Association of PML Expression with Chemotherapy-Resistance In Multiple Myeloma Cells

Abstract Abstract 2959 Background: Although several novel agents have improved the prognosis of patients with multiple myeloma (MM), it still remains an incurable disease because of the difficulty to eradicate MM cells by current therapeutic approaches. Recent studies have revealed that a subset of malignant cells, cancer stem cells, contribute to chemotherapy-resistance in cancer treatment. Promyelocytic leukemia gene product (PML), known as a tumor suppressor through a variety of cellular functions in a nuclear macromolecular structure called the PML nuclear body, has been reported to be responsible for the chemotherapy-resistance by regulating cell cycle in chronic myeloid leukemia. We therefore investigated the impact of PML expression on the cellular proliferation status of MM cells and patients' prognoses. Materials/Methods: Bone marrow clot sections from 48 patients with newly diagnosed MM from Jan 1998 to Dec 2009 before any therapy at diagnosis were obtained, and analyzed, according to appropriate procedure approved by IRB at the Tokai University School of Medicine (Kanagawa, Japan) with written informed consent. They were doubly-stained with a combination of anti-PML/anti-CD138 and anti-Ki67/anti-CD138. For evaluation of the relation between PML status and cellular proliferation, the positive rates of PML and Ki67 in CD138 positive cells were compared. For investigation of the impact of PML expression on the prognosis of MM, the patients were divided into 3 groups, according to the PML positive rates in the CD138 positive cells: negative/low (less than 25 percentile: 12 cases), intermediate (from 25 to 75 percentile: 24 cases) and high (more than 75 percentile: 12 cases). Their overall survivals were compared using log-rank test. Furthermore, the PML positive rates between before and after treatments were compared using paired t-test. Results: The median observation period of 48 cases was 915 days. The median age of the patients was 62.5 (38-76) at diagnosis. All the patients were underwent combination chemotherapies containing alkylating agents as initial therapies. Two and nine patients were underwent allogeneic and autologous stem cell transplantation during the clinical courses, respectively. The numbers of patients of international staging system (ISS) stage I, II and III were 17, 14 and 17 cases. The PML positive rates in each case ranged from 0% to 83.8%. They were not correlated with ISS stages (Spearman r = 0.083) and the Ki67 positive rates (Spearman r = -0.13). The PML positive rates in the negative/low, intermediate and the high groups were less than 22.1%, from 22.1 to 56.6% and more than 56.6%, respectively. No significant difference in overall survival was observed among the 3 groups (p>0.05). However, there were significant differences in two year survival rate when the 3 groups were compared (100%, 85.2% and 54.7%; p=0.015) (Fig. 1). In 13 patients whose bone marrow clot sections were sequentially collected, the PML positive rates after treatments were significantly higher than those at diagnosis (p=0.0042) (Fig. 2). Especially, PML positive rates in all the 3 patients from the negative/low group were progressively increased (0.3 to 82.6%, 14.1 to 100%, 19.0 to 37.5%), and 2 of them died due to disease progression. On the other hand, 2 patients whose PML positive rates decreased after treatment were alive more than 5 years without therapies. Conclusion: Our data indicated that the level of the PML expression at diagnosis was a possible prognostic factor for early course of the disease (2 years after diagnosis). Chemotherapies might induce PML expression in MM cells or select PML positive MM cells. These findings suggest that PML expression presumably reflect chemotherapy-resistance in MM cells. The molecular mechanism of the association is now under investigation. Disclosures: No relevant conflicts of interest to declare.

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TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.4866.4866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4866-4866

Author(s):

Luciana Correa Oliveira de Oliveira ◽

Juliana Alves Uzuelli ◽

Ana Paula Alencar de Lima Lange ◽

Barbara Amelia Aparecida Santana-Lemos ◽

Marcia Sueli Baggio ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Prognostic Factors ◽

Bone Disease ◽

Cox Regression ◽

Conflicts Of Interest ◽

Newly Diagnosed ◽

Significant Difference ◽

The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

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Immunophenotypic Response After Allografting In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3371.3371 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3371-3371 ◽

Cited By ~ 1

Author(s):

