Durie-Salmon Staging System Research Articles

Impact of HIV on Clinical Presentation and Outcomes of Individuals with Multiple Myeloma

Introduction:HIV infection and the resulting immunodeficiency predispose individuals to various plasma cell disorders including reactive plasmacytosis, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plamacytomas. Studies have demonstrated nearly 4.5-fold increased risk of MM in HIV-infected (HIV+) individuals. Limited evidence from case reports/small series of MM in HIV+ patients have suggested a younger age at presentation, more disseminated disease, an aggressive clinical course and inferior outcomes as compared to uninfected counterparts. However, these studies included small numbers of patients, and often lacked appropriate comparison groups. We aim to compare clinical characteristics and outcomes of HIV+ and uninfected subjects with MM, with the hypothesis that significant differences will be detected between the two groups.Methods:We analyzed all patients with histologically proven MM in the Veterans Aging Cohort Study (VACS). VACS is a prospective, observational cohort, beginning in 1996, of > 40,000 HIV+ and > 80,000 age-, race/ethnicity-, sex-, and clinical site- matched (1:2) uninfected patients under care in the Veterans Health Administration. Clinical variable were obtained via chart review. The variables studied included stage at diagnosis (Durie-Salmon and International Staging System- ISS), bone marrow plasma cell involvement at diagnosis, presence of asymptomatic vs clinical MM, involvement with bone lesions at diagnosis, and presence of extramedullary (EM) involvement during the course of disease. Differences between the HIV+ and uninfected patients were compared using appropriate bivariate methods (chi-squared or Fisher's test, where applicable). All p values were two sided and the level of significance chosen was 0.05.Results:A total of 162 patients (62 HIV+, 100 uninfected) with MM were included in this study. Patients were predominantly male 99.4%; 57% were black, 28% white, 15% Hispanic or other ethnicity. Average age at the time of diagnosis was 59, and did not differ between the two groups. The distribution by Durie-Salmon stage was as follows: 28% stage 1, 18% stage 2 and 54% stage 3. By ISS, 43% had stage 1, 25% had stage 2 and 31% had stage 3 disease. 10% had asymptomatic disease. 54% had lytic lesions on skeletal survey. When HIV+ and uninfected patients were compared, based on the available data, there were no statistically significant differences in the distribution of MM by stage, presence of clinically symptomatic MM or presence of lytic lesions. However, we observed a significantly higher rate of the presence of extramedullary disease in the HIV+ as compared with uninfected group (>1 EM site 21% vs 19%, 1 EM site 21% vs 11%, none 57% vs 78%; p value 0.02). Comparison of overall survival between the two groups, and analysis of the impact of HAART on survival are ongoing.Conclusion:This is the largest published study to date to compare the clinical characteristics and outcomes of MM between HIV+ and uninfected individuals. We observed a significantly higher rate of EM disease in the HIV+ group, an important finding since EM disease is associated with poor prognosis. Ongoing analysis will provide additional data on treatment responses, including the role of HAART, and a comparison of clinical outcome data between these two groups. DisclosuresNo relevant conflicts of interest to declare.

Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry.

Multiple myeloma (MM) is a monoclonal plasma cell malignancy. The primary choice of treatment for MM is induction therapy followed by autologous stem cell transplantation (ASCT). This study aimed to analyze the treatment efficacy of ASCT in a Taiwanese cohort and evaluate possible prognostic factors. From the database of the Taiwan Blood and Marrow Transplantation registry, data on 396 patients with MM who underwent ASCT were reviewed. The average age of participants was 54.8 years, and there were more men than women (57.6% vs. 42.4%). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). Patients with Durie Salmon Staging System (DSS) III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 46.5 months and 70.4 months, respectively. DSS III was a poor prognostic factor affecting both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages (p=0.006 and p=0.03, respectively). In addition, patients with better treatment response before ASCT had better PFS and OS compared with those who did not show a response (both p<0.0001). The overall incidence of organ toxicities associated with transplantation was low. In conclusion, our cohort showed that myeloma patients with early DSS and better treatment response before ASCT had better long-term survival outcomes.

The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma

ABSTRACTPurpose: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III.Experimental design: We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients.Results: We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response in vitro and that the immunophenotype of patients with high IKZF3 expression shows features that are contrary to the changes induced by immunomodulatory drugs. Although we observed higher IKZF3 expression levels in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment.Conclusion: In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality.

