scholarly journals Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib

2021 ◽  
Author(s):  
Damian Mikulski ◽  
Paweł Robak ◽  
Ewelina Perdas ◽  
Edyta Węgłowska ◽  
Aleksandra Łosiewicz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Serum Levels ◽  
First Line Therapy ◽  
Cytokine Levels ◽  
Bony Lesions ◽  
The Impact ◽  
Pretreatment Serum

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The aim of the present study was to assess the impact of pretreatment serum levels of 27 selected cytokines on progression-free survival (PFS) and overall survival (OS) in MM patients before first-line therapy with bortezomib-based regimens. Serum cytokine levels were assayed with a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad) including IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. A total of 61 MM patients were examined. Most patients received a bortezomib, cyclophosphamide and dexamethasone (VCD) chemotherapy regimen. In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302), and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p=0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p=0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p=0.0059) and two cytokine levels- IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p= 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147) were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

scholarly journals Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 Are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib

2021 ◽  
Vol 11 (1) ◽  
pp. 112
Author(s):  
Damian Mikulski ◽  
Paweł Robak ◽  
Ewelina Perdas ◽  
Edyta Węgłowska ◽  
Aleksandra Łosiewicz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Gm Csf ◽  
First Line Therapy ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Bony Lesions

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240–0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826–0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046–0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471–9.949, p = 0.0059), and two cytokine levels—IL-1Ra (HR 1.017, 95% CI: 1.004–1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037–0.698, p = 0.0147)—were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

Impact of Chromosomal Abnormalities Del(13), T(4;14), and Del(17p) and Prior Treatment on Outcomes in Patients with Relapsed or Refractory Multiple Myeloma Treated with Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3685-3685 ◽  
Author(s):  
Herve Avet Loiseau ◽  
Jean Soulier ◽  
Jean-Paul Fermand ◽  
Thierry Facon ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Median Number ◽  
Phase Iii ◽  
Free Survival ◽  
The Impact

Abstract The chromosomal abnormalities of del(13), t(4;14), and del(17p) are associated with poor progression-free survival (PFS) and shorter overall survival (OS) in newly diagnosed multiple myeloma (MM) treated with traditional chemotherapy. In patients with relapsed or refractory MM, a recent study demonstrated that lenalidomide (Revlimid®) can overcome poor prognosis conferred by del13q and t(4;14) but not del17p13 (Bahlis et al 2007). Here, we performed a retrospective analysis of medical records obtained from 49 clinical centers participating in the French Autorisation Temporaire d’Utilisation program. Patients with relapsed or refractory MM received dexamethasone 40 mg orally (days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and lenalidomide 25 mg orally on days 1–21 of a 28 day cycle. CD138-purified plasma cells were analyzed with fluorescent in-situ hybridization (FISH) for del(13), t(4;14), and del(17p) at diagnosis. Response and disease progression endpoints were evaluated using the European Group for Blood and Marrow Transplantation criteria. A multivariate analysis was performed to assess the impact of the following 7 variables on outcomes: any chromosomal change, prior bortezomib use, prior thalidomide use, prior transplant, progression on thalidomide, age, and number of lines of previous therapy. In total, 207 patients were included in the analysis; the median number of treatment cycles was 5 (range, 1–22). Most patients in the current study had received prior thalidomide (87%) or bortezomib (81%). The overall response rate (ORR) was 59%, including 7% complete response and 14% very good partial response. Median progression-free survival (PFS) and overall survival (OS) were 9.6 months and 15.1 months, respectively. These values are comparable to the recently published phase III trials (Weber et al., 2007; Dimopoulos et al., 2007), despite the higher median number of prior therapies in this analysis (5 vs. 3). Overall, 41% of patients had del(13), 14% had t(4;14) and 5% had del(17p). The ORR was significantly lower, and PFS and OS significantly shorter, in patients with del(13) compared with patients without del(13) (ORR: 43% vs. 71%, P<0.001; PFS: 5.0 months vs. 12.5 months, P<0.0001; OS: 10.4 months vs. 17.4 months, P=0.001). A similar pattern was observed in patients with t(4;14) versus patients without t(4:14) (ORR 39% vs. 62%, p=0.04; PFS 5.5 months vs. 10.6 months, p<0.01; OS 9.4 months vs. 15.4 months, p=0.005). Multivariate analysis identified hemoglobin (<10 g/dL), progression on thalidomide, and del(13) as independent predictors of reduced PFS (Table). There was a trend towards reduced PFS with prior bortezomib use and number of prior therapies. Age, sex, prior transplant, prior thalidomide use, and t(4;14) did not affect PFS. The results from the analysis indicate that del(13), progression on thalidomide, and hemoglobin levels ≥10 g/dL have a significant impact on outcomes in heavily pre-treated patients with relapsed or refractory MM. Randomized trials are needed to further assess these findings.