Luisa Giaccone ◽

Lucia Brunello ◽

Roberto Passera ◽

Moreno Festuccia ◽

Milena Gilestro ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

First Line ◽

Significant Difference ◽

The Impact

Abstract Background Minimal residual disease (MRD) by multiparameter flow-cytometry recently showed a promising role in predicting outcomes in patients with multiple myeloma. However, data on immunophenotypic response (IR) after allografting are lacking. Aim To evaluate the impact of IR and compare it to conventional complete remission (CR) following allografting in myeloma patients. Methods Sixty-six consecutive patients, median age 54 years (35-66), who underwent an allograft between January 2000 and December 2011 with a follow-up of at least 3 months were included. Disease response was evaluated by serum and urine electrophoresis, and bone marrow aspirate at baseline, 3, 6, 12, 18, 24 months after transplant and yearly thereafter. Skeletal survey or MRI were performed yearly or as clinically indicated (overt relapse or complaints of bone pain). Bone marrow aspirates had to contain at least 13000 cells/µL for flow-cytometry studies and IR was defined as absence of monoclonal plasma-cells detected by 4 or 6-colour staining with the following antibodies: CD38, CD138, CD56, CD19, CD45, cyKappa, cyLambda. CR was defined according to standard criteria (Durie et al, Leukemia 2006; 20:1467-73). Results Conditioning regimen was non-myeloablative 2Gy TBI-based in 55 patients, reduced intensity (fludarabine-melphalan-based) in 10 and myeloablative in 1 patient. Post-grafting immunosuppression consisted of cyclosporine with mycophenolate mofetil or methotrexate. Donors were HLA identical siblings in 58 patients and unrelated in 8. Only 1 patient received bone marrow as source of stem cells. Thirty-five/66 (53%) received the allograft as part of the first line treatment, whereas the remaining 31/66, (47%) were transplanted at relapse. At the time of transplant, 5/66 were both in IR and CR, 16 were only in IR and 4 patients were only in clinical CR. All 21 patients in IR at the time of transplant maintained it, while 26/45 (58%) entered IR after the allograft. Among patients surviving at least 3 months, overall treatment related mortality was 10.6% at 3 years. After a median follow-up of 69 months (range 19-147), the incidence of acute and chronic graft-versus-host disease was 45.6% and 49.3% without significant difference between responsive and non-responsive patients. At follow-up, overall, 24 patients achieved CR and IR (CR/IR group), 21 achieved IR but not CR because of persistence of urine/serum M-component (noCR/IR group), and 21 did not achieve either CR or IR (noCR/noIR group). Interestingly, none achieved CR without IR. Median overall survival (OS) and event-free survival (EFS) in patients who achieved IR were 96 and 55 months versus 36 and 7 months in those who did not (p<0.001). Median OS and EFS were not reached and 59 months in the CR/IR group, 77 and 15 months in the noCR/IR, and 30 and 5 months in the noCR/noIR respectively (p<0.001 for both EFS and OS-fig.1). In univariate analysis, being in the CR/IR group was the only significant predictor for prolonged OS and EFS (p<0.001). Of note, cumulative incidence of extra-medullary disease at first relapse after the allograft was 4% in the CR/IR, 32% in the noCR/IR and 15% in the noCR/noIR groups respectively (p<0.001). Receiving the allograft as first line therapy or later during the disease course did not significantly impact on OS and EFS. Conclusion The achievement of IR confers a favorable impact on OS and EFS after allografting. A higher incidence of extra-medullary in the noCR/IR group (some 30% of our patient cohort) may suggest that myeloma cells escape immune control outside the bone marrow. In this group, imaging studies such as positron emission tomography may clinically be indicated during follow-up to detect early relapse. Disclosures: No relevant conflicts of interest to declare.

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Association of bone marrow plasma cell infiltration pre-auto transplant with adverse outcomes in multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8102 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8102-8102

Author(s):

Qaiser Bashir ◽

Simrit Parmar ◽

Yvonne Dinh ◽

Sofia Qureshi ◽

Gabriela Rondon ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Standard Of Care ◽

