scholarly journals RNA-Sequencing-Based Transcriptomic Score with Prognostic and Theranostic Values in Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 988
Author(s):  
Elina Alaterre ◽  
Veronika Vikova ◽  
Alboukadel Kassambara ◽  
Angélique Bruyer ◽  
Nicolas Robert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Risk Score ◽  
Dna Microarrays ◽  
Kinase Inhibitors ◽  
Plasma Cells ◽  
Aurora Kinase ◽  
Interferon Response ◽  
High Dose ◽  
Rna Seq

Multiple myeloma (MM) is the second most frequent hematological cancer and is characterized by the clonal proliferation of malignant plasma cells. Genome-wide expression profiling (GEP) analysis with DNA microarrays has emerged as a powerful tool for biomedical research, generating a huge amount of data. Microarray analyses have improved our understanding of MM disease and have led to important clinical applications. In MM, GEP has been used to stratify patients, define risk, identify therapeutic targets, predict treatment response, and understand drug resistance. In this study, we built a gene risk score for 267 genes using RNA-seq data that demonstrated a prognostic value in two independent cohorts (n = 674 and n = 76) of newly diagnosed MM patients treated with high-dose Melphalan and autologous stem cell transplantation. High-risk patients were associated with the expression of genes involved in several major pathways implicated in MM pathophysiology, including interferon response, cell proliferation, hypoxia, IL-6 signaling pathway, stem cell genes, MYC, and epigenetic deregulation. The RNA-seq-based risk score was correlated with specific MM somatic mutation profiles and responses to targeted treatment including EZH2, MELK, TOPK/PBK, and Aurora kinase inhibitors, outlining potential utility for precision medicine strategies in MM.

scholarly journals Aberrant Plasma Cell Contamination of Peripheral Blood Stem Cell Autografts, Assessed by Next-Generation Flow Cytometry, Is a Negative Predictor for Deep Response Post Autologous Transplantation in Multiple Myeloma; A Prospective Study in 199 Patients

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4047
Author(s):  
Ioannis V. Kostopoulos ◽  
Evangelos Eleftherakis-Papaiakovou ◽  
Pantelis Rousakis ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Chrysanthi Panteli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Plasma Cells ◽  
Autologous Transplantation ◽  
Predictive Marker ◽  
Induction Treatment ◽  
High Dose ◽  
Next Generation ◽  
Potential Biomarker

High-dose chemotherapy with autologous stem cell support (ASCT) is the standard of care for eligible newly diagnosed Multiple Myeloma (MM) patients. Stem cell graft contamination by aberrant plasma cells (APCs) has been considered a possible predictive marker of subsequent clinical outcome, but the limited reports to date present unclear conclusions. We prospectively estimated the frequency of graft contamination using highly sensitive next-generation flow cytometry and evaluated its clinical impact in 199 myeloma patients who underwent an ASCT. Contamination (con+) was detected in 79/199 patients at a median level 2 × 10−5. Its presence and levels were correlated with response to induction treatment, with 94%, 71% and 43% achieving CR, VGPR and PR, respectively. Importantly, con+ grafts conferred 2-fold and 2.8-fold higher patient-risk of not achieving or delaying reaching CR (4 vs. 11 months) and MRD negativity (5 vs. 18 months) post ASCT, respectively. Our data also provide evidence of a potentially skewed bone marrow (BM) reconstitution due to unpurged grafts, since con+ derived BM had significantly higher prevalence of memory B cells. These data, together with the absence of significant associations with baseline clinical features, highlight graft contamination as a potential biomarker with independent prognostic value for deeper responses, including MRD negativity. Longer follow-up will reveal if this corresponds to PFS or OS advantage.

Multiple Myeloma Patients Who Are Chemosensitive and Present with Plasma Cells Lacking Phosphorylated Retinoblastoma and/or Cyclin A Expression Benefit From High Dose Therapy and Autologous Stem Cell Transplantation More.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1345-1345
Author(s):  
Selami Kocak Toprak ◽  
Gulsah Kaygusuz ◽  
Nazmiye Kursun ◽  
Duygu Ozu ◽  
Merih Kizil Cakar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Initial Treatment ◽  
Plasma Cells ◽  
Cyclin A ◽  
Response To Therapy ◽  
Novel Agents ◽  
High Dose ◽  
Cell Transplant ◽  
Group 1

Abstract Abstract 1345 Background and aim: Multiple Myeloma (MM) plasma cells are known to posses low replicative potential and plasma cell labelling index is generally accepted as a strong prognostic factor. TC classification of MM defines categories of myeloma cases expressing different cyclins (Fonseca et all, Leukemia 2009). Although cyclin dependent kinase inhibitors (CDKI) are important for cell cycle, they are not included in this molecular classification. Patients and Methods: With an aim to define high and low proliferative myeloma cases antibodies detecting cyclins (Cyc) A, D1, D2, D3, phosphorylated retinoblastoma (Rb), p16, p21, p27, Ki67 were applied to tissue sections obtained from either marrow plasmacytoma of 106 consequtive myeloma patients (median: 59, 32–79 years) diagnosed between 1998–2007. 100 patients <65 years (n:51) were evaluable for treatment outcome and received an induction of VAD (4-6 cycles), followed by a novel agent containing regimen (2-4 cycles) or autologous stem cell transplant (ASCT) depending on the response to induction. Postransplant consolidation or subsequent transplants were performed when < VGPR was obtained. Elderly patients (n:49) received induction for at least a year. Novel agents (Thalidomide: 66.7%, Bortezomib: 27.5%) were given in 94.2% of patients as ≥2 line treatment. Mann Whitney U, Kaplan-Meier or log rank analysis were performed using the SPSS version 15.0. Results: Loss of CDKI's were detected in 55.4–88.5 % of the cases. Cyclin D1D2D3 or Cyclin A expression was detected in 29.2, 21.7, 5.7 or 19.8 % of the cases. Rb was detected in 25%. Among the CDK's or CDKI's only Cyc D2 was correlated with Ki67 percentage (p=0.027). Loss of all CDKI's was observed in 31.1 %. The majority of p16 (-) cases were Cyc A (-) too (p=0.001). Loss of p16 and p 27 was observed more frequently than loss of p 21 (88 and 85% versus 54%). Patients were either both CycA and p21 (-) (50%) or both CycA and p21 (+) (31 %) (p=0.025). However there was no patient expressing Rb and p16. On the contrary, the majority patients were both Rb and p16 (-) (60%) (p=0.037). Groups of patients with high proliferative protential group 1 (Cyc D+ p16-), group 2 (CycA+ p21-), group 3 (CycA+ Rb+) and low proliferative protential group 4 (Rb- p16+), group 5 (CycA- Rb-) were analyzed. These were observed 42.5 %, 5.5%, 11.7%, 15.4% and 57.1%. No correlation could be found between the CDKI/Cyc defined risk groups and ISS, B2MG, LDH, CRP, OS. However among p16 (-) cases Rb (-) ones (n:39) had longer OS than Rb (+) patients (n:18) (49 vs 39 months). All p16 (+) patients were Rb (-) too and had a shorter OS (42 vs 84 months, p=0.006). Response to initial treatment was ≥ VGPR 16.8 %, ≥ PR 52%, refractory 21.4 %. High proliferative group 1 or patients with high LDH values had higher initial response rates (82.1 vs 53.8 %, p: 0.016 and 67.6 % vs 36 % p= 0.018). The deepest response was observed with initial treatment among 47.3 % and was improved following ASCT (18.3%). ASCT also improved OS among all (58 vs 34 months, p=0.0) but more strongly among Rb and/or CycA (-) patients (Table). The response to initial treatment did not influence OS. However if response is not upgraded following subsequent treatments OS deteriorated (5 year OS: 34 vs 44 months p=0.022) (Figure). These suboptimal responding patients could not be predicted by ISS, age, B2MG, high/low proliferating group definition. Although LDH was high in 72.7 vs 54.5 % of poor-responders this comparison was not significant. Conclusion: While depth of response to therapy did not, improvement of response with subsequent therapy ie novel agents or ASCT prolongged OS (34 vs 44 months, p=0.022) and was associated with lower LDH values. Compared to gene expression profilling, tissue array using monoclonal antibodies is a method which can be more widely applicable and in our study was able to define new prognostic parameters. Overall ASCT extended OS. This effect was stronger among patients lacking Rb and/or Cyc A, This finding echoes the need for better treatment modalities for patients with poorer prognosis ie Rb and/or Cyc A positivity. Multivariate analysis results will be presented during the congress. Disclosures: No relevant conflicts of interest to declare.

scholarly journals UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

2012 ◽  
Vol 4 (1) ◽  
pp. e2012069 ◽  
Author(s):  
Patrizia Tosi ◽  
Manuela Imola ◽  
Mianulli Anna Maria ◽  
Simona Tomassetti ◽  
Anna Merli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Plasma Cells ◽  
Standard Of Care ◽  
New Drugs ◽  
High Dose ◽  
Hematopoietic Stem

Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

Combination High-Dose Cyclophosphamide and Bortezomib Is Safe and Effective for Stem Cell Harvesting in Chemotherapy Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5459-5459 ◽  
Author(s):  
Miriam Katzman ◽  
Theresa George ◽  
Heather Doell ◽  
Patricia Danyluk ◽  
Sheri Briggs ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Combination Chemotherapy ◽  
Plasma Cells ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Cell Harvesting ◽  
Cell Mobilization ◽  
Cell Harvest

Abstract Introduction: High-dose melphalan and autologous stem cell transplantation is the accepted therapy for most patients with multiple myeloma (MM) following steroid-based induction therapy. In a significant proportion of patients, however, the disease is refractory to standard induction. The use of dose-intense combination chemotherapy, such as D-PACE (dexamethasone, doxorubicin, cyclophosphamide, and cisplatin), may affect the ability to harvest an adequate number of hematopoeitic stem cells prior to transplantation. In addition, in those patients not achieving adequate cytoreduction despite combination chemotherapy, there is a theoretical risk of stem cell product contamination by malignant plasma cells. Bortezomib is a therapeutic agent with a novel mechanism of action, which in preliminary studies appears to be synergistic to alkylating agents and does not appear to affect stem cell yield. We piloted the addition of bortezomib to high-dose cyclophosphamide during stem cell harvesting in a series of patients failing to achieve an adequate response to D-PACE salvage. Patients and Methods: Between 2002 and 2006, fifteen MM patients refractory to standard dexamethasone-based induction therapy received ≥ 2 cycles of D-PACE prior to proceeding to autologous stem cell harvest and transplantation. 7/15 patients achieved adequate cytoreduction and proceeded to high-dose cyclophosphamide (3 g/m2) and filgrastim plus ancestim stimulation for stem cell mobilization. However, 8 patients in this cohort did not achieve adequate disease cytoreduction following D-PACE. Therefore, bortezomib was added to the mobilization regimen on days 1, 4, 8, and 11, in addition to high-dose cyclophosphamide given on day 11. Identical growth factor stimulation was provided. Response assessment included days to stem cell harvest, number of CD34 cells harvested, plasma cells in the product, disease response, and hematologic parameters. Results: Pre-treatment toxicities from D-PACE were similar in both groups. The addition of bortezomib to cyclophosphamide during stem cell mobilization did not lead to increased symptomatic toxicity. Grade 3/4 thrombocytopenia occurred in 5/8 patients receiving combination bortezomib/cyclophosphamide. No episodes of significant bleeding, peripheral neuropathy, or skin rash were noted. The average CD34-positive stem cell harvest in both groups was >5.0 × 106/kg. Time to stem cell harvesting was not significantly different between the groups. Flow cytometric examination of the harvested product from the bortezomib/cyclophosphamide group consistently demonstrated <2% cells bearing plasma cell markers. One patient in each group failed to mobilize sufficient stem cells. Bone marrow plasmacyte counts following combination therapy and harvesting decreased in all assessed patients. Time to engraftment was similar in both groups. Post-transplant disease control and survival remains to be assessed, as some patients in the combination group have only recently undergone transplantation. Conclusion: The addition of bortezomib to high-dose cyclophosphamide during stem cell mobilization does not increase toxicity or decrease stem cell harvest yield or quality, and appears to achieve adequate disease reduction in patients otherwise refractory to combination chemotherapy. This may result in improved relapse-free survival in patients with refractory MM.