Retrospective study to assess the impact of hepatitis C virus infection on the prognosis and management of multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20001-e20001
Author(s):  
David Kaldas ◽  
Andrew Wahba ◽  
Radwa Hamdy Azab ◽  
Ehab Mostafa Elnakoury ◽  
Nagla Fawzy Abdel Karim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Hepatitis C Virus ◽  
Retrospective Study ◽  
Hepatitis C ◽  
Progression Free Survival ◽  
Hcv Infection ◽  
Cytotoxic Agents ◽  
Free Survival ◽  
The Impact

e20001 Background: Multiple Myeloma (MM) is a neoplasm of the post-germinal center, terminally differentiated B-cells. MM accounts for 1% of all types of cancer and 10% for all hematologic malignancies. Chronic hepatitis C virus (HCV) is an infection that affects over 71 million patients worldwide. Cytotoxic agents and immunosuppressive therapy as steroids are the main line of therapy in lymphoid malignancies, but these drugs may exacerbate chronic viral hepatitis and cause uncontrolled replication of hepatitis viruses. The impact of HCV infection on MM patients remains unclear. Objective: To assess the impact of HCV infection on the prognosis and management of MM patients. Methods: A 10-year retrospective study of MM patients was conducted at Cairo University Clinical Oncology Department from January 2009 to April 2019. Results: During this time, 150 patients were diagnosed with MM, 109 (72.7%) were HCV negative, 24 (16%) were HCV positive, and 17 (11.3%) with unknown HCV status. The median age was 51 and 54 years for HCV negative and positive groups respectively, with a statistically insignificant difference (p-value > 0.2). In the multivariate analysis, HCV infection was not an independent factor related to overall survival (OS), however age, creatinine and hemoglobin levels correlated significantly with OS (p < 0.009, 0.008, 0.031 respectively). The median OS for the HCV negative group was 31.11 months (95% CI: 22.62 - 39.61) compared to 37.66 months (95% CI: 7.19 - 68.13) for the HCV positive group. The median progression-free survival (PFS) for all patients was 18.9 months, for HCV positive patients was 15.36 months (95% CI: 13.18 – 17.54), and for HCV negative patients was 20.49 months (95% CI: 14.13 – 26.85). Age below 60 years and creatinine level less than 2 mg/dL were statistically significant for favorable disease-free survival (DFS) (p < 0.030, 0.034 respectively). Conclusions: Age, creatinine and hemoglobin levels are significant prognostic factors in MM but HCV status doesn’t affect the overall survival or progression-free survival. HCV infection should not contraindicate MM therapy.

CXCR3 Binding Chemokines MIG, IP-10 and ITAC Are Predictors of Overall Survival in Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2052-2052
Author(s):  
Arnold Bolomsky ◽  
Niklas Zojer ◽  
Martin Schreder ◽  
Heinz Ludwig
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Plasma Cells ◽  
In Silico Analysis ◽  
Serum Levels ◽  
Newly Diagnosed ◽  
Myeloma Cells ◽  
Detection Call ◽  
Silico Analysis