Adverse Outcomes ◽

Rank Test ◽

High Group ◽

Significant Difference ◽

Bone Marrow Plasma ◽

The Impact

8102 Background: Auto-stem cell transplantation (SCT) has become the standard of care for eligible patients (pts) with multiple myeloma (MM). However, the impact of bone marrow (BM) plasma cell (PC) percentage before SCT is not yet known. Methods: Retrospective review of 1489 MM pts who underwent auto-SCT from 7/8/98 – 12/31/2010 with post-induction, pre-SCT BM biopsy information available. Pts were divided into 2 groups: <10% PC infiltration (“PC low”) and >10% PC infiltration (“PC high”). Progression-free (PFS) and overall (OS) survivals were estimated by the Kaplan-Meier method. Log-rank test was performed to test differences in survival. Results: 1489 pts were studied. 1174 pts had <10% involvement of BM by PCs and 315 had > 10% involvement. For pts in the PC low group, 32% had a CR, 20% had a VGPR, 31% had a PR, 13% had <PR and 3% had progressive disease (PD) after SCT. For pts in the PC high group, 11% had a CR, 14% had a VGPR, 48% had a PR, 21% had <PR and 5% had PD after SCT. Median PFS was significantly shorter for the PC high group vs the PC low group (24.8 vs 29.5 months, p=0.05), as was median OS (52.5 vs 79.4 months respectively, p<0.001). When only pts who had a PR to induction were examined, there was a significant difference in both PFS (24.4 vs 33.2 months, p=0.04) and OS (58.3 vs 81.2 months, p =0.002) for the PC high vs PC low groups, respectively. For the 1299 (87%) pts treated in the era of novel therapeutics (after 2000), the differences between the PC high and PC low groups were maintained for both PFS (24.4 vs 29.5 months respectively (p=0.029)) and OS (54.8 vs 88.4 months respectively, p<0.001). Chemo-mobilization before SCT did not improve PFS or OS but this was done in only 44 (14%) of PC high pts. Conclusions: PC BM infiltration before auto-SCT is associated with a worse outcome. This finding persists in pts with a PR before SCT. Thus BM disease burden may further stratify pts with a PR. Though additional therapy did not significantly change the outcome for pts with high PC burden, this was done only in a minority of pts. Additionally, differences between PC high and PC low groups are maintained despite new salvage agents over the last 10 years. Further prospective study is warranted to determine the true impact of BM PC infiltration.

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Short and Long Term Efficacy of Autologous Bone Marrow Cells To Support Intensive Chemotherapy in Patients Failing Peripheral Blood Stem Cell Mobilization.

Blood ◽

10.1182/blood.v110.11.2999.2999 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2999-2999 ◽

Cited By ~ 1

Author(s):

Tara Seshadri ◽

Khalil Al-Farsi ◽

Julie Stakiw ◽

Clement Ma ◽

Ronnie Saragosa ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Peripheral Blood ◽

Intensive Therapy ◽

Significant Proportion ◽

Rank Test ◽

High Dose ◽

Transfusion Requirements ◽

Significant Difference ◽

The Impact

Abstract Introduction: Most autologous hematopoietic cell transplants (AHCT) are performed using peripheral blood mobilized progenitor cells (PBSC). However a small but significant proportion of patients (pts) are unable to mobilize adequate numbers of PBSC. The use of G-CSF-stimulated bone marrow (BM) derived progenitor cells is one method to circumvent this problem and enable AHCT to be performed. However, the long and short-term ability to engraft and the impact of this method on overall and progression free survival (OS and PFS) have not been established. Methods: We reviewed 52 pts (17 AML, 24 NHL, 11 HL) who failed PBSC collection between Jan 1999-Dec 2006 (<2×5106 CD34+cells/kg) and underwent G-CSF stimulated BM harvest to permit high dose therapy (etoposide 60 mg/kg + melphalan 160–180 mg/m2, + TBI 500 or 1200 cGy for pts with AML). 23 pts were supported by harvested BM (44%) and 29 (56%) with a mixture (Mx) of BM and PBSC. Overall and PFS was compared to pts undergoing AHCT using chemotherapy-mobilized PBSCs (n=440) in the same time period (AML n=32, NHL n=273, HL=135) who had a similar median age, pre-transplant induction, salvage therapy and intensive therapy regimens. Kaplan-Meier curves and the Log-rank test were used to compare the OS and PFS between cases and controls. Due to skewed data, the non-parametric Wilcoxon Rank Test was used for simple comparisons of clinical factors. Results: Median age of the cohort at AHCT was 43 years (range 24–68, 67% females). Status prior to AHCT was CR 44%, PR 54%, and SD 2%. Number of chemotherapy regimens (median):AML: 3; NHL: 3; HL: 2. Median BM CFU-GM infused was 4.4×104/kg and median PBSC infused was 0.1×106/kg (n=29). Median follow up times for AML/NHL/HL was 20, 18 and 50 months respectively. Twenty-three pts died:18 from disease progression, 4 treatment-related (TRM) and one of second cancer. Median engraftment time for neutrophils (>0.5×109/L) was 14 days and platelets (>20×109/L) was 27 days and was significantly longer compared to pts who received PBSC alone (10 and 11 days, respectively, p<0.0001). Pts receiving Mx grafts had significantly faster engraftment vs those receiving BM alone (p<0.001). Transfusion requirements (median) during the ASCT admission were 4 units for RBC and 25 units for platelets. Median 12 month Hb, platelet and neutrophil counts were 116 g/L (70–149), 113×109/L (21–238) and 2.4×109/L (0.3–6.2). Two year OS of patients who received harvested BM versus PBSC alone was: 63%/71% (AML, p=0.51), 57%/70% (NHL, p=0.04) and 71%/94% (HL, p=0.04). There was no significant difference in PFS between BM recipients and controls. Non relapse mortality was 5/52 (9.6%) for pts receiving BM compared to 18/440 (4%) supported by PBSCs. Conclusion: Performing an AHCT with BM in patients failing PBSC collection is feasible. Although engraftment is significantly delayed it appears sustained at 12 months post AHCT. Overall survival is inferior compared with patients receiving PBSC alone. Reasons for inferior disease-specific outcomes for pts with lymphoma receiving BM need to be determined.

