Ocular Complications of Bortezomib Therapy in Multiple Myeloma

Abstract Introduction: Bortezomib (Velcade¨; V), a proteasome inhibitor, is currently FDA (Food and Drug Administration) approved for the treatment of multiple myeloma (MM) and relapsed mantle cell lymphoma. Common side effects reported with its use include thrombocytopenