Natalia Schutz

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty‐eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow‐up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy‐related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575–580, 2016.

Glutathione S-transferase P1 mRNA expression in plasma cell disorders and its correlation with polymorphic variants and clinical outcome

BACKGROUND Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in detoxification of carcinogens. GSTP1 gene overexpression has been observed in a variety of human cancers but there are no studies in plasma cell disorders. The aim of this study was to examine GSTP1 mRNA expression level in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). In addition, we have determined GSTP1 polymorphic variants in order to estimate MM risk and their relationship with the expression level. Results were also correlated with laboratory parameters and clinical outcome. METHODS Bone marrow mononuclear cells from 125 patients with plasma cell disorders were studied. Peripheral blood samples of 110 age and sex matched healthy controls were also evaluated. Real-Time Quantitative RT-PCR and PCR-RFLP assays were used. RESULTS Upregulation of GSTP1 was observed in 37.7% MM and in 22.6% MGUS patients. A significant increase of GSTP1 expression in MM with respect to MGUS was detected (p=0.0427). Most MM patients that achieved complete remission had low transcription levels (77.8%) compared to those who did not reach this condition (44.4%) (p=0.0347). GSTP1 heterozygous carriers showed reduced expression compared to those with homozygous wild type genotype (p=0.0135). CONCLUSION Our findings suggest, for the first time, a role for GSTP1 expression in development and/or progression of plasma cell disorders, and a probable influence of functional capacity of the enzyme on clinical outcome. These results and those of the literature support GSTP1 as an interesting tumor marker and a potential therapeutic target.

Quantitative analysis of CKS1B mRNA expression and copy number gain in patients with plasma cell disorders

In this study, we have examined CKS1B gene expression and copy number in a total of 114- patients at diagnosis: 83 with multiple myeloma (MM) and 31 with monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with cytogenetics, FISH and clinical characteristic. Significant CKS1B mRNA levels in MM compared to MGUS cases (p<0.048) were detected. In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared to patients with normal karyotype (p=0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (p<0.0001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2 microglobulin in cases with 1q21 gains than those without (p=0.0094) was observed. Overall survival was shorter in cases with 1q21 gain compared to those with normal 1q21 region (p=0.0082). Our results suggest a role for CKS1B in the multiple step process of progression of MGUS to MM and show that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated to chromosome 1q alterations resulting in a more aggressive behavior of the disease.

Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders

Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.

Acute Loss of Vision as the Initial Symptom of Multiple Myeloma

Multiple myeloma is the second most common hematologic can-cer.Itischaracterizedbytheclonalproliferationofmalignantplasmacells in the bone marrow microenvironment, monoclonal protein inthe blood or urine, and associated organ dysfunction. It usually af-fects elderly people, and the median age at diagnosis is 70 years.Myeloma is classified as asymptomatic or symptomatic, dependingon the absence or presence of myeloma-related organ or tissue dam-age, including hypercalcemia, renal insufficiency, anemia, and/orlytic bone disease. Other less-frequent clinical manifestations areneuropathyandtumoralspinalcordcompressionhyperviscosity,andthe production of cryoglobulins associated with autoimmune phe-nomena. There is an increased risk of infections due to immunedeficiency that results from hypogammaglobulinemia.

Management of pancreatitis related to Bortezomib treatment: report of two cases

Bortezomib is a proteasome inhibitor, which has radically changed the treatment and prognosis of patients with multiple myeloma. Its mechanism of action is based on a reversible inhibition of proteasome subunit 26s, thereby inhibiting its chymotrypsin activity. This leads to the accumulation of an inhibitor of nuclear factor kappa B (NF B). Inhibition of this factor diminishes the expression of adhesion molecules, as well as growth, survival and angiogenic factors, increasing the number of misfolded proteins promoting apoptosis of malignant cells.1 Its most common side effects are hematological toxicity, mainly thrombocytopenia, gastrointestinal toxicity (nausea, vomiting, diarrhea, constipation) and peripheral neuropathy. Pancreatitis due to bortezomib is very rare, with an estimated incidence of 0.1–2%,2 with only isolated reports in the literature. Bortezomib has proven to be especially beneficial in patients with multiple myeloma with renal involvement and the 17p deletion.