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Variable Risk of Second Primary Malignancy In Multiple Myeloma Patients of Different Ethnicities

Blood ◽

10.1182/blood.v118.21.678.678 ◽

2011 ◽

Vol 118 (21) ◽

pp. 678-678

Author(s):

Pedram Razavi ◽

Gaurav Patel ◽

Asher Chanan-Khan ◽

Sikander Ailawadhi

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Latency Period ◽

Incidence Rates ◽

Second Primary ◽

Solid Organ ◽

Specific Patient ◽

Significant Difference ◽

Race Ethnicity ◽

The Impact

Abstract Abstract 678 Background: Second primary malignancies (SPM) among multiple myeloma (MM) patients have been reported with an estimated incidence varying from 1%–15%. We have previously reported that significant disparity exists in MM survival across patients of different ethnicities. We undertook a Surveillance Epidemiology and End Results (SEER) based analysis to describe the incidence of SPM among MM patients of different ethnicities, in order to explore the variable impact that SPM might have on MM outcomes of patients across racial subgroups. Methods: SEER database was used to examine the standardized incidence rates (SIR) of SPM among MM patients diagnosed between 1973–2008. Observed to expected ratio (O/E) of SPM was calculated using incidence rates of cancers for the general population. The 95% confidence limits (CI) were constructed using Fisher's exact test. The analysis was restricted to patients with MM as first primary, microscopic confirmation of diagnosis, reporting sources not coded as autopsy- or death-certificate-only, and SPM reported more than 2 month after MM diagnosis. Mutually exclusive race/ethnicity categories were: African-Americans (AA), Asians/Pacific Islanders (API), Hispanic whites (HW), Non-Hispanic whites (NHW), and others. The risk of SPM among MM patients was explored by ethnicity, type of SPM, and latency period. Results: A total of 3090 cases of MM with SPM were diagnosed between 1973–2008, of which, 2021 patients met our inclusion criteria. Stratification of SPM by ethnicity revealed: 387 AA (19%), 72 API (4%), 51 HW (3%), 1500 NHW (74%) and 11 other (<1%) cases. There was an average 4.7-year latency period between diagnosis of MM and SPM (mean age 68.2 and 72.9 years, respectively). The latency period was not significantly different by type of SPM (solid organ vs. hematological) or ethnicity. AA had the youngest age at diagnosis for both, MM and SPM (65.6 and 70.1 year, respectively). (Figure 1) For all SPM sites analyzed together, there was no significant difference between the observed and expected incidence (O/E 0.98; 95% CI 0.94–1.02). However, O/E risk was significantly decreased for solid organ SPM (N=1695; O/E 0.92; 95% CI 0.88–0.96) and increased for hematological malignancies (N=263; O/E 1.63; 95% CI 1.44–1.84). Highest excess risk among all SPM was noted for acute non-lymphocytic leukemia (ANLL) (O/E 6.51; 95% CI 5.37–7.83). The overall risk of observed SPM was not different from expected rates by ethnicity, with the exception of HW who had a significantly decreased overall SPM risk. Table 1 summarizes significant results of O/E risk of SPM by race and site. HW and NHW were less likely to develop overall solid organ SPM. Within solid organ sites, HW had a significantly decreased O/E risk of developing lung/bronchus and prostate SPM. NHW were the only ethnic subgroup with an increased O/E risk of developing melanoma of skin, while the O/E risk of developing SPM of kidney/renal pelvis was increased only among AA. The risk of ANLL as SPM was significantly increased among AA, API, and NHW, while risk of NHL as SPM was only increased among NHW. Conclusion: Exploring potential causes of outcome disparities is important for evaluating disease characteristics and optimal triaging of healthcare resources for specific patient populations. We have performed the largest population-based analysis for the risk of SPM in MM patients stratified by race/ethnicity. We found that the risk of developing SPM among MM patients is variable depending on the patient's ethnic background. This warrants further exploration of the impact of SPM on outcomes of MM patients across different racial subgroups. Disclosures: No relevant conflicts of interest to declare.