Abstract Background. The chemokine receptor CXCR3 and its binding molecules MIG, IP-10 and ITAC have been associated with tumor progression, immune escape and angiogenesis in several human malignancies. In multiple myeloma (MM), CXCR3 binding molecules were shown to induce migration of MM cells without effecting proliferation. More recent results suggest a tumor suppressive activity of IP-10. Presently, information about the precise role of CXCR3 binding chemokines in MM is limited and evidence for their clinical significance is lacking. Therefore we aimed to evaluate the prognostic relevance of CXCR3 binding chemokines in patients with MM. Patients and Methods. Serum levels of MIG, IP-10 and ITAC were analyzed by FACS-CBA array in 65 newly diagnosed MM patients. Expression of CXCR3 and its binding molecules was also analyzed by quantitative PCR in 7 human MM cell lines (HMCLs) and in a publically available gene expression dataset (GSE2658). Further analysis of MIG serum levels was performed by ELISA in an extended cohort of MM (n=105) and MGUS patients (n=17), and in healthy volunteers (n=37). Results. Determination of serum levels by FACS-CBA revealed significant expression of MIG (range: 33.4 – 157 960 pg/ml) and IP-10 (12 - 4418.8 pg/ml), while ITAC (0 - 351.5 pg/ml) was only detectable in a subset (20 of 65) of patients. Interestingly, serum levels of all three molecules showed a positive correlation with each other (MIG vs. IP-10, R=0.38, P=0.002; MIG vs. ITAC, R=0.62, P<0.0001; ITAC vs. IP-10, R=0.41, P=0.0007). We also observed a significant correlation with beta 2 microglobulin (B2M) (MIG: R=0.45, P<0.0001; IP-10: R=0.36, P=0.003; ITAC: R=0.3, P=0.016) and a trend regarding ISS stage (MIG: R=0.23, P=0.06; IP-10: R=0.24, P=0.05; ITAC: R=0.11, P=0.39). Importantly, a significant association with overall survival (OS) was observed as well. Survival was significantly worse in patients with high compared to low MIG (median OS 25.3 months vs. not reached, P=0.003) and IP-10 (19.97 months vs. not reached, P=0.0006) as well as in patients with detectable compared to absent ITAC serum levels (19.97 vs. 65.8 months, P=0.019). In multivariate analysis, MIG (P=0.03) and ITAC (P=0.013) along LDH and calcium were revealed as independent predictors of survival. Expression of CXCR3 binding chemokines was rarely detected in HMCLs (1 of 7 expressed MIG, 3 of 7 IP-10 and 2 of 7 ITAC, respectively). In line with this, in-silico analysis of previously published primary MM cell samples (n=414) (GSE2658), showed a present detection call of MIG, IP-10 and ITAC in 51 (12.3%), 11 (2.7%) and 0 (0%) patients, respectively. In contrast, all three cytokines were detectable in 100% of bone marrow plasma cells of healthy donors, MGUS and smoldering MM patients in this dataset. Hence, CXCR3 binding chemokines are silenced in myeloma cells indicating that the increased serum levels of CXCR3 binding chemokines are derived from other cell types. As MIG serum concentration was identified as one of the most important predictors for OS, we studied the prognostic relevance of this molecule in an extended cohort (n=105) of MM patients by ELISA. Median MIG levels (161.3 pg/ml, range: 9.4-1966) were significantly elevated in newly diagnosed MM patients compared to MGUS (92.7 pg/ml, range: 6.29-1303.1) and healthy volunteers (106.2, range: 51–390.6 pg/ml). MIG levels were significantly correlated with B2M, ISS stage, calcium, albumin, LDH, hemoglobin and with age (R=0.466, P<0.001). Importantly, high MIG levels predicted adverse survival (17.0 months vs. not reached, P<0.001), which was upheld when age-adjusted cut-off levels were used. In accordance with our findings, in-silico analysis of MIG expression in purified plasma cells of MM patients (n=559) treated within the total therapy 2 and 3 protocol (GSE2658) revealed shorter OS in patients with a present compared to those with an absent detection call for MIG (P=0.004). Conclusion. Our findings depict MIG, IP-10 and ITAC as novel prognostic markers for shorter survival in newly diagnosed MM patients. High serum levels of CXCR3 binding chemokines in conjunction with silenced expression in MM cells may shield myeloma cells from immune attack as previously shown for T cell lymphomas. Further experiments will aim to confirm these initial results by extending our patient cohort and define the source as well as functional role of CXCR3 chemokines in MM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of CRBN Signaling Pathway Proteins Assessed By Immunohistochemical Staining As Candidate Biomarkers for Outcome in Myeloma Patients Treated with IMiDs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1909-1909
Author(s):  
Lijuan Chen ◽  
Qinglin Shi ◽  
Rong Wang ◽  
Xiupan Lu ◽  
Yan Gu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Expression Level ◽  
Positive Staining ◽  
Myeloma Cells ◽  
Low Level ◽  
First Line Therapy