Chronic Myelomonocytic Leukemia and Systemic Autoimmune Disorders: Experience in Argentina

S262 with claims for HMA/LEN during baseline were excluded. Measures: Patient and area-level baseline measures were examined as predictors of HMA/LEN initiation: age, sex, race, region, rural location, Charlson Comorbidity Index (CCI), del(5q) syndrome, prior transfusions (y/n), prior hematopoietic-stimulating agent use ( 12 weeks/<12 weeks/none); and census-tract residential variables of median annual income, college-educated residents, and residents below the poverty line (>40%/20e40%/<20%). Results: 2,139 of 7,700 (27.8%) newly-diagnosed MDS patients used HMA or LEN; 630 were initiators meeting all selection criteria. HMA (n1⁄4498) and LEN (n1⁄4132) initiators versus matched non-initiators were younger at diagnosis (76.2 vs 82.0 years; p<0.001) and predominantly White (86.2% vs 83.0%; p1⁄40.034). Differences in sex, rural location, and CCI were not significant. In the logistic regression model, positive predictors of receiving first-line treatment were del(5q) syndrome (OR[95% CI] 4.62[2.31e9.26]), prior transfusion (2.98[2.23e3.98]), and prior hematopoietic-stimulating agent (EPO/G-CSF) use 12 weeks (2.01[1.22e3.31]). Advanced age (80e84 years 0.35[0.17e0.74]; 85 years 0.12 [0.06e0.26] vs 64), census-tract residents below the poverty line >40% (0.23[0.07e0.74] vs <20%), and CCI (0.93[0.89-0.97]) decreased likelihood of treatment initiation. Conclusions: Advanced age and poverty may contribute to disparities in firstline treatment initiation among MDS patients. Other treatment decisions are likely guided by clinical factors (e.g. disease severity, comorbidities, prior treatments). Research funded by Celgene.

Experience in Autologous Stem Cell Transplantation in Elderly Multiple Myeloma Patients

Context: Most symptomatic multiple myeloma (MM) patients are elderly (>65 years old). Autologous stem cell transplantation (ASCT) is a standard treatment for patients under 65 years old age, whereas it is a procedure that must be individualized for elderly patients, mainly due to increase in toxicity. Objective: To determinate effectiveness of ASCT in patients older than 65 years and compared them with patients below 65 years treated in the same period. Design: Retrospective cohort study, 201 patients with MM evaluated in our centre, from January 2008 to November 2017, who received high dose chemotherapy with melphalan with ASCT were included. Group < 65 years was compared with group > 65 years. Main Outcomes Measures: Primary endpoint was overall survival (OS) and progression free survival (PFS). Secondary endpoints were induction conditioning regimen, time to engraftment, disease response, transplant-related complications and mortality. Results: Two hundred and one patients were included in the analysis. Forty-five patients were older than 65 years (7 patients were over 70 years old). Patient characteristics were analyzed in both groups. There were no significant differences in days of admission, response, complications or death related to transplant. There was a tendency to an increase mortality in patients with more comorbidities in both groups. OS at five years of the entire cohort was 72.2% (IC95% 62.5-79.8). There was no significant difference in OS at 3 years between patients younger than 65 years and patients older than 65 (81% IC95% 72.4-87.2 versus 85.8% IC95% 64.894.8 p:0.17). PFS was 37.7 months (IC95%24.3-45.1). The median PFS was 29.6 months (20.1-45.1) in the younger group and 44.6 months (20.1-48.5) in the elderly ones (p1⁄4 0.967). Conclusions: In our experience, consolidating induction treatment with ASCT is possible for patients older than 65 years and even in those older than 70 years. The exclusion of patients should be done according to frailty and comorbidities, not according to chronological age. The correct selection of elderly patients makes transplantation a treatment option, even in developing countries.