The Role of 18F-FDG PET/CT in Multiple Myeloma Staging according to IMPeTUs: Comparison of the Durie-Salmon Plus and Other Staging Systems.

We aimed at comparing the Durie–Salmon Plus (DS Plus) staging system based on Italian Myeloma criteria for PET USe (IMPeTUs) with other two staging systems in predicting prognosis of patients with all stages of newly diagnosed multiple myeloma (MM). A total of 33 MM patients were enrolled in this retrospective study. The variation between the DS Plus classification and Durie–Salmon staging system (DSS) or Revised International Staging System (RISS) classification was assessed. When staged by the DSS, patients in stage I and stage II did not reach the median overall survival (OS), and the median OS was 33 months for stage III (p=0.3621). When staged by the DS Plus, patients in stage I did not reach the median OS of stage I, and the median OS for stages II and III was 38 and nine months, respectively (p=0.0064). When staged by the RISS, patients in stage I did not reach the median OS, and the median OS was 33 and 16 months for stage II and stage III, respectively (p=0.0319). The concordances between two staging systems were 0.07 (DS Plus versus DSS) and 0.37 (DS Plus versus RISS), respectively. Multivariate analysis revealed that DS Plus stage III (HR: 11.539, p=0.021) and the Deauville score of bone marrow ≥4 (HR: 3.487, p=0.031) were independent prognostic factors associated with OS. Both the DS Plus based on IMPeTUs and RISS possessed a better potential in characterizing and stratifying MM patients compared with the DSS. Moreover, DS Plus stage III and the Deauville score of bone marrow ≥4 were reliable prognostic factors in newly diagnosed MM patients.

Expert consensus for the diagnosis and treatment of patients with renal impairment of multiple myeloma

Renal impairment (RI) is a common complication of multiple myeloma (MM), which is presented as chronic kidney disease (CKD) or acute kidney injury (AKI). The typical pathological feature is cast nephropathy. Presently international system staging (ISS) is used in evaluating MM. Although the classic Durie-Salmon staging system could be still used in clinical practice, it may miss out some patients with renal impairment. For evaluations of RI in MM patients with CKD, it's recommended to assess the estimated glomerular filtration rate (eGFR) by creatinine based formula CKD-epidemiology collaboration (EPI) or modification of diet in renal disease(MDRD) and to stage the renal injuries according to 2013 Kidney Disease Improving Global Outcomes (KDIGO) CKD guidelines. For MM patients with AKI, KDIGO AKI guidelines is recommended for evaluation. Renal biopsy is not a routine procedure in all MM patients. It's necessary for patients presenting with glomerular injuries such as albuminuria > 1 g/24 h to eliminate immunoglobulin associated amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD). The effective treatment of MM can reduce serum light chain concentration and improve renal function. The basis of the RI treatment in MM is bortizomib-based regimen, which does not require dosage adjustment in patients with dialysis or renal insufficiency. Thalidomide and lenalidomide are two major immunomodulators in MM treatment. Thalidomide can be used effectively in RI patients without dosage adjustment while lenalidomide should be used cautiously in patients with mild or moderate RI with dosage adjustment and serum toxicity surveillance. High-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (APBSCT) can be therapeutical options for RI patients younger than 65 y, and they should be considered more prudently in patients with severe renal insufficiency (GFR<30 ml/min). For patients who are not suitable for the treatment mentioned above, they can be treated with conventional chemotherapy, including VAD (vincristine, adriamycin and dexamethasone), MP (mephalan and prednisolone) and high-dose dexamethasone regimen. Adequate hydration (at least 3 litres of fluid intake a day or 2 L·m(-2)·d(-1)) and correcting reversible causes of RI are key points for the supportive care. Renal replacement therapy (more often hemodialysis) should be started in patients with severe AKI and end stage renal disease (ESRD). High flux or high cut-off membrane are recommended because routine hemodialysis could not remove the serum free light chain (sFLC) effectively. Plasmapheresis (PE) is recommended for patients with hyperviscosity syndrome or cast nephropathy presented with AKI, which may help to increase the dialysis-independency.