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Improved Survival in African American Patients Undergoing Autologous Transplant for Multiple Myeloma in the Chemotherapy and Novel Agent Era

Blood ◽

10.1182/blood.v128.22.4631.4631 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4631-4631

Author(s):

Karen Sweiss ◽

Annie L. Oh ◽

Gregory S. Calip ◽

Damiano Rondelli ◽

Pritesh R. Patel

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

African American ◽

Proteasome Inhibitor ◽

Conflicts Of Interest ◽

Hematologic Toxicity ◽

Racial Groups ◽

Significant Difference ◽

The Impact ◽

Novel Agent

Abstract African Americans (AA) have a 2- to 3-fold higher incidence of multiple myeloma (MM) when compared to other racial groups. Evidence suggests that there may be differences in the biology of MM, which confer a more favorable prognosis in AA patients. Prior studies are conflicted as to whether AA patients achieve equal or improved outcomes compared to non-African American (non-AA) patients. Our purpose was to evaluate the impact of AA race on outcomes of MM patients undergoing ASCT at a single center in both the chemotherapy and novel agent era. One hundred and twenty-nine patients who received melphalan 200 mg/m2 and ASCT between 2000 and 2013 were included in the analysis. Sixty-one (47%) patients were African-American and 68 (53%) were non-AA. Baseline characteristics including age, FISH, cytogenetics, paraprotein subtype, median number of prior therapies and International Staging System (ISS) stage were similar between racial groups. Overall, 77 (60%) patients received any novel agent prior to transplant and 52 (40%) received only chemotherapy. More non-AA patients were male (59% vs. 38%, p=0.02), received initial induction with a proteasome inhibitor (59% vs. 28%, p=0.0007), and were treated with post-ASCT maintenance therapy (41% vs. 23%, p=0.008). Time from diagnosis to ASCT in AA patients was 10 (range: 4-144) versus 8 (range: 3-54) months in non-AA patients (p=0.01). The ASCT hospital course was similar between both groups with no significant differences in time to neutrophil and platelet engraftment as well as the duration of hospitalization. Additionally, there was no significant difference in the extra-hematologic toxicity between the two groups including the incidence of diarrhea, mucositis, and infection. Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and between 90 to 180 days after transplant. No differences were observed in pre-transplant (p=0.13) or post-transplant (p=0.28) response rates between the two groups. African American patients had a significantly improved median OS compared to non-AA patients (not reached vs. 108 months, p=0.03). We further stratified analyses of OS by those treated in the chemotherapy versus novel agent era. Improved OS was observed in both the chemotherapy (93 vs. 68 months, p=0.02) and novel agent (not reached vs. 79 months, p=0.01) treatment era. In a multivariate Cox proportional hazards model, AA race was associated with improved overall survival (adjusted HR 0.30, 95% CI 0.11 to 0.81; p=0.017). Multiple myeloma has one of the most apparent ethnic disparities in incidence and outcomes among cancers. In our study, AA patients had a longer time to transplant and received less proteasome inhibitor-based induction and post-ASCT maintenance suggesting disparities in access to care. Despite these differences in treatment, we observed improved overall survival after ASCT compared to non-AA patients. We demonstrated this improved OS in patients who had received either chemotherapy or novel agents prior to ASCT. These findings provide further evidence for more favorable outcomes among AA patients. One explanation could be a difference in disease biology that may result in a lower risk disease. Investigation of these biologic differences between AA and non-AA MM patients may increase our understanding of the pathogenesis and future treatments of myeloma. Disclosures No relevant conflicts of interest to declare.

