Agnieszka Druzd-Sitek

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.

Procollagen I amino-terminal propeptide as a potential marker for multiple myeloma

OBJECTIVES Investigating relationship between bone markers, cytokines and conventional prognostic parameters in patients with multiple myeloma (MM) and to assess the clinical application of bone turnover markers. DESIGN AND METHODS Sixty-four patients with MM were examined before treatment and followed for survival for over 7 years. Serum concentrations of bone markers and cytokines were determined by the Roche and R&D kits, respectively. Standard deviation scores (SDS) were employed to normalize values. RESULTS Collagen fragments (beta-CTX) were elevated in 47%, procollagen I amino-terminal propeptide (PINP)-in 28%, and osteocalcin (OC) in 11% of patients. The values of the SDS of PINP and OC, but not beta-CTX significantly decreased with MM stage. beta-CTX inversely correlated with vascular endothelial growth factor (VEGF) and albumin, and directly correlated with serum macrophage colony-stimulating factor (M-CSF). OC values correlated with albumin and beta2-microglobulin. PINP inversely correlated with LDH. The SDS values of PINP were significantly lower in MM patients with advanced bone disease. CONCLUSIONS Circulating PINP concentration may be a useful marker for monitoring of treatment of multiple myeloma patients with bone lytic lesions, in particular, of patients treated with preoteasome inhibitors.

Cutaneous involvement in multiple myeloma: a multi-institutional retrospective study of 53 patients

Abstract Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS.

A survey of prognostic value of serum factors in multiple myeloma patients before treatment: macrophage-colony stimulating factor (M-CSF) is a powerful predictor of survival

Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of this study was to evaluate a range of cytokines of diverse activity in patients with multiple myeloma for a possible prognostic value. Concentrations of the following cytokines and cytokine receptors were measured by ELISA in the sera of 64 untreated MM patients: IL-6, IL-8, IL-10, TNFα, sTNF R I and II, sIL-2Rα, IL-1ra, M-CSF, G-CSF, VEGF, and bFGF. Serum levels of sTNF RI, IL-6, and bFGF were elevated in over 50% of patients. There was an inverse relationship between sTNF RII, TNFα, IL-1ra, and albumin levels. There was no significant relationship between cytokines/cytokine receptors and other serum correlates of myeloma. In a univariate survival analysis, β2-microglobulin, LDH, sIL-2Rα, sTNF RI, and M-CSF were significant variables. In a multivariate analysis, only M-CSF and β2-microglobulin retained a significant influence on survival. Serum M-CSF may be considered another independent and clinically useful prognostic factor in multiple myeloma.

Case-adjusted bortezomib-based strategy in routine therapy of relapsed/refractory multiple myeloma shown to be highly effective—A report by Polish Myeloma Study Group

The observational study was aimed at evaluating response, survival and toxicity of bortezomib-based, case-adjusted regimens in real-life therapy of 708 relapsed/refractory MM patients. Bortezomib was combined with anthracyclines, steroids, thalidomide, alkylators or given in monotherapy. The ORR was 67.9% for refractory and 69.9% for relapsed MM. The median PFS was 14 months and OS 57 months. Patients responding to the therapy had the probability of a 4-year OS at 67.0%. No toxicity was noted in 33.1% of patients. Severe events (grade 3/4) were reported in 35.9% of patients: neurotoxicity (16.7%), neutropenia (9.2%), thrombocytopenia (8.5%), and infections (6.5%). Bortezomib-based, case-adjusted regimens are in real-life practice effective in salvage therapy offering reliable survival with acceptable toxicity for relapsed/refractory MM patients.

Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety‐eight patients were treated with novel agents, with an overall response rate of 78%. Fifty‐five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow‐up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109/l and peripheral blood plasma cell count ≥20 × 109/l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.

Chromosome 1 amplification has similar prognostic value to del(17p13) and t(4;14)(p16;q32) in multiple myeloma patients: analysis of real-life data from the Polish Myeloma Study Group

Abstract The study aimed to assess prognostic significance of del(13q14), del(17p13), t(4;14)(p16;q32), and amp(1q21) in newly diagnosed myeloma patients treated mostly with thalidomide-based therapies. All genetic abnormalities except del(13q14) were independent prognostic factors associated with shortened progression-free survival (PFS) and overall survival (OS). Patients with no abnormalities, one abnormality, and ≥2 abnormalities had a median PFS of 41.8, 17.0, and 10.0 months, respectively; a median OS was not reached, 48.0 and 23.3 months, respectively. According to the presence of amp(1q21), t(4;14)(p16;q32), and del(17p13) and the International Staging System (ISS), we stratified patients into low-risk, intermediate-risk and high-risk groups. A median PFS was 52.9, 25.6, and 10.0 months, respectively; a median OS was not reached, 64.0 and 25.0 months, respectively. In conclusion, our study confirmed the prognostic value of cytogenetic changes and showed that prognostic models based on ISS and cytogenetic studies should include not only del(17p13) and t(4;14)(p16;q32), but also amp(1q21).

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18–1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44–3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2‐rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2‐rs4148388 and MM outcome that is supported by a plausible biological explanation.

Identification of miRSNPs associated with the risk of multiple myeloma.

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA‐binding sites in target genes (miRSNPs) may alter the strength of miRNA–mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome‐wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta‐analyzed with data from a previously published genome‐wide association study (GWAS). The SNPs rs13409 (located in the 3′UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome‐wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.