Clinical implications of c-maf expression in plasma cells from patients with multiple myeloma

BackgroundMultiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM.MethodsNuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well.ResultsAmong the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed.ConclusionPatients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

Correlation Between Prognosis and Morphological Abnormalities in Multiple Myeloma

BackgroundMultiple myeloma shows various morphological abnormalities such as plasmablastic morphology, cytoplasmic granules, vacuolation, and nuclear atypia. Although plasablastic morphology has been revealed as a poor prognostic factor, little is known about clinical significance of other abnormalities. Therefore we investigated a correlation between morphological abnormalities and clinical outcome.MethodsPatient SelectionA total of 76 multiple myeloma patients who hospitalized in National Center for Global Health and Medicine (NCGM), Japan, between 2010 and 2015 were enrolled in this study.Morphological EvaluationBone marrow smears were obtained from each patient before initiation of treatments. We evaluated Greipp's morphological classification and morphological abnormalities of myeloma cells including cytoplasmic granules, vacuolation, and nuclear atypia. We also evaluated morphological abnormalities of other hemocytes. All specimens were observed at 400x magnification with an optical microscope.Clinical InformationClinical information obtained from medical records of NCGM includes gender, age, overall survival, Durie-Salmon staging system (DS), international staging system (ISS), types of M protein and light chain. The results of G-banded chromosomal analysis and fluorescent in situ hybridization (FISH) analysis were also collected from medical records.Statistical AnalysisWe performed survival analysis by generalized Wilcoxon test with EZR (version 1.31).ResultsClinical DataOf all the patients, 46 (60.5%) are male. Mean age of the patients is 63.5 years old.Morphological Abnormality of Myeloma CellsAccording to Greipp's morphological classification, we identified 13 cases as mature type (17.1%), 28 cases as intermediate type (36.8%), 31 cases as immature type (40.8%), 4 cases as plasmablastic type (5.3%). We found cytoplasmic granules in 20 cases (26.3%), vacuolation in 8 cases (10.5%), atypical myeloma cells in 54 cases (71.1%), Russell bodies in 5 cases (6.6%), and Dutcher bodies in 3 cases (3.9%).Morphological Abnormality of Other HematocytesAs for myeloid cells, we found Auer rods in 1 case (1.3%), pseudo-Pelger-Huet anomaly in 2 cases (2.6%), neutrophils with ring-shaped nuclei in 2 cases (2.6%), megakaryocytes with multiple separated nuculeus in 3 cases (3.9%).Statistical AnalysisWe revealed that overall survival of granular group is significantly longer than non-granular group (p=0.04, Fig.1). Median overall survivals are 66.2 months (granular group) vs 54.5 months (non-granular group). However, there are no significance of vacuolation and nuclear atypia on overall survival.ConclusionsA variety of morphological abnormalities were identified in multiple myeloma. We found that presence of cytoplasmic granules in myeloma cells correlates with good prognosis.DiscussionPrevious reports have shown that cytoplasmic granules of myeloma cells contain immunoglobulin however pathophysiological roles of them remain unclear. Further studies with molecular and cellular analysis should be carried out to elucidate roles of cytoplasmic granules. [Display omitted] DisclosuresHagiwara:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Prognostic Value of the Parameters of Myeloma Bone Disease Signaling in Patients with Newly Diagnosed Multiple Myeloma Treated with Proteasome Inhibitors