Abstract Cereblon (CRBN), Ikaros (IKZF1), Aialos (IKZF3) and multiple myeloma oncogene 1 (MUM1) are important component of CRBN signaling pathway when treat MM cells with IMiDs. CRBN interacts with the DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B) and regulator of Cullins 1 (ROC1) to form the functional E3 ubiquitin ligase complex (E3ULC). CRBN increases the interaction between E3ULC and IKZF1/3, leading to increased ubiquitination degradation of IKZF1/3, and then induce cytotoxicity in myeloma cells. Subsequently, degradation of IKZF1/3 induce depression of multiple myeloma oncogene 1 (MUM1), which is also called interferon regulatory factors (IRF4) and proved to be involved in the anti-MM activity of IMIDs in previous studies. Immunohistochemical (IHC) staining may be a convenient approach for researchers to differentiate the myeloma cells and non-myeloma cells in BM samples. In this study, we evaluated CRBN, IKZF1/3 and MUM1 expression level in bone marrow (BM) by immunohistochemical (IHC) staining and investigated the relationship between expression level and treatment outcome after IMiDs-based or bortezomib-based therapy in 123 newly diagnosed multiple myeloma (NDMM) patients. H-score method was applied according to both intensity and extent of staining. The intensity was graded from 0 to 3("0"for absent staining, "1" for weak expression, "2" for intermediate expression, and "3" for strong expression of the protein). The extent was graded from "0" to "100" to represent the percentage of MM cells with positive staining of any intensity. H-score was obtained by multiplying the intensity and extent score, ranging from 0 to 300, which reflected protein expression level in MM cells. The median H-score of CRBN, IKZF1, IKZF3 and MUM1 were 200, 0, 180 and 180, respectively. According to the median H-score, we classified the patients into high or low expression group. One hundred and twenty-three NDMM patients were enrolled in this study, including 64 males (52.0%) and 59 females (48.0%). The median age was 60 years (range 34-84). Fifty-one patients (41.5%) received IMiDs-containing regimen as the first-line therapy. The median follow-up time was 24.0 months (range, 10-76 months). After treated with IMiDs, patients with high level of CRBN and MUM1 achieved better overall response rate (ORR) than those expressed low level (CRBN, 88.0% vs. 42.3%, P=0.001; MUM1, 83.3% vs. 48.1%, P=0.009). Besides, patients with CRBN and MUM1 overexpression also had better overall survival (median OS, CRBN, not reached vs. 21.0 months, P=0.004; MUM1, not reached vs. not reached, P=0.021) and progression free survival (median PFS, CRBN, 28.0 vs. 12.0 months, P=0.002; MUM1, 32.0 vs. 12.0 months, P<0.001) than patients with low level, as well as 2-year OS rate (CRBN, 86% vs. 44%, P=0.005; MUM1, 81% vs. 51%, P=0.003) and PFS rate (CRBN, 66% vs. 17%, P=0.001; MUM1, 63% vs. 20%, P<0.001). In addition, in high CRBN and MUM1 expression group, patients treated with IMiDs had a higher 2-year PFS rate than Bortezomib presentation (CRBN, 66% vs. 45%, P=0.004; MUM1, 63% vs. 36%, P=0.003). In low CRBN and MUM1 expression group, patients treated with IMiDs had an inferior OS (median OS, CRBN, 21.0 vs. 57.0 months, P=0.001; MUM1, not reached vs. 57.0 months, P<0.001) and PFS (median PFS, CRBN, 12.0 vs. 31.0 months, P=0.003; MUM1, 12.0 vs. 32.0 months, P<0.001) than patients with Bortezomib, as well as 2-year OS rate (CRBN, 44% vs. 91%, P=0.002; MUM1, 51% vs. 100%, P<0.001) and PFS rate (CRBN, 17% vs. 59%, P=0.010; MUM1, 20% vs. 68%, P<0.001). This study identified high levels of CRBN pathway proteins CRBN and MUM1 were correlated with favorable ORR and survival in NDMM patients with IMiDs therapy, also suggested that expression levels of CRBN signaling pathway proteins in plasma cells assessed by IHC staining could better direct clinic individualized therapy. Disclosures No relevant conflicts of interest to declare.

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan: A New Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1159-1159 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Marilyn S. Davis ◽  
Aleman Ana ◽  
Linda Roden ◽  
Floralyn Libunao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Survival Probability ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Kaplan Meier ◽  
The Impact

Abstract Backround: Arsenic trioxide (ATO), an active agent against multiple myeloma, has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as prepaprative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation (AHPCT) for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Twenty-five patients with secretory myeloma (11 females, 14 males median age: 53, range: 49 – 69) were treated b/w 4/04 and 1/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days −9 to −3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days −9 to −3 (arm 2) and ATO 0.25 mg/kg IV on days −9 to −3 (arm 3). Seven patients had a prior autograft. Median CD34 cells dose infused was 4.4 x 106/kg (range 2.3–10.9). Results: Patients were evenly matched except for a high median β2m level (3.6 vs. 2.4 in arms 1 and 2, p=0.04) in arm 3. With a median F/U of 7.1 months post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Median ATO level on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Toxicity was limited grade I or II nausea, vomitting and diarrhea. Median time to neutrophil engraftment (ANC &gt;500/dl) was 9 days. There were no engraftment failures or delays in the ATO arms. Response rates (RR) are shown in Table 1. With a median F/U of 7.1 months (range, 6.4 – 8.9 months), the progression-free survival (PFS) and overall survival (OS) are as shown in Figure 1. There was no significant difference in RR, PFS or OS between the 3 arms. Melphalan PK was not altered by ATO pretreatment. Conclusions: Arsenic trioxide, given in combination with melphalan and ascorbic acid as preparative regimen, is safe and well tolerated. A longer follow up is needed to determine the impact of this combination on survival. Response Rate at 3-Month Evaluation Response at 3 months CR PR MR SD PD p = 0.55 CR = complete response, PR = partial response, MR = minimal response, SD = stable disease, PD = progressive disease Arm 1 (no ATO) 1 5 0 1 1 Arm 2 (ATO 0.15) 1 5 2 0 1 Arm 3 (ATO 0.25) 0 7 0 0 0 Figure 1. The Kaplan-Meier estimates for progression-free survival probability (N=25). Figure 1. The Kaplan-Meier estimates for progression-free survival probability (N=25). Figure 2. The Kaplan-Meier estimates for overall survival probability (N=25). Figure 2. The Kaplan-Meier estimates for overall survival probability (N=25).

What Is the Frequency of Transplant-Eligible Multiple Myeloma Patients Being Cured? the Impact of an MGUS-like Signature at Diagnosis and MRD-Negativity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 725-725 ◽  
Author(s):  
Bruno Paiva ◽  
Maria Belen Vidriales ◽  
Noemi Puig ◽  
Teresa Cedena ◽  
Lourdes Cordon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Binding Site ◽  
Residual Disease ◽  
Limit Of Detection ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Classification Model ◽  
The Impact

Abstract Introduction: Although multiple myeloma (MM) is typically described as an incurable disease, it has been shown in recent years that a small fraction of patients may reach more than 10-years progression-free survival (PFS), which is considered as the minimum threshold to identify patients in "operational cure". However, because of the scarcity of available data there is significant lack of knowledge in MM regarding the frequency of cases attaining operational cure, nor the existence of biomarkers that could prospectively predict such curability. Methods: Herein, we sought to define the frequency as well as the biomarkers predictive of operational cure in a large series of uniformly-treated transplant-eligible patients enrolled in the PETHEMA/GEM2000 protocol (VBMCP/VBAD followed by HDT/ASCT and 2 years of maintenance with interferon and prednisone). Patients' follow-up was updated at the time of abstract submission, and the median follow-up of the series is now of 12-years. We used an automated multiparameter flow cytometric (MFC) classification model focused on the analysis of the bone marrow plasma-cell compartment to identify among newly diagnosed symptomatic MM those with MGUS-like vs. MM-like phenotypic signatures. Minimal residual disease (MRD) was monitored using a first-generation 4-color MFC assay (CD38-FITC / CD56-PE / CD19-PerCPCy5.5 / CD45-APC) with a limit of detection of 10-4. PFS and overall survival (OS) were measured from the time of diagnosis. Results: From a total of 1075 patients enrolled in the GEM2000 protocol, 763 were eligible for this analysis because they either relapsed or died during the first 10-years from diagnosis (n=666; 87%), or remained progression-free and alive for more than 10-yers (n=97; 13%); accordingly, all patients remaining progression-free and alive but for which the follow-up was inferior to 10-years were excluded from the analysis. We then investigated the biomarkers that could help to identify patients reaching operational cure after HDT/ASCT. As compared to the vast majority of cases, patients reaching >10-years PFS (13%) had significantly less frequent anemia (76% vs. 60%, respectively; P=.002), as well as more frequent Durie-Salmon stage IA (14% vs. 6%; P=.004), MGUS-like signature as determined by the automated MFC algorithm (28% vs. 6%; P<.001), complete response (CR) after HDT/ASCT (51% vs. 35%; P=.003), and MRD-negativity by MFC (72% vs. 31%; P<.001). Other biomarkers such as ISS, LDH, ploidy and proliferation were not significantly different among patients reaching >10-years PFS vs. those who relapsed earlier. On multivariate analysis, only the presence of an MGUS-like signature at baseline (P=.04; HR: 3.9) and MRD-negativity at day+100 after HDT/ASCT (P=.006; HR: 6.3) emerged as independent predictive markers for >10-years PFS; anemia, Durie-Salmon and CR status were not retained in the logistic regression model. Accordingly, patients with an MFC-defined baseline MGUS-like signature reaching MRD-negativity after HDT/ASCT (n=14) had a median PFS of 10-years and a 10-year OS rate of 79%, which were significantly superior to those observed among cases with MM-like signatures being MRD-negative (n=54) or positive (n=99) after therapy [median PFS of 6 and 3 years (P<.001); 10-year overall survival rates of 55% and 19% (P<.001)]. Conclusions: We demonstrated that operational cure (i.e.: >10-years PFS) was possible for 13% of transplant-eligible MM patients before the era of novel agents. Curability rates were particularly frequent among patients with a benign phenotypic signature at diagnosis and MRD negativity after HDT/ASCT, suggesting a remarkable clinical benefit of attaining deep remissions after intensive treatment for patients with early MM. Disclosures Paiva: Sanofi: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy; BD Bioscience: Consultancy; EngMab AG: Research Funding; Binding Site: Consultancy; Celgene: Consultancy. Puig:The Binding Site: Consultancy; Janssen: Consultancy. Mateos:Takeda: Consultancy; Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. San Miguel:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Janssen-Cilag: Honoraria.

scholarly journals Immunoglobulin Recovery after ASCT for Patients with Multiple Myeloma: Impact on Overall Survival and Progression-Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2263-2263
Author(s):  
Victor Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Jason Tay ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Research Funding ◽  
Progression Free Survival ◽  
Partial Recovery ◽  
Maintenance Strategy ◽  
Free Survival ◽  
Immune Enhancement ◽  
The Impact

Abstract Introduction Immunoparesis, defined as suppression of uninvolved immunoglobulins (Igs), has been described as one of the most common indicators of immune dysfunction in patients with multiple myeloma (MM). The role of immunoglobulin recovery, however, has not been properly evaluated, in particular in the setting of immunomodulatory therapy. In the present study, we aimed to assess the impact of immunoparesis and Igs recovery after ASCT on Overall and Progression-Free survival (OS and PFS). Methods All consecutive patients undergoing ASCT at our center from 01/2004 to 03/2016 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Definitions of response and progression were used according to the EBMT modified criteria. Immunoglobulin recovery was assessed at 12 months post-ASCT in those cases where immunoparesis was noted at diagnosis. Results Clinical characteristics are shown in Table 1. Decrease of uninvolved Ig's was noted in 94% of cases. At the time of analysis, 69.2% of patients are alive and 54.9% have already progressed, respectively. Median OS did not differ between patients with or without immunoparesis (p=0.851). With regards to Ig recovery at 12 months post-ASCT, median OS was longer for those patients with complete or partial normalization of Ig's compared to those with no recovery at all (Estimate median OS of 97, 77 and 69 months, respectively, p=0.008) (Fig1a). In addition, median PFS was longer for those patients with normalization or partial recovery of Ig's at 12 months post-ASCT (median of 40.3 and 38 months, compared to 24.6 months for those without Ig recovery, p=0.002) (Fig1b). Furthermore, 121 patients receiving lenalidomide maintenance were evaluated, 49% of cases exhibited complete or partial recovery of Ig's at 12 months post-ASCT, compared to 40% for those cases that were not treated with any maintenance strategy (p=0.6). In conclusion, Immunoglobulin recovery at 12 months post-ASCT is an important factor to predict for better progression-free and overall survival. The use of lenalidomide as a maintenance strategy did not seem to affect the process of Ig recovery. Based on our observations, the use of immune enhancement strategies in the post-transplant setting seem appealing and requires further investigation. Disclosures Jimenez-Zepeda: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.

Serum Cytokine Levels Predict Time to Progression after Rituximab as Initial Therapy in Patients with Follicular Grade 1 Non-Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3410-3410
Author(s):  
Stephen M. Ansell ◽  
Anne J. Novak ◽  
Steven Ziesmer ◽  
Betsy LaPlant ◽  
James R. Cerhan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Serum Levels ◽  
Initial Therapy ◽  
Response To Therapy ◽  
Time To Progression ◽  
Serum Cytokine ◽  
Cytokine Levels ◽  
Hodgkin's Lymphomas ◽  
Pretreatment Serum

Abstract Background: Patients with newly diagnosed, advanced-stage, follicular B-cell non-Hodgkin’s lymphomas (NHL) commonly receive rituximab as initial therapy. While antibody dependent cytotoxicity (ADCC) is felt to be the predominant mechanism of action for rituximab, the immunologic effects of rituximab are largely unknown. We have previously shown that genetic polymorphisms in IL-8, IL-2, IL-12 and IL-1 receptor antagonist (IL-1RN) have prognostic significance in follicular lymphoma. The goal of this study was to measure changes in the abovementioned and other serum cytokine levels in patients receiving single agent rituximab as initial therapy for follicular NHL and to identify cytokines that are associated with an increased risk of disease relapse. Methods: Patients with untreated follicular grade 1 NHL, and measurable stage III/IV disease were treated with rituximab 375 mg/m2 intravenous weekly for 4 doses and were then followed for response and time to progression (TTP); no maintenance therapy was provided. Thirty-seven patients were enrolled in this clinical trial between July 1999 and May 2001. As previously reported, the overall response rate in the 36 eligible patients was 72%, with 36% complete remissions. Now, with a median follow up of 5.1 years, the median TTP is 2.2 years (95% CI, 1.2–3.3 years) and the 5-year overall survival is 77% (95% CI: 64–92%). We measured the serum levels of a variety of inflammatory cytokines by ELISA at baseline and 1 month after completing treatment. Serum specimens were available in 30 patients. Thirty two cytokines or receptors including IL-1β, IL-1RN, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p40/p70, IL-13, IL-15, IL-17, TNF-α, IFN-α, IFN-γ, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, RANTES, MCP-1, VEGF, GCSF, EGF, FGF-basic, HGF, BLyS and APRIL were analyzed. Results: A significant increase was seen in the serum levels of BLyS (p=0.0001) after rituximab therapy, while IL-12 (p=0.0002), IL-1RN (p=0.0001), IL-2R (p=0.0001), IL-1β (p=0.02), IL-7 (p=0.02), IL-10 (p=0.02), and MIG (p=0.05) all significantly decreased. All other cytokines/receptors remained unchanged. Higher pretreatment serum levels of IL-2R (p=0.008) and IL-12 (p=0.001) correlated with a shorter TTP. Furthermore, elevated serum IL-2R levels pretreatment correlated with a lack of response to rituximab (p=0.03). Differences in overall survival could not be determined due to the fact that only 8 patients enrolled in the study have died. Because serum IL-2R levels correlated with response and TTP, we measured the cell surface expression of IL-2R in the tumor by flow cytometry. IL-2R was detected on a subpopulation of CD4+ T-cells in all specimens tested (n=14), and on malignant B-cells in 5 cases (36%). Conclusions: Pretreatment serum levels of IL-2R and IL-12 are important prognostic factors for response to therapy or TTP in follicular lymphoma patients treated with rituximab. Furthermore, serum levels of BLyS, IL-1RN, IL-7, IL-10, IL-1β and MIG also change after rituximab treatment. Targeting these cytokines may therefore provide additional clinical benefit to patients treated with rituximab.

A Case Control Study of Syngeneic Transplantation Versus Autologous Transplantation for Multiple Myeloma: Two Decades of Experience at MD Anderson

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4613-4613
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Muhammad Salman Faisal ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Research Funding ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Disease Status ◽  
Free Survival ◽  
First Remission ◽  
Equity Ownership ◽  
Relapsed Disease

Abstract INTRODUCTION: High-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is the standard of care for eligible patients with newly diagnosed multiple myeloma. However, almost all patients eventually relapse possibly due to incomplete elimination of malignant plasma cells. For patients with an identical twin, syngeneic-HCT provides a tumor-free graft without the risk of graft vs. host disease. We hypothesized that syngeneic-HCT would result in better disease control than auto-HCT. METHODS : We identified 10 patients with multiple myeloma who underwent syngeneic-HCT at our institution from 1994 to 2014. Using a propensity score, we identified 48 controls that received auto-HCT during the same time interval. Matching was done for the year of transplant, age and disease status at auto-HCT (Table 1). Primary endpoint was progression-free survival (PFS). Secondary endpoints were complete remission (CR) rates and overall survival (OS). RESULTS: Baseline characteristics are shown in Table 1. The two groups were well matched, with no significant statistical differences in age, sex, race, stage at diagnosis, lines of therapy received, or disease status prior to transplant. At the time of transplant, 7 (70%) patients in the syngeneic cohort were in first remission, with 3 (30%) having relapsed disease. Similarly, 28 (58%) patients in the autologous cohort were in first remission, with 20 (41%) having relapsed disease (p value 0.49). Patient outcomes are summarized in Table 2. All patients engrafted, with a median time to engraftment of 11 and 10 days, for the syngeneic and auto-HCT cohorts respectively (p=0.22). There was no treatment related mortality in the first 100 days post-transplant in either of the cohorts. In the syngeneic group 8 (80%) patients achieved ≥ CR, 1 achieved very good partial remission (VGPR), and 1 achieved a partial remission (PR), with an overall response rate (ORR) of 100%. Amongst the control group, 18 (37%) achieved ≥ CR, 5 (10%) achieved ≥ VGPR, 21 (43%) achieved ≥PR, 3 (6%) had stable disease and 1 (2%) had disease progression, with an ORR of 91.6%. There was no significant difference in the ORR between the two groups (p=0.21). At the time of last follow-up, a total of 4 (40%) patients had relapsed in the syngeneic cohort, and 31 (65%) had relapsed in the autologous cohort (p=0.15). The median progression free survival (PFS) for the syngeneic cohort was 98.6 months (95% CI from 76-118 months), while the median PFS for auto-HCT cohort was 34.5 months (95% CI from 16-52 months) (p=0.05). Median overall survival (OS) for the syngeneic and auto-HCT cohorts were not reached and 131 months, respectively (p=0.15). The PFS difference was not due to a difference in maintenance therapy after transplant, as 6 (60%) syngeneic patients and 32 (66.7%) auto-HCT (p=0.69) received maintenance therapy respectively. CONCLUSION: Our study shows that patients with multiple myeloma who underwent syngeneic-HCT had a trend to a higher CR rate and longer PFS compared to a matched cohort that underwent auto-HCT. This benefit may be related to the absence of malignant plasma cells in the syngeneic graft, and a normal donor immune system. The efficacy of syngeneic transplants needs to be assessed in a larger number of patients to provide sufficient power to detect clinically meaningful differences with autologous transplants. Table 1 Pre-transplant variables for cases and controls. Table 1. Pre-transplant variables for cases and controls. Table 2 Transplant Outcomes Table 2. Transplant Outcomes Kaplan Maier Curves for Progression Free Survival and Overall Survival. Kaplan Maier Curves for Progression Free Survival and Overall Survival. Disclosures Bashir: Takeda: Consultancy; Spectrum: Consultancy; Takeda: Research Funding; Celgene: Research Funding. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

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