Association in Outcome of Advanced Multiple Myeloma with Polymorphisms of Inflammatory-Related Genes IL-1A, IL-1B, IL1RN, TNF-a and TNFRSF1B.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1723-1723
Author(s):  
Gabriele Buda ◽  
Alessandro Martino ◽  
Enrico Orciuolo ◽  
Antonella Lupia ◽  
Sara Galimberti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Plasma Cells ◽  
Response Rate ◽  
Interleukin 1 ◽  
High Dose ◽  
Cell Transplant ◽  
Tnf Receptor ◽  
Overall Response

Abstract Abstract 1723 Poster Board I-749 Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients (1). Interleukin-1 (IL-1) is a cytokine involved in the maturation and proliferation of B cells and plays a significant role in the development of lytic bone lesions, a major clinical feature of MM patients (pts). Previous studies demonstrated that the polymorphism of IL1b-31 significantly influenced overall survival, as reported in patients undergoing high-dose melphalan treatment followed by autologous-stem cell transplant (2). TNF-a, a potent mediator of inflammation and bone resorption, seems to be involved in the malignant transformation of plasma cells, since mononuclear cells, obtained from MM patients and exposed in vitro to TNF-a and interleukin-4, produced monoclonal plasma cells. In addition, TNF-a can stimulate plasma cell proliferation, by triggering interleukin-6 secretion, and shows proangiogenic properties in vitro. In addition, TNF-a determination was reported to be a good parameter for estimating tumor mass and for monitoring therapy outcome during treatment with different protocols. TNF-a is also able to activate NF-kB, which is the main target of bortezomib. Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism (SNP). Single nucleotide SNPs have been identified at position -308 and -238 in the gene promoter. Specifically, a G to A substitution at position -308 is associated with higher levels of TNF-a (3). TNFRSF1B is a member of the TNF-receptor superfamily. This protein through the recruitment of two anti-apoptotic proteins upgrades TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways (4). In this study, we investigated the correlation between the SNPs of IL1A -889, IL1B -511, IL1B -31, IL1RN -371 (interleukin 1 receptor antagonist), TNF-a -308 and TNFRSF1B -587 on the outcome of refractory and relapsed MM pts, receiving bortezomib containing regimen as second line therapy. From September 2005 to April 2009 we selected 98 MM pts, who received at least one cycle of chemotherapy before treatment with bortezomib and at least one cycle of high dose chemotherapy with peripheral blood stem cell transplantation in 25 pts. No associations between the SNPs at the loci regarding IL-1A, IL-1B, IL-1RN and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. TNF-a SNP at position -308 and TNFRSF1B SNP at position -587 were determined on genomic DNA extracted from blood samples. These genotypes frequencies obtained were in agreement with Hardy–Weinberg equilibrium. Patients were categorized as responders (complete + partial response = R) or non responders (stable + progression disease = NR) to treatment. The overall response in our patients was about 74.5% (73/98). In MM pts carrying the rarest A allele of TNF-a the overall response was reduced to 61% (14/23 pts), whilst GG carriers showed a better response rate of 79% (59/75pts)(OR=0.42). We obtained similar results from the analysis of TNFRSF1B SNP. Pts carrying the rarest G allele the overall response was reduced to 69% (27/39 pts), whilst TT carriers showed a better response rate of 79% (46/59pts). Our results indicate that the cytokines (IL-1A, IL-1B, IL-1RN) gene SNPs do not confer differences in the outcome of advanced MM. On the contrary TNF-a and TNFRSF1B SNPs seems to be independent factors to predict the response and the outcome in patients affected by MM and treated with bortezomib containing regimen. If these preliminary results will be confirmed, they may represent a rationale for targeting TNF-a in novel therapeutic approaches to MM. Disclosures No relevant conflicts of interest to declare.

The Reason Why High-Dose Melphalan Followed by Autologous Stem-Cell Transplantation Produces Good Response in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5201-5201
Author(s):  
Yoshiaki Kuroda ◽  
Akira Sakai ◽  
Yoshiko Okikawa ◽  
Shoso Munemasa ◽  
Yuta Katayama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Plasma Cells ◽  
High Dose ◽  
Myeloma Cells ◽  
Before And After ◽  
High Dose Melphalan

Abstract Multiple myeloma (MM) is the result of a clonal proliferation of plasma cells. And myeloma cells have been shown to be heterogeneous with regard to their morphology and biological character. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. But it is still unclear how those molecular events work on the prognosis of MM patients. And it is difficult to find the heterogenesity of myeloma cells in each MM case by molecular analysis. Twenty years ago Greipp et al. classified myeloma cells as mature, intermediate, immature and plasmablastic type, and then they showed that plasmablastic morphology is an independent predictor of poor survival rate after autologous stem-cell transplantation. On the other hand, Kawano et al. classified myeloma cells into three types by their phenotype (Huang N, Blood82: 3721, 1993, Kawano MM, Blood82: 564, 1993); immature (MPC1−, CD49e−, CD45−/+), intermediate (MPC1+, CD49e−, CD45−), and mature (MPC1+, CD49e+/−, CD45+). This classification according to the phenotype is good correlation with that by morphology. And they indicated that immature myeloma cells have activity of proliferation. We analyzed both phenotypic and morphological findings of myeloma (plasma) cells consecutively before and after chemotherapy in 23 MM cases in order to find what kind of drug might be useful to reduce the main population of heterogeneous myeloma cells. The phenotypic and morphological analysis were performed before and after ten-cycles of melphalan-predonine (MP) in 2 cases, three or four-cycles of vincristine-doxorubicin-dexamethasone (VAD) in 10 cases, high-dose cyclophosphamide (HD-CPA) for stem cell harvest after three or four cycles of VAD in 5 cases, high-dose melphalan followed by autologus stem-cell transplantation (HD-Mel+ASCT) in 6 cases, and administration of thalidomide at least for two months in 7 cases. First, total myeloma cells decreased after VAD, however, immature myeloma cells increased relatively (9/10). Second, HD-CPA was not effective in reducing myeloma cells furthermore after VAD (5/5). Third, HD-Mel+ ASCT could reduce immature myeloma cells clearly (4/6). In particular, a less than 5% reduction of immature myeloma cells after this course were important for the long duration of good response, but the residue of immature myeloma cells was a predictor of progressive disease (PD). Interestingly, MP was also useful to reduce immature myeloma cells (2/2). Finally, thalidomide was effective in reducing mature and intermediate myeloma cells (3/6), but not effective in immature myeloma cells. In conclusion, melphalan, if it is high-dose, has more effects on immature myeloma cells compared with those of other drugs, which might be a reason of the superiority of HD-Mel+ASCT over conventional treatment in terms of the response rate and event-free survival.

Comparison of High-Dose Cyclophosphamide and Growth Factor with Growth Factor Alone for Mobilization of Stem Cells for Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2301-2301
Author(s):  
Morie Abraham Gertz ◽  
Shaji Kumar ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Suzanne Hayman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Growth Factor ◽  
Plasma Cells ◽  
Patient Characteristics ◽  
Median Number ◽  
P Value ◽  
High Dose ◽  
Duration Of Hospitalization

Abstract Introduction: We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using cyclophosphamide and growth factor (n=370) or growth factor alone (n=346) before stem cell transplantation. Table. Patient Characteristics (N=716) Variable Cyclophosphamide (n=370) Growth Factor Only (n=346) P Value Abbreviation: IQR, interquartile range. *Or equivalent dosage. Men, No. of patients (%) 224 (61) 202 (58) .50 Age, median (IQR), y 58 (52–64) 60 (53–65) .11 b-2 Microglobulin, median (IQR), mcg/mL 2.7 (1.9–4.0) 2.3 (1.9–3.2) .01 Creatinine, median (IQR), mg/dL 1.1 (0.9–1.3) 1.0 (0.8–1.2) .002 Apheresis, median (IQR) collections, No. 2 (1–3) 4 (3–6) .001 Marrow plasma cells, % 17 (5–34) 5 (1–13) .001 CD34+cells, median (IQR), cells/kg Total collected 10.3x106(7.2x106–14.6x106) 9.9x106(7.6x106–11.9x106) .01 Infused 5.6x106(4.5x106–7.6x106) 4.2x106(3.8x106–5.0x106) &lt;.001 Duration of hospitalization, median (IQR), d 4 (0–10) 4 (0–9) .92 Nonstaphylococcal bacteremia, No. of patients (%) 48 (13) 25 (7) .01 Melphalan dosage, No. of patients (%) .04 200 mg/m2* 337 (91) 298 (86) 140 mg/m2* 33 (9) 48 (14) Exposure before mobilization, No. of patients (%) Melphalan 45 (12) 44 (13) .50 Lenalidomide 14(4) 63(18) .01 Results: Patients receiving cyclophosphamide had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, 2 vs 4 sessions, respectively [P=.001]). However, patients treated with cyclophosphamide required more time for engraftment of platelets and neutrophils (P&lt;.001 for both). For patients receiving cyclophosphamide, 75% achieved engraftment (defined as a platelet count of 50x109/L) by day 39, whereas 75% of patients not receiving cyclophosphamide achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with cyclophosphamide had a higher incidence of posttransplant nonstaphylococcal bacteremia. For cyclophosphamide-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session. Conclusion: Our data suggested that cyclophosphamide damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment. We suggest that the cyclophosphamide used for mobilization may affect the marrow microenvironment. Cyclophosphamide improves yields but increases bacteremia rates after transplantation. Cyclophosphamide increases time required to collect stem cells and slows engraftment. Figure Figure

High-Dose Therapy with Peripheral Blood Stem Cell Transplantation for Patients with Multiple Myeloma: Prognostic Impact of Chromosomal Aberrations and Correlation with the ISS-Score

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2708-2708
Author(s):  
Kai Neben ◽  
Anna Jauch ◽  
Dirk Hose ◽  
Friedrich Cremer ◽  
Christiane Heiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chromosomal Aberrations ◽  
Plasma Cells ◽  
P Value ◽  
High Dose ◽  
Prognostic Impact ◽  
Response To Chemotherapy

Abstract Multiple Myeloma (MM) is a malignant lymphoproliferative B-cell disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Acquired genomic aberrations have been shown to significantly impact response to chemotherapy and survival in MM. The aim of our study was to assess the clinical relevance of genomic abnormalities in 306 MM patients treated with high-dose chemotherapy (HDCT) and peripheral stem cell transplantation (PBSCT) in our center. We analyzed 171 males and 135 females with a median age of 60 years (range 25 – 73 years). According to the international staging system (ISS), MM patients were classified as stage I (46.6%), stage II (36.1%) and stage III (17.4%) at the onset of chemotherapy. All patients underwent frontline HDCT with 200 melphalan mg/m2 and PBSCT according or in analogy to the GMMG-HD3- or GMMG-HD4-trials. Interphase-FISH-analysis was performed on CD138-purified plasma cells using probes for chromosomes 1q21, 6q21, 8p21, 9q34, 11q23, 13q14.3, 15q22, 17p13, 19q13, and 22q11, as well as IgH-translocations t(4;14)(p16.3;q32.3) and t(11;14)(q13;q32.3). For the entire group, the median overall survival (OS) and progression-free survival (PFS) after HDCT was 6.4 and 2.2 years, respectively. Table 1. Chromosomal abnormalities with significant results (a-level=0.05) on PFS or OS (univariate analysis, unadjusted p-values) Aberration yes vs. no Frequency % 3-year PFS % P value 3-year OS % P value del(8p21) 19 26 vs. 37 0.01 58 vs. 78 0.02 del(13q14.3) 46 23 vs. 53 &lt;0.001 65 vs. 83 0.03 del(17p13) 10 22 vs. 40 0.02 44 vs. 82 &lt;0.001 t(4;14) 14 10 vs. 42 &lt;0.001 54 vs. 81 0.04 +1q21 35 20 vs. 46 &lt;0.001 67 vs. 85 0.002 +19q13 54 49 vs. 22 0.03 76 vs. 73 0.92 In a first step, we analyzed the prognostic impact of each individual chromosomal aberration on PFS and OS (Table 1). After adjustment for the ISS-score, del(8p21), del(13q14.3), del(17p13), t(4;14) as well as gains of 1q21 and 19q13 preserved significant impact on PFS, while del(17p13), t(4;14) and gain of 1q21 were of statistical significance for OS, indicating that these chromosomal aberrations give prognostic information in addition to the ISS-score. Subsequently, we performed a multivariate analysis including all the chromosomal aberrations analyzed. While del(17p13) and gain of 1q21 showed significant results on OS, del(13q14.3), del(22q11) and gain of 15q22 were significant for PFS. In conclusion, our results show that the heterogeneity seen in the clinical course of MM patients after HDCT can be correlated with distinct chromosomal aberrations. This analysis may have implications for the risk-adopted management of patients with MM.