Aims: The aim of our study was to assess the prognostic potential of parameters reflecting myeloma bone disease (MBD) assessed at the time of multiple myeloma (MM) diagnosis with respect to the extent of the disease, treatment approach and response to treatment.Patients and methods: We assessed prospectively a cohort of 52 patients with newly diagnosed multiple myeloma indicated for treatment initiation. The median age was 68 years (40-88) with M/F ratio 1:1,3. All patients were treated initially using proteasome inhibitor (PI) based regimen - either bortezomib based (N=48) or carfilzomib based (N=4). 15 patients (29%) underwent autologous stem cell transplant (ASCT). 3 patients only continued with lenalidomide based maintenance.We evaluated parameters reflecting the extent of the disease and bone involvement, presence of extramedullary masses, and activation of MBD signaling pathways with respect to treatment response and progression free survival (PFS). For the assessment of the extent of bone involvement we used whole-body techniques, either low-dose computed tomography scan (LD-CT) or magnetic resonance imaging (WB-MRI) or both. Following parameters reflecting MBD signaling were assessed from peripheral blood: hepatocyte growth factor (HGF, Human HGF Quantine ELISA), macrophage inflammatory factor alpha (MIP-1 α,Human CCL3/MIP-1a Quantikine ELISA), Syndecan-1 (Human Syndecan-1 (CD138) ELISA), osteoprotegerin (OPG, Human Osteoprotegerin ELISA), Activin A (Human Activin A Quantikine ELISA), Dickkopf-related protein-1 (DKK1, Human DKK-1 Quantikine ELISA), Annexin A2 (Human Annexin A2 ELISA kit), nuclear factor-kappa B (NF-κB, Human Nuclear factor-kappa B),Sclerostin (Sclerostin ELISA kit, Biomedica), matrix metalloproteinase 9 (MMP9, BlueGene Biotech ELISA kit).For statistical estimation we used Kaplan-Meier analysis, Chi-square test, with log rank test (Mantel-Cox) at p < 0,05. To construct the PFS curves for each serum parameter we used median levels as cut-off for even distribution.Results: PFS of the whole cohort was 21months. Overall survival did not reach median (M) yet, with 36-month survival of 79,6%. Despite low patient count there were significant differences between patients reaching complete remission (CR), very good partial remission (VGPR) and partial remission (PR) with PFS medians 36 vs 23 vs 17 months (p = 0,039, RR 3,189). The curves reflecting relationship of PFS and Durie-Salmon staging system showed better course with lower stages, still, the limited number of patients with stage I (N=3) precluded valid statistical estimation. Similarly, we could trace differences between ISS stages (M not reached vs 20 vs 17 months), the difference was, however, not statistically significant.Out of the whole cohort, 16 patients were found to have an extramedullary myeloma. Interestingly, there was no significant difference in PFS based on the presence of extramedullary disease. Similarly, we did not find significant difference with respect to skeletal involvement based on LD-CT or WB-MRI.From the selected parameters of MBD signaling, we found significant correlation to PFS in the case of HGF and MIP-1α. Patients with HGF≤ 3048pg/mL had significantly better PFS than patients with HGF>3048pg/mL (M 36 vs 17 months, p = 0,001, RR 3,835), and patients with MIP-1α≤25,5pg/mL had sigificantly better PFS than patients with MIP-1α>25,5pg/mL (29 vs 17 months, p = 0,025, RR 2,361).With regard to treatment apporach, patients undergoing ASCT had significantly better PFS than patients with standard treatment only (M not reached vs 17months, p = 0,0005).Conclusions: We found statistically significant prognostic value of HGF and MIP-1α in patients with newly diagnosed MM treated using PI based induction treatment. Despite limited number of patients, our cohort confirmed the significance of the depth of treatment response and ASCT on PFS. Interestingly, patients with extramedullary disease treated with PI based regimen did not have adverse PFS with respect to patients without the presence of extramedullary massess.With support of the grant IGA_LF_2016_001. DisclosuresNo relevant conflicts of interest to declare.

Is it feasible to use granulocyte-colony stimulating factor alone to mobilize progenitor cells in multiple myeloma patients induced with a cyclophosphamide, thalidomide and dexamethasone regimen?

BackgroundCyclophosphamide plus thalidomide as induction for multiple myeloma patients eligible for autologous stem cell transplantation may be a limiting factor for cell mobilization. The minimum acceptable mobilized peripheral blood stem cell count to prevent deleterious effects during transplantation is 2.0 × 106 CD34+ cells/kg. Combining other treatments to granulocyte-colony stimulating factor, such as cyclophosphamide, could overcome the mobilization limitation. The objective of this study was to assess the number of CD34+ cells mobilized using granulocyte-colony stimulating factor with and without cyclophosphamide after induction with cyclophosphamide, thalidomide and dexamethasone.MethodsA retrospective study was performed of a cohort of multiple myeloma patients submitted to autologous stem cell transplantations at two Brazilian centers between May 2009 and July 2013. The oral cyclophosphamide and thalidomide induction doses used were 1500 mg/month and 100–200 mg/day, respectively. Mobilization doses were 10–15 mcg/kg granulocyte-colony stimulating factor with 2–4 g/m2 cyclophosphamide, or 15–20 mcg/kg granulocyte-colony stimulating factor alone for 5 days. Collection of >2.0 × 106 CD34+ cells/kg was considered sufficient.ResultsEighty-eight patients were analyzed; only 18 received cyclophosphamide. The median age was 58 years old (range: 51–62) for the granulocyte-colony stimulating factor group and 56.5 years old (range: 54–60) for granulocyte-colony stimulating factor plus cyclophosphamide group. Fifty-two patients were male. Eighty cases (90.9%) were Durie-Salmon Staging System III-A/B and 38 (44.7%) and 20 cases (23.5%) were International Staging System 2 and 3, respectively. The group that received cyclophosphamide collected a higher median number of progenitor cells [3.8 (range: 3.1–4.4) vs. 3.2 (range: 2.3–3.8)] (p-value = 0.008). No correlation was observed between better responses or number of induction cycles and the number of cells collected.ConclusionThe number of cells mobilized with granulocyte-colony stimulating factor plus cyclophosphamide was higher. However, in both groups, the median number of CD34+ cells was sufficient to perform a single autologous stem cell transplantation; no deleterious effects were reported during harvesting.