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Serum Kappa/Lambda Ratio, An Independent Prognostic Factor at Diagnosis and Serum Free-Light Chains Level, An Early Indicator of Relapse/Progression In Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.2954.2954 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2954-2954

Author(s):

Mohamad Sobh ◽

Stephane Morisset ◽

Taoufik Guilli ◽

Sophie Ducastelle-Lepretre ◽

Fiorenza Barraco ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Conflicts Of Interest ◽

Fish Analysis ◽

Cox Regression Analysis ◽

Serum Free ◽

Treatment Type ◽

Significant Difference ◽

The Impact

Abstract Abstract 2954 Background: The serum free light chain (sFLC) analysis has been used for the diagnosis and monitoring of plasma cell dyscrasias and has proved its usefulness in disease treatment response in multiple myeloma (MM). Some studies have evaluated the prognostic value of the sFLC levels expressed as K/L ratio (sFLCR) at diagnosis. In contrast, performing this analysis during patient's follow up and on therapy is still not very well defined yet. Aim: Our first objective was to evaluate the impact of sFLCR, measured at diagnosis in MM patients, on the progression free survival (PFS) and overall survival (OS); the second objective was to assess the importance of sFLC analysis during the follow-up especially for relapse/progression detection comparing to concomitant monoclonal-protein (M-p) traditional serum protein electrophoresis (sPE). Methods: Between years 2002 and 2008, we have analysed 174 MM patients for which a concomitant measurement of sFLC and sPE was done during follow-up. Only 118 patients had the sFLCR analysis performed at diagnosis. The sFLC analysis was performed using the Freelite™ test from the Binding site on a BNIIÒ, Dade BehringÓ, and for sPE, analysis was done using a Paragon CZE 2000Ò, Beckman CoulterÓ. There were 92 (53%) males and 82 (47%) females, median age at diagnosis 57 years (34-72), 120 (69%) were IgG (87K&33L), 52 (30%) IgA (41K&11L) and 2 (1%) IgD (1K&1L). According to the ISS, there were 16 (9%) in stage I, 17 (10%) in stage II and 141 (81%) in stage III. Among 61 (35%) FISH analysis done, 31 (51%) detected a chromosome 13 deletion. Twenty six (15%) patients had renal insufficiency. According to the distribution of the different ratios at diagnosis, we have defined three groups: group1 (n=25): patients with 0.13<sFLCR<3.3 which represents the double of the normal range (0.26-1.65); group2 (n=63): patients with sFLCR>3.3 and group3 (n=30): patients with sFLCR<0.13.We also monitored the behaviour of sFLC and sPE in a way to early detect relapse/progression independently of treatment type. Kaplan Meier and cox regression analysis were performed to study the PFS and OS in different groups, slopes of the increase period corresponding to each measurement were compared using the student t-bilateral test with R statistical software. Results: After a median follow-up of 38 months [3.3-93.7], the 5-years OS for groups 1, 2 and 3 was 75% [56-100], 60% [47-76] and 40% [23-69] respectively; and the 5-years PFS was 69% [49-96], 43% [31-60] and 29% [15-54] respectively. The multivariate analysis studying age, ISS, sex, cytogenetics and sFLCR, showed that both OS and PFS are worslty affected with a more abnormal sFLCR, hazard ratios (HR) in Figure1. After monitoring all patients, we observed 117 (67%) patients with relapse/progression and 57 (33%) patients were still in response to treatment. In 77 (66%) cases, relapse or progression was detected by concomitant increase of both sFLC and the M-p with a significant earlier increase for sFLC (Figure2A). In 17 (15%) patients, the relapse or progression was characterised by the only increase of sFLC without any increase of the M-p (Figure2B). Contrarily, in 5 (4%) patients there was only an increase of the M-p without increasing the sFLC (Figure2D). Finally, in 18 (15%) patients, the relapse or progression was revealed by the increase of M-p faster than the concerned sFLC (Figure2C). When comparing slopes of increasing sFLC to increasing M-p, we found a very high significant difference (p<0.001), thus showing that sFLC have a faster detection of relapse or progression. Conclusion: Our study has showed that abnormal sFLCR at diagnosis affects OS and more strongly the PFS independently of any other concomitant variable. In 81% of patients, sFLC analysis enabled an earlier detection of relapse/progression compared to sPE, this could be very important for early treatment intervention especially for high risk patients. Since there are no uniform recommendations for the use of this analysis during follow-up, we recommend its concomitant use with sPE, waiting for guidelines and we suggest that the sFLCR at diagnosis deserves more focus for its validation as a prognostic factor in MM. Disclosures: No relevant conflicts of interest to declare.