Malignant Plasma Cells Responsible for Multiple Myeloma Relapse Are Detectable and Survive Nine Days After High Dose Melphalan: Highlight of An Optimal Therapeutic Window ?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 131-131
Author(s):  
Anouk Caraux ◽  
Laure Vincent ◽  
Jerome Moreaux ◽  
Guilhem Requirand ◽  
Caroline Bret ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factor ◽  
Plasma Cells ◽  
Therapeutic Window ◽  
High Dose ◽  
Myeloma Cells ◽  
Time Points ◽  
High Dose Melphalan

Abstract Abstract 131 Background and Objectives: Multiple myeloma (MM) is still an incurable plasma cell dyscrasia. In an attempt to further improve MM patients' outcome, we have characterized malignant plasma cells resistant to treatments as well as their cellular and molecular environment. The aim is to highlight interactions that could be targeted at optimal time points of the treatment schedule. Methods: Twenty-four newly diagnosed MM patients treated in first line by bortezomib and dexamethasone induction followed by high dose melphalan (HDM) and autologous stem cell transplantation were included. Tumor and normal plasma cell were detected and counted in peripheral blood and bone marrow using 7-color multiparameter flow cytometry at different time points of treatment: at the end of induction, 9 days, 3 months and 6 months after high dose melphalan and autologous stem cell reinjection. The sensitivity of detection reached was 10−5. The cellular content of the leukapheresis product was also analyzed after thawing before being reinjected. Plasma cells were characterized in terms of tumor markers (CD200, CD56, CD117, CD27, CD19, CD45), proliferation status (KI67) and expression of CCR2 chemokine receptor. Using multiplex technique, we also evaluated the medullary cytokine / chemokine environment (Interleukin-1b (IL-1b), IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, Epidermal Growth Factor (EGF), eotaxin, Fibroblast Growth Factor-basic (FGF-b), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), G-CSF, Hepatocyte Growth Factor (HGF), Interferon-a (IFN-a), IFN-g, Inducible Protein 10 (IP-10, CXCL10), Monocyte Chemotactic Protein-1 (MCP-1, CCL2), Monokine Induced by IFN-g, Regulated on Activation Normally T-cell Expressed and Secreted (RANTES, CCL5), Tumor Necrosis Factor a (TNF- a), and Vascular Endothelial Growth Factor (VEGF) at the end of induction, 9 days and 3 months post HDM. IGF1, IL21, BAFF and APRIL were measured by Elisa. Results: Two thirds of the 24 patients had detectable tumor plasma cells after induction treatment and in all these patients, tumor plasma cells (median 5.9 cells/ mm3, range 0.1–76.9 cells/mm3) as well as normal plasma cells (median 3.3 cells/mm3, range 0.4–32.2 cells/mm3) could be detected 9 days after HDM treatment in an aplastic bone marrow (median cell count 400 cells/mm3). Nine days post HDM, a burst of cytokines / chemokines was detected in bone marrow plasma which could prompt survival, growth and homing of tumor plasma cells. CCL2 chemokine (chemokine C-C motif ligand 2) which is a chemotactant and survival factor for myeloma cells was the only cytokine / chemokine differentially expressed in immuno-phenotypic complete response patients compared to patients with persistent tumor plasma cells, with a concentration 2.1 times higher in the last ones. In parallel, preliminary data show an enrichment in CCR2 positive tumor plasma cells 9 days after HDM, CCR2 being the receptor for CCL2. This interaction could be a clinically significant target to get rid of minimal residual disease. Conclusions: In conclusion, we show that the early post intensification (HDM) period could be an interesting therapeutic window to target resistant myeloma cells and their interactions with the pro-survival micro-environment. The CCL2-CCR2 interaction could be of particular interest, an anti CCR2 antibody already being in clinical development in rheumatoid arthritis (Van Driel et al. 2008). Disclosures: No relevant conflicts of interest to declare.

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