Clinical Features of 46 Multiple Myeloma Patients with Different Renal Pathology

To explore the clinical features of multiple myeloma with different renal pathology, and to evaluate its prognosis. Clinical features and prognosis of 46 multiple myeloma patients with different renal pathology were analyzed retrospectively. According to renal pathology, the 46 patients were divided into 3 groups: cast nephropathy (24 cases), amyloidosis (15 cases) and other type (7 cases). By durie-Salmon staging system, 70.8% cases (17/24) in the cast nephropathy group were in Phase III, 90.9% (20/24) were in subtype B, while in amyloidosis group 53.3% (8/15) were in Phase I, 40% (6/15) were in subtype B, and in other types group, 71.4% (5/7) were in phase III, 57.1% (4/7) were in subtype B, the differences among them were statisticaily significant (P < 0.05). In cast nephropathy group, the monoclonal immunoglobulin could not be detected in 75% (18/24) cases, which was light chain type, while immunoglobulin in amyloidosis and other type groups were mainly IgG type in 73.3% (11/15) and 71.4% (5/7) respectively, the difference among them also was statistically significant (P < 0.05). The median survival time of patients in cast nephropathy group was 11 months, while that in amyloidosis and other type groups was 19 and 18 months, the differences among 3 groups were not significant (P > 0.05). In renal pathologic types, the cast nephropathy is the most common, followed by amylordosis. The multiple mycloma patients with defferent renal pathology show different clinical features. The multiple myeloma patients with renal amyloidosis have slighter clinical manifestations possibly with a better prognosis. Meanwhile, the non-amyloidosis types, especially cast nephropathy may predict a more serious manifications with poor prognosis.

Macrofocal Multple Myeloma Is a Particular Subgroup of Multiple Myeloma

Some young multiple myeloma (MM) patients, coined macrofocal MM, have been reported to present with multiple lytic bone lesions and less than 10% bone marrow plasma cells (BMPCs). They usually have low tumor burden and favorable outcome. To further understand the clinical and laboratory features of macrofocal MM, we retrospectively analyzed about 1000 symptomatic MM patients of two centers and found that 49 (4.9%) patients fulfilled the criteria of macrofocal MM. Median age was 54 years; 39 (80%) were male. The immunoglobulin subtype included IgG (13), IgA (5), IgD (4), light chain only (4) and non-secretory type (23). International Staging System (ISS) stage 1 in 45 (92%), and no stage 3 patient. Durie-Salmon (DS) Staging System stage 3A in 48 (98%), and 2A in 1. Extramedullary plasmacytomas (EMPs) in 39 (80%) patients. The mean percentage of BMPCs was 2.1%, and 44 (90%) patients had less than 5% BMPCs. No patients had hypercalcemia and renal impairment. FISH cytogenetics, available in 11 patients, showed IgH translocation in 7, 13q del in 2, t(4;14) in 1, 1q21 amp in 6 and p53 del in 2 patients. Serum free light chain (sFLC), available in 14 patients, showed abnormal sFLC in 7 of 14 patients and 4 in 7 non-secretory type patients. Thirty eight (77.6%) patients received new drug-based induction therapies and 14 patients received autologous stem cell transplantation (ASCT) as consolidation therapy. After a median follow-up of 36 months,the estimated median progression-free survival (PFS) was 41 months and the median overall survival time (OS) had not been reached. Forty four macrofocal MM with ISS stage 1 and DS stage 3A were compared to all (93) typical symptomatic MM patients who were diagnosed at the same period with the same stages according to both ISS and DS Staging System. For macrofocal MM, there were significantly more male patients and EMPs, higher hemoglobin levels and lowerb2-microglobulin (b2M) levels than that of typical MM. There were no significant differences in the proportions of patients received novel agents-based chemotherapy and ASCT between two groups, however, the estimated median PFS of macrofocal MM was significant superior to typical MM (41 vs 23 months, respectively; P= 0.001) (Figure 1), and the estimated median OS was also better in macrofocal MM than typical MM (not reached vs 61 months; P= 0.004) (Figure 2). Multivariate analysis showed that only the type of disease was the independent prognostic factor of both PFS and OS. In summary, Macrofocal MM is a particular subgroup of MM with multiple bone lesions and lower tumor burden, higher frequency of EMPs, and better survival than typical symptomatic MM. [Display omitted] [Display omitted] DisclosuresFan:The National Natural Science Foundation of China: Research Funding. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees.

Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma.

Bortezomib is used to treat patients with multiple myeloma. It is primarily metabolized by the enzyme cytochrome P450 (CYP). Variations in the capacity of bortezomib metabolism affect the treatment outcomes and the side-effects experienced by patients. In the present study, polymorphisms in the CYP3A4 and CYP2C19 genes were analyzed by polymerase chain reaction in 56 newly-diagnosed patients with multiple myeloma. The polymorphisms analyzed included the c.681G>A, c.636G>A and c.-806C>T polymorphisms of CYP2C19. The CYP3A4 gene was sequenced after amplification and was classified into normal and mutant types. Associations between the metabolizer genotypes of CYP3A4 and CYP2C19, the therapeutic efficacy of bortezomib-based regimens, and the occurrence of peripheral neuropathy were studied. The results identified no significant differences in gender, serum β2 microglobulin, creatinine, blood albumin, isotypes, and the Durie-Salmon and International Staging System stages between the CYP2C19 poor + intermediate metabolizer types and the extensive + ultrarapid metabolizer types. In addition, it was revealed that the CYP2C19 and CYP3A4 phenotypes did not affect the efficacy of bortezomib-based regimens, nor were they correlated with peripheral neuropathy. Additional large-scale studies are required in order to evaluate the role of CYP enzymes in bortezomib treatments for patients with multiple myeloma.

Understanding multiple myeloma

Understanding multiple myeloma

A Case of Occipito-Thoracic Fusion for Skull Base and Cervical Multiple Myeloma

Multiple myeloma is a systemic malignancy that causes bone destruction due to bone marrow infiltration. Treatment options for myeloma of the spine include radiation therapy and surgery. The case of a 59-year-old woman with multiple myeloma is reported. She was Stage 3B according to the Durie-Salmon staging system and responded to highdose chemotherapy and peripheral blood stem cell transplantation and achieved complete remission. However, her skull base and cervical bones showed marked osteolysis which required external fixation and bed rest. Surgery with occipito-thoracic (OT) fusion was performed, which yielded neurological improvement and could walk completely on her own 2 months after surgery. She had no recurrence over a 5-year follow-up period. Surgical stabilization allowed this multiple myeloma patient to remain ambulatory.

Light chain multiple myeloma, clinic features, responses to therapy and survival in a long-term study.

BackgroundWe intended to investigate the long-term clinical characteristics, responses to therapy and survival in patients with lightchain multiple myeloma (MM).MethodsNinety-six patients were enrolled into the study. There were 42 κ-chain MM patients and 54 λ-chain MM patients. All the patients werestage III in the Durie-Salmonstaging system. Among them, 66 patients received Velcade (bortezomib) treatment and the other 30 did not.ResultsThe main symptoms of these patients included bone pain (77.1%), weakness and fatigue (12.5%), foamy urine (8.3%) and extramedullaryplasmocytomas (33.3%). The overall response rate (ORR) was 95.5% in patients treated with Velcade and 60%in the patients without. The median survival times were 23 months in patients treated with Velcade and 12 months in patients without. The median time of progression-free survival (PFS) was nine months in patients treated with Velcade and five months in patients without. The one-year PFS and two-year PFS were 37% and 25%, 27% and 9% for patients treated with Velcade, or without, respectively. The three-year overall survival (OS) and five-year OS were 33% and 24%, 28% and 9% for patients treated with Velcade, or without, respectively. There was no significance in OS between the two groups (P = 0.335). But there was significant difference in PFS between the two groups (P = 0.036).ConclusionsOur long-term study demonstrated that patients with lightchain myeloma appeared to have more aggressive disease courses and poor outcomes, which could be improved by treatment with Velcade.