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Cytogenetic Analysis and Correlation Study in Prognosis of Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.5006.5006 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5006-5006

Author(s):

Chengcheng Fu ◽

Xue Xin ◽

Wu Depei

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Chromosome Aberration ◽

Conflicts Of Interest ◽

Response To Therapy ◽

Chromosome 1 ◽

Banding Technique ◽

Hematopoietic Stem ◽

The Impact ◽

Abnormal Group

Abstract Abstract 5006 Multiple myeloma (MM) is a fatal neoplasm characterized by the accumulation of malignant plasma cells within the bone marrow (BM) and the presence of a monoclonal immunoglobulin in the serum and/or urine, it was reported that patients with abnormal metaphases by conventional cytogenetics at diagnosis had active disease and a reduced survival rate compared with those normal metaphase. To further explore the cytogenetic characteristics of multiple myeloma and its correlation with clinical treatment and prognosis, 38 cases of MM were collected and chromosome specimens of bone marrow cells were prepared by 24-hour culture. R-banding technique combined with interphase fluorescence in situ hybridization(i-FISH) was used for karyotype analysis. The impact of different treatments and chromosome aberrations on progression-free survival(PFS) and overall survival(OS) time as well as related prognosis factors of MM were analyzed. The detected total chromosome aberration rate was 34. 2% (13/38), with chromosome complex aberration 53. 8%(7/13). The detection rate of R-banding technique was 23. 7%(9/38) and 21. 1%(8/38) by FISH. The most frequent chromosome aberration was chromosome 1 abnormality. The median PFS time of abnormal group was 16 months and was not reached of normal group after median follow up for 36 months(P=0. 045). Also, the median PFS time of complex abnormal group was 15 months, and the median PFS time of non-complex abnormal group was not reached(P=0. 012). The median OS time of complex abnormal group was 22 months and the median OS time of non-complex abnormal group was not reached(P=0. 041). Boretizomib or autologous hematopoietic stem cell transplantation prolonged the PFS and OS of the chromosome aberration group compared with traditional chemotherapy, but there were no significant statistical differences between the two groups(P>0. 05). It was concluded that chromosome complex aberration is the mainly cytogenetic characteristics of multiple myeloma, and multiple numerous and structural aberrations are involved. The patients with chromosome complex aberration have poor prognosis. Chromosome abnormalities detected in metaphases from multiple myeloma (MM) cells have a clear impact on prognosis and response to therapy. Techniques to explore cytogenetic and molecular genetic changes of myeloma cells should be used to improve chromosomal aberration detection to guide clinical treatments and evaluate prognosis. Disclosures: No relevant conflicts of interest to declare.

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Bone Marrow-Derived Mesenchymal Stem Cells Inhibit CD8+ t Cell Immune Responses Via PD-1/PD-L1 Pathway in Multiple Myeloma

Blood ◽

10.1182/blood-2020-138418 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 53-54

Author(s):

Zhaoyun Liu ◽

Fu Mi ◽

Mei Han ◽

Mengyue Tian ◽

Hui Liu ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Cd8 T Cells ◽

Conflicts Of Interest ◽

Significant Difference ◽

Normal Controls

High expression of the inhibitory receptor programmed death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the PD-1/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in Multiple Myeloma (MM) remain poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSCs-mediated regulation of CD8+T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased than that in normal controls (NC) (18.81±1.61% vs. 2.78±0.70 %; P<0.001). Furthermore, the PD-1 expression on CD8+T cells with NDMM patients was significantly higher than that in normal controls (43.22±2.98% vs. 20.71±1.08%; P<0.001). However, there was no significant difference in PD-1 expression of CD4+ T cells and NK cells between NDMM group and NC group. Additionally, the co-culture assays revealed that BMSCs significantly promoted CD8+ T cells apoptosis and suppressed CD8+ T cells function. However, PD-L1 inhibitor effectively reversed BMSCs-mediated suppression in CD8+ T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8+T cells through the PD-1/PD-L1 axis and inhibit the release of perforin and granzyme B from CD8+ T cells so as to promote the immune escape of MM. Disclosures No relevant conflicts of interest to declare.

