performed in 71% and autologous or allogeneic SCT in 49% and 11% of pts, respectively. Lenalidomide induced an overall response rate (ORR: CR+PR) in 27% (n=12) and clinical benefit rate (CBR=CR+PR+MR) in 37% (n=14). Median PFS and OS for all pts were 13 and 25 months, respectively, which is consistent with the results of both lenalidomide/dex-FDA-approved studies, albeit our pt cohort was older and more pretreated. Lenalidomide was well tolerated as previously reported. Although baseline renal function appeared normal with a median creatinine of 1.0mg/dl (range: 0.6–2.7), mild renal impairment was readily detectable via eGFR measurement (median 80ml/min/1.73m2; range: 25–119). Of note, eGFR <90 and <60ml/min/1.73m2 before lenalidomide-initiation was prominent, with 64% and 29%, respectively. Within various eGFR groups of ≥ vs. <90, 80, 70, 60 and 50ml/min/1.73m2, and creatinine groups of ≥ vs. < 0.9, 1.0, 1.1, 1.3 and 1.4mg/dl median PFS as well as 1- and 2-year PFS rates were similar in pts without or with renal impairment. With eGFR-changes of 10ml/min/1.73m2 and serum creatinine-changes of 0.1mg/dl, hazard ratios (HR) were 0.973 (95% CI: 0.849–1.115, p=0.6927) and 0.989 (95% CI: 0.923–1.059, p=0.7538) for PFS, respectively. For OS, HR were 0.839 (95% CI: 0.708–0.994, p=0.0421) and 1.047 (95% CI: 0.972–1.128, p=0.2253), respectively. This data and our HR suggest that large PFS and OS differences under lenalidomide treatment were unlikely existing between pts with vs. without renal impairment, albeit this does not exclude smaller differences detectable with larger pt scrutiny. In order to also determine reasons for and the implications of initial eGFR declines as compared to pts with improved renal function under lenalidomide, we compared pts who displayed decreasing vs. increasing eGFR. After 1 month of treatment, we observed no differences in specific pt characteristics, but notably more pts staying longer on lenalidomide-therapy and showing an ORR of 42% vs. 20% with decreasing vs. increasing eGFR, respectively. After 6 months, ORR in pts with decreased vs. increased eGFR was 8% vs. 47%, respectively, suggesting that an initial eGFR decline does not impair therapy efficacy, whereas after 6 months the group comparison suggested that pts with persistent renal impairment constitute a pt group with a more unfavourable prognosis. Conclusions:Our results underline that treatment with lenalidomide is feasible and well tolerated in elderly and intensively pretreated MM pts, including pts with renal impairment. We suggest that consequent measurement of eGFR - rather than solely via traditional serum creatinine - may predict therapy response. Group comparison of different eGFR and creatinine subgroups indicated that lenalidomide can reverse the adverse prognosis of renal impairment in MM pts with hematological and renal treatment response. Disclosures:Kleber:Celgene: educational grant. Engelhardt:celgene: educational grant.

Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency.

8128 Background: Renal impairment (RI) affects >50% of patients (pts) with multiple myeloma (MM). It confers shorter survival and prevents adequate dosing by exacerbating drug side effects. Carfilzomib (CFZ) is a selective proteasome inhibitor with established single-agent activity in pts with relapsed and/or refractory (R/R) MM (even in the bortezomib-refractory setting), including those with moderate RI. Methods: This open-label, multicenter phase II trial enrolled pts with MM and varying degrees of RI (Table). Pts received CFZ 15 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 every 28 d for cycle (C) 1, escalating to 20 mg/m2 in C2 and 27 mg/m2 in C3. After response assessment, pts failing to achieve ≥PR by C2 or CR by C4 could receive dexamethasone 40 mg/week. Study objectives included PK, safety, pharmacodynamics (proteasome inhibition in blood and PBMC [PDn]), and efficacy (overall response rate [≥PR; ORR], clinical benefit response [≥MR; CBR] stable disease (SD) ≥6 wk, duration of response, and time to progression). Results: To date 39 pts have been enrolled. Pts received a median of 5 prior therapies (range 2–10). 97% had received bortezomib; all had received ≥1 immunomodulatory agent; 67% had prior stem cell transplant. Thus far, 22 pts received a median of 3 C (range 1–10+); 9 have completed ≥6 C. Side effects (AEs), including grade (G) 3/4 AEs (apparently independent of renal status), are presented in the Table. No QT/QTc prolongations were seen. PK/PDn were similar across all groups; CFZ was undetectable in plasma within 3 h (t¾ = 30–60 min) and did not accumulate after 2 C. Proteasome inhibition 1 h post-dose ranged from 75–89% at doses of 15–20 mg/m2. The CBR was 37% (8 PR and 5 MR) with an additional 37% SD (n = 13). Conclusions: Pts with MM and substantial RI can receive CFZ without dose adjustment. Responses are encouraging and toxicity is mild and manageable. Evaluable pts Cohort CrCL, mL/min Enrolled Efficacy Safety PK Normal 80 10 10 2 4 Mild RI 50-79 9 8 8 6 Moderate RI 30-49 9 7 6 6 Severe RI <30 9 8 4 6 On hemodialysis 2 2 2 2 Total 39 22 35 24 AE All G (n) G 3/4 (n) Fatigue 14 3 Anemia 10 9 Diarrhea 9 Nausea 8 Constipation 7 Thrombocytopenia 7 6 Hypokalemia 7 Creatinine increase 4 Mental status change 3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Celgene, Millennium, Onyx Onyx Celgene, Millennium Celgene, Cepahlon, Millennium, Onyx, Seattle Genetics