Myeloma genetics and genomics: practice implications and future directions.

Multiple myeloma (MM) is a heterogeneous, clonal disorder of the plasma cells originating from the B-cell line. The diagnosis and monitoring of MM requires routine measurement of biomarkers such as serum protein electrophoresis, urine protein electrophoresis, serum free light chains, among others. Prognostic models such as the Durie-Salmon staging system and International Staging System are available and account for the disease burden. Advanced biomarker and genetic testing includes cytogenetics, fluorescent in situ hybridization, and gene expression profiling to estimate the aggressiveness of the disease and personalize the patient's treatment. Future goals of therapy will be to achieve minimal residual disease (MRD), which incorporates biomarkers and genomic data. MRD testing might provide a better estimate of the depth of response to therapy and overall survival. A robust genomic program of research is still needed to provide additional information for the best MM care practices and to gain new strategies to treat the disease, in particular, in the relapsed and/or refractory setting.

Follicular Erythematous Papules with Keratotic Spicules: A Quiz

A 63-year-old man presented with an asymptomatic “rash” that had started on the face 6 months ago and subsequently extended to the trunk and the arms. A few days before consultation at our department, he had been admitted to the Department of Haemato-Oncology due to unclear anaemia. Laboratory workup, serum electrophoresis and bone marrow biopsy had revealed multiple myeloma type IgG kappa stage III according to the Durie-Salmon staging system. The Follicular Erythematous Papules with Keratotic Spicules: A Quiz

Bortezomib-Based Chemotherapy Regimens Can Inmprove The Complete Remission In Newly Diagnosed Multiple Myeloma Patients With Bcl-2 and Survivin Overexpression

Compared with the traditional chemotherapeutic agents, Bortezomib-based chemotherapy regimens can increase the complete remission and improve the prognosis significantly in the newly diagnosed multiple myeloma patients. Molecular markers which can predict the chemotherapeutic efficacy and safety could help the physicians to make the right decisions and benefit the patients, and it has been one of most interesting research fields in MM. It has been reported that Survivin and Bcl-2 was involved in the adverse clinical events and therapeutic resistance, respectively. In order to investigate the relationship between the Survivin and Bcl-2 expression and the different regimens therapeutic efficacy, we retrospectively studied the proteins expression in the bone marrow biopsy specimens by inmmunohistochemistry and the efficacy of different chemotherapy regimens in the newly diagnosed MM in a single center of Tongji Hospital. Total 59 newly diagnosed MM were admitted into this study. The positive expression rate for Survivin and Bcl-2 was 35.3%（n=21）and 73.5%（n=43）, respectively. The protein expression had no relationship with the Durie-Salmon and International Staging System stratification, which suggested that Survivin and Bcl-2 were not responsible for the clinical manifestations. Bortezomib-based regimens (n=22) could effectively decrease the tumor burden and achieve response (CR+PR: 67.5% ). The non-bortezomib regimens (n=37), containing VAD(T), MP(T), TAD, were effective in the absent of Survivn and Bcl-2 expression(n=7; CR+PR 62.5% ). When Survivin and Bcl-2 were single or double positive (n=30), the newly diagnosed MM patients had no response for non-bortezomib regimens with none reaching complete remission or partial remission (p=0.0088). According to this study, we recommend the newly diagnosed MM which were Survivin and Bcl-2 single or double positive by inmmunohistochemistry received the regimens containing bortezomib for anti-myeloma therapy. Disclosures:No relevant conflicts of interest to declare.