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Evaluation of Angiogenesis and the CD57+ Lymphocytic Population on Bone Marrow Biopsies (BM) in Multiple Myeloma Patients Treated with Thalidomide (Thal)

Blood ◽

10.1182/blood.v118.21.5095.5095 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5095-5095

Author(s):

Edvan Crusoe ◽

Adriana Quero ◽

Eliana C M Miranda ◽

Manuella Sampaio ◽

Ana Lucia Peres ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Conflicts Of Interest ◽

Day Treatment ◽

Post Treatment ◽

Unexpected Finding ◽

Bone Marrow Biopsies ◽

Overall Response ◽

Significant Difference ◽

Angiogenic Effect

Abstract Abstract 5095 Introduction – Multiple myeloma (MM) is a plasma cell dyscrasias characterized by the bone destruction, renal insufficiency, anemia and hypercalcemia. Studies suggest that the disease activity and the degree of angiogenesis in the bone marrow (BM) are related. It has been shown that increased microvessel density (MVD) in MM patients`BM specimens is associated with poor prognosis, and BM MVD at diagnosis is an important prognostic factor for survival of patients. Due to the anti-angiogenic effect, Thal is becoming consolidated as a therapeutic option for the treatment of MM. The presence of cytotoxic CD57+ T lymphocytes in the BM in MM patients who have never been treated correlates with the clinical progression of the patients. The present study has the objective of presenting findings of the anti-angiogenic effect of thalidomide, correlating with the reduction of MVD in the obtained response, as well as verifying the presence of CD57+ lymphocytes before and after the treatment, correlating this with the rate response. Materials and methods– BM were collected from the posterior iliac crest in MM patients who had never been treated at least 12 weeks after having initiated treatment with Thal or up to the fourth week after discontinuing its use. Patients who had previously received Thal were excluded. The bone marrow biopsies were done by two pathologists who were blind as to the disease treatment phase. Angiogenesis was estimated based on the MVD, utilizing the anti-CD34 antibody as an immunohistochemical marker. The slides were photographed at 03 sites of densely concentrated vessels selected by counting under 400X magnification. The final density of the microvessel site median was determined. The CD57+ lymphocyte analysis was made for plasmocyte concentration zones, determining the final count using the median of three sites. Statistical analysis was performed with the SPSS 15.0 for Windows, a t-parametric test for equal averages and Spearman correlation. Results– There was a total of 20 patients (pre- and post-treatment). The median age was 64 (40–82 years), 65% of the cases being male. The Durie-Salmon Staging distribution: IIA/B= 10 % and IIIA/B=90%, and ISS: 2=45% and 3=35%. The IgG isotype was present in 70% of the cases. The therapeutic schedule made use of target doses of thalidomide at 200mg/d. Fourteen patients utilized the Thal and dexamethasone (TD) schedule, four patients, cyclophosphamide+TD (CTD), one patient, Melphalan+prednisone+Thal (MPT) and one patient combination TD+CTD. Eleven patients received a 90-day treatment between collections, seven, a 120-day treatment, one, a 150-day treatment and one, a 270-day treatment. The median MVD count of pre-thal CD34 was 11.42, and post-thal, 7.17 (p=0.01). The pre-thal CD57 median was 26.42 and the post-treatment, 21.58 (not significant). There was a negative post-CD34 versus overall response correlation (p=0.04) and a positive CD57+ versus overall response correlation (p=0.05). Pre-CD34 versus International Staging System correlations (p=0.01) were observed. Another unexpected observation was the analysis of the gender as an independent variable, it was observed that the post-treatment CD57+ was significantly different between the sexes (p=0.008). Conclusion– This study confirms the anti-angiogenic effect of Thal in MM patients, with reduced MVD by CD34 analysis, in addition to its correlation with the overall response. It also demonstrates the significant correlation between the post-treatment CD57+ lymphocytic population and the overall response. The unexpected finding was the significant difference in the quantity of lymphocytes present in the post-treatment BM between the genders (increased in men and reduced in women). Furthermore, it was observed that a greater quantity of MVD correlates with the worst ISS staging. Disclosures: No relevant conflicts of interest to declare.

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