Higher Vascular Endothelial Growth Factor (VEGF) and Endothelial Progenitor Cells (EPCs) in Multiple Myeloma (MM) Patients (pts) as a Reflection of Their Governing Role in Pathological Angiogenesis: Comparison of VEGF and EPC Levels Between Healthy Donors (HD), MGUS and MM Pts and Correlation Analysis with MM Activity

Introduction: In MM pathogenesis, angiogenesis and growth factors have a governing role. VEGF, secreted by malignant bone marrow (BM) plasma cells (PCs) and stroma, acts as an important mediator of tumor angiogenesis. VEGF has been suggested as an adverse prognostic factor, being elevated in advanced and plasmablastic MM. Circulating as well as BM-residing endothelial cells (ECs) have been shown to contribute to angiogenesis in MM as well as other tumors. Moreover, endothelial progenitor cells (EPC) have been demonstrated to contribute to vascular repair and to be decreased in number and function with end-stage renal impairment (RI). Whereas VEGF and/or EPCs have been described in small former analysis in MM, larger comparisons with MGUS pts and healthy donors (HD) are lacking, differences in various MM subsets (such as BM; peripheral blood and apheresis [AP] samples) have not been addressed, nor the role of EPCs and hemangioblasts in advanced vs. mild RI in MM pts.Methods: We sought to characterize ECs (namely VEGF+ cells, EPCs as VEGFR2+/CD133+/CD34+, hemangioblasts as VEGF+/CD34+) and other subtypes (CD34+, CD45+, CD38+, CD45+/CD38+, CD45−/CD38+) via multiparametric flow cytometry. This was performed in MM pts (n=70), MGUS pts (n=8) and HD (n=14). In MM, BM (n=70), PB (n=14) and AP (n=21) specimens were compared, as well as changes in EPCs and hemangioblasts with and without mild or severe RI. Renal function was determined via estimated glomerular filtration rate (eGFR), classifying mild RI as eGFR <90ml/min/1.73m2 and severe RI as eGFR <30ml/min/1.73m2.Results: MM pts' age, BM-infiltration and serum creatinine were 63 years (range: 35–84), 15% (0–96) and 0.91mg/dl (0.5–8.6), respectively. BM specimens from MM and MGUS pts showed 4-fold and 2-fold higher VEGF levels, respectively as compared to HD (Table 1). EPCs were also elevated in MM as compared to MGUS and HD (Table 1). Hemangioblasts, CD45+/CD38+ and CD45−/CD38+ were increased in MM BM specimens as compared to MGUS and HD, whereas CD45+ and CD34+ cell numbers were decreased in myeloma specimens (Table 1).Table 1. Median endothelial cells and other subtypes in MM, MGUS and healthy donorsBM MM (n=70)BM MGUS (n=8)BM healthy donors (n=14)VEGF+ (%)0.38 (0 – 12.9)0.18 (0 – 0.7)0.09 (0 – 0.6)EPCs (%)0.03 (0 – 0.4)0.02 (0 – 0.07)0.01 (0 – 0.2)VEGF+/CD34+ (%)0.21 (0 – 2.2)0.11 (0 – 0.4)0.04 (0 – 0.5)CD34+ (%)0.65 (0 – 6.6)1.23 (0.02 – 4.0)1.50 (0.07 – 2.8)CD45+ (%)39.54 (2.8 – 99.1)39.34 (13.8 – 69.7)51.70 (10.3 – 90.9)CD45+/CD38+ (%)24.61 (0.9 – 89.7)21.68 (1.4 – 49.4)17.20 (2.6 – 56.9)CD45−/CD38+ (%)1.54 (0 – 77.7)1.15 (0 – 2.4)0.62 (0.1 – 5.6)The comparison of BM, PB, AP specimens in MM showed similar VEGF levels in BM and PB with 0.38% which were increased in AP specimens with 0.5%. This was similarly observed for EPCs with 0.03% in BM and PB as compared to 0.04% in AP samples. Other markers showed similar values for CD34, CD45, CD38+ cells in BM and PB; similar hemangioblast numbers in all 3 subsets, and higher CD34+ and CD45+ cells, and lower CD45−/CD38+ cells in AP specimens. Correlation of EPCs and hemangioblasts with renal function revealed that EPCs decreased with RI, whereas hemangioblasts remained comparable (Table 2).Table 2. Median EPCs and hemangioblasts (VEGF/CD34) with and without RIEPCs (%)VEGF+/CD34+ (%)eGFR >90 (n=41)0.050 (0 – 0.41)0.195 (0 – 0.86)eGFR <90 (n=46)0.025 (0 – 0.41)0.230 (0 – 0.8)eGFR >30 (n=81)0.030 (0 – 0.41)0.210 (0 – 2.23)eGFR <30 (n=6)0.025 (0 – 0.41)0.190 (0 – 2.23)Conclusions: These results demonstrate that all ECs, namely VEGF+ cells, EPCs and hemangioblasts are higher in MM than MGUS and HD. Lower CD34+ and CD45+ cells in MM suggest this as a result of the disease and most likely also due to anti-MM therapy. We observed differences in BM, PB and AP specimens in MM pts. RI influenced EC numbers. These results suggest that elevated ECs in MM may reflect disease activity and may be useful as MM biomarkers. The quantification of ECs in MM may also be informative to monitor the efficacy of anti-angiogenic treatment, such as thalidomide and lenalidomide. Further analyses will evaluate the prognostic significance of EPCs, hemangioblasts and other markers in MM, their role in mild and severe RI is ongoing, as well the correlation with disease outcome.

Hemorheological considerations in the pathophysiology of renal impairment in multiple myeloma: implications for therapy and the role of plasma exchange

Hemorheological considerations in the pathophysiology of renal impairment in multiple myeloma: implications for therapy and the role of plasma exchange