Circulating microRNA 483-5p in multiple myeloma as a novel biomarker for diagnosis and predicting survival

BackgroundMicroRNAs (miRNAs) are a class of small non-coding single stranded RNAs whose dysregulation of expression plays an important role in cancer development. Circulating miRNAs are novel biomarkers in several cancers including acute myeloblastic leukemia and diffuse large B cell lymphoma. Thus, we explored whether the miRNAs in plasma could be a useful clinical biomarker for multiple myeloma (MM) patients. MethodsMiRNA microarray was conducted to determine deregulated miRNAs in plasma of MM patients. TaqMan real-time PCR was used to validate the results. Receiver operating characteristic (ROC) analysis was performed to reveal the diagnostic accuracy of the significantly deregulated miRNAs as potential biomarkers. The Kaplan-Meier and log-rank tests were used to assess the correlation of miRNAs with progression-free survival (PFS). ResultsThe expression levels of five miRNAs in plasma were up-regulated while eight miRNAs were down-regulated in MM patients compared to normal controls according to microarray. Validation of the five miRNAs detected as promising biomarkers was carried out. MiR-483-5p was found to have potential as diagnostic biomarkers in myeloma. ROC analysis revealed that miR-483-5p had considerable diagnostic accuracy, yielding an ROC-AUC (the areas under the ROC curve) of 0.722 (sensitivity 61%, specificity 75%). The expression levels of miR-483-5p are associated with Durie-Salmon (DS) staging system and ISS staging system (p < 0.01). After a median follow up of 10 months (range: 2-60 months) from diagnosis, the median PFS of patients highly expressing miR-483-5p and of low expression patients was 11 and 21 months, respectively (p=0.04). ConclusionsThese data demonstrate that miR-483-5p highly expresses in the plasma of MM patients. MiR-483-5p may serve as a diagnostic and prognostic biomarker in MM. Disclosures:No relevant conflicts of interest to declare.

Extramedullary Multiple Myeloma Associated With Reduced Overall Survival: A Retrospective Single-Center Study

IntroductionMultiple Myeloma (MM) is an incurable neoplasm, however recent advancements in therapies have led to median overall survival of 7-10 years in standard risk patients. High risk patients still succumb to the disease within 3 to 5 years. Traditionally used clinical prognostic markers such as the International Staging System (ISS), the Durie-Salmon (DS) staging system, and cytogenetics do not adequately predict response to novel agents or overall prognosis. We previously presented data identifying high risk sub-groups that succumb to shorter progression free survival (PFS) and overall survival (OS) after hematopoietic stem cell transplant (HSCT). Extramedullary disease (EMD) was a highly significant risk factor for poor survival. MethodsA retrospective single institution cohort study was performed of 251 patients who underwent HSCT for MM between 1/1/2001 and 12/31/2011. Of these 251 patients, 18 were identified as having EMD, which was defined by the presence of ≥ 2 plasmacytomas in organs other than bone marrow or bone at any stage of disease. Data points collected included patient and disease characteristics, ISS and DS stage, cytogenetics and FISH, induction therapy, type and number of HSCT, treatment type and cycles, as well as maintenance therapy. Outcome measures included overall response rate (ORR), PFS and OS. Descriptive statistical analysis was conducted for all primary and secondary endpoints. Univariate and multivariate analysis were conducted using the Cox proportional hazards regression model. ResultsPatients with EMD represented 6.6% of our total population. Patient and disease characteristics are found in table 1. Seven of 18 patients had died by the time of data collection. With a median follow up time of 29 months, the median PFS and OS for the entire group (n= 251) compared to the EMD group (n= 18) were PFS: 22.3 months (95% CI 19.75 – 30.32) vs. 12.9 and OS: 57.3 months (95% CI: 46.52 - 77.77) vs. 17.2 (Figs 1 and 2). Results of univariate and multivariate analysis are in table 2. [Display omitted] Table 2Uni and Multivariate analysis of PFS and OS of Patients with EMDPFSOSHazard Ratio (95% Confidence Interval)Pr>ChiSqHazard Ratio (95% Confidence Interval)Pr>ChiSqUnivariate analysis1.65 (0.84- 3.25)0.1402.43 (1.11 – 5.29)0.026Multivariate analysis1.55 (0.63- 3.83)0.3523.65 (0.14 – 9.36)0.007 [Display omitted] [Display omitted] ConclusionExtramedullary multiple myeloma represents a small but highly aggressive subgroup of multiple myeloma. It prevails as a poor prognostic indicator despite the use of novel agents, yet it is not included in traditionally used staging systems. Further confirmatory studies are needed, and likely, new therapeutic approaches will be required for MM patients with EMD. Disclosures:Chen:Genzyme: supported database used for this study Other. Scott:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.