Prevalence of iron overload vs iron deficiency in multiple myeloma: resembling or different from MDS--and stem cell transplant (SCT)--patients?

BACKGROUND: Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism. PATIENTS AND METHODS: We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism. RESULTS: Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 µg/dL, 446 µg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of < 400 µg/L, 400 to 1000 µg/L, and > 1000 µg/L were observed in 46%, 30%, and 24%, and TRFS levels < 20%, 20% to 45%, and > 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant. CONCLUSION: Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM.

Validation of the Freiburg Comorbidity Index in 466 multiple myeloma patients and combination with the international staging system are highly predictive for outcome.

BACKGROUND: The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated. PATIENTS AND METHODS: We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age. RESULTS: Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P < .0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P < .0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P < .0001). CONCLUSION: Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies.

Prognostic risk factor evaluation in patients with relapsed or refractory multiple myeloma receiving lenalidomide treatment: analysis of renal function by eGFR and of additional comorbidities by comorbidity appraisal.

INTRODUCTION: Renal impairment (RI) is a dreaded complication in multiple myeloma (MM) and has been associated with decreased progression-free survival (PFS) and overall survival (OS). METHODS: Forty-five consecutive patients with MM received lenalidomide therapy combined with either dexamethasone or standard chemotherapy, with dose modification according to current guidelines. Comorbidity indices (hematopoietic cell transplantation-specific comorbidity index [HCT-CI], Kaplan Feinstein [KF], and the Freiburg comorbidity index [FCI]) were analyzed and renal function was determined by estimated glomerular filtration rate (eGFR) before lenalidomide treatment and 1, 3, and 6 months after treatment. RESULTS: The median patient age was 66 years. Pretreatment was substantial with ≥ 2 treatment lines in 71% of patients. Lenalidomide induced median PFS and OS of 13 and 25 months, respectively. The analysis of comorbidity scores identified only the FCI as significant, with different PFS for low-risk vs. high-risk patients of 20 vs. 9 months (p = .0036) and OS of not reached vs. 12.8 months (p < .0001), respectively. Although baseline renal function by serum creatinine evaluation appeared normal (median 1.0 mg/dL), mild RI was readily detectable by eGFR (median 83 mL/min/1.73 m(2)). When patients without RI were compared with those with mild, moderate, and severe RI, 1- and 2-year PFS rates were similar (hazard ratio [HR] with decreasing eGFR, 1.028; p = .6927). For OS, the HR of 1.192 indicated decreased survival probabilities with deteriorating eGFR (p = .0411), which was perceived by eGFR but not serum creatinine assessment (p = .2253). CONCLUSIONS: Lenalidomide was well tolerated in intensively pretreated and elderly MM patients, including those with RI. PFS was not significantly different in patients with decreasing eGFRs, albeit RI and other comorbidities remained significant for OS.

Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients.

OBJECTIVES: Comorbidity factors have been reported in cancer patients to predict progression free survival (PFS) and overall survival (OS). Renal impairment (RI) is postulated as one negative prognostic factor in multiple myeloma (MM). The study aim was to detect the best way to define RI and the impact of different RI stages on MM outcome. METHODS: In this multicenter analysis, we determined RI [serum creatinine, estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) and Cockcroft-Gault] and other prognostic factors in 198 MM patients to ascertain their value on PFS and OS. RESULTS: Median serum creatinine was 0.9 mg/dL in all patients, whereas the eGFR - being decreased with a median of 80 mL/min/1.73 m(2)- allowed to detect early stages of RI. Via univariate analysis, we observed increasing hazard ratios (HRs) for impaired OS with deteriorating eGFR: with eGFR(MDRD)<90 and <30, HRs were 1.3 and 2.9, respectively. Multivariate analysis determined RI with eGFR<30 and <50 as well as age >59 yr as most important variables for OS. By incorporating eGFR<30 as the most relevant factor determined via multivariate analysis and beta(2)-microglobulin (beta(2)-MG) in a novel MM-risk score, we identified patients with significantly differing OS: median survival with 0, 1 or 2 risk factors were 71, 48, and 24 months, respectively. CONCLUSIONS: These findings demonstrate that RI is frequent in MM, best detected via eGFR determination and an important prognostic factor. eGFR in combination with beta(2)-MG allows definitive risk stratification with largely differing survival in MM.

Selected topics of hypoglycemia care.

OBJECTIVE: To review 4 topics in hypoglycemia (HoG) care: diagnosis, circumstances predisposing to HoG, risk of adverse effects, and prevention. QUALITY OF EVIDENCE MEDLINE: was searched using the words hypoglycemia and diabetes mellitus. Other relevant sources were hand searched. Evidence was mostly level III and IV from consensus, from observation, and from the author's clinical experience. MAIN MESSAGES: Hypoglycemia can be diagnosed using clinical criteria or using a glucometer; it cannot be diagnosed after death. Capillary blood glucose testing for HoG is required only for patients taking insulin and insulin secretagogues. With intensified treatment of diabetes, a greater incidence of HoG is inevitable. Chronic morbidity and mortality resulting from HoG are believed to be rare. There are no reliable data on HoG-related mortality for idiopathic or accidental sudden death. Interventions by friends, family, colleagues, and teachers can prevent HoG. CONCLUSION: Clinical diagnosis of HoG deserves greater emphasis; when patients are unaware of having HoG, physicians must rely on blood glucose testing. Patients not taking insulin or insulin secretagogues need neither fear nor test for HoG. The risk of HoG should not preclude efforts to achieve best possible control of blood sugar. Patients with unstable cardiac arrhythmias, drivers of motor vehicles, and those in high-risk industrial occupations require special vigilance for HoG.

Mutation analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride.

Vinyl chloride (VC) is a potent liver carcinogen that induces angiosarcomas in humans and animals. Recent evidence shows that liver tumors from patients with VC exposure may have a specific K-ras mutation pattern. This study was performed to determine the status of K-ras-2 in liver angiosarcomas (LAS) from workers occupationally exposed to VC. We examined the presence of K-ras-2 mutations in 15 LAS from patients with known exposure to VC (median exposure: 8,260 ppm [range 3,900- 21,000 ppm]]. In all cases, other risk factors for the development of LAS were excluded. Direct DNA sequencing after microdissection of the tumor cells was used for the analysis. Heterozygous mutations of K-ras-2 were detected in 8/15 LAS (53%). Five patients (33%) had a mutation of codon 12 and three of codon 13 (20%). The most common changes were G-->A transitions in five LAS which lead to the substitution of aspartic acid for glycine in the resulting p21 protein. In two patients (13%), mutations of the K-ras-2 gene were identified in the adjacent nonneoplastic liver tissue. These data indicate that VC induces a high frequency of G-->A transitions in human LAS. This mutation pattern is likely a consequence of VC-DNA-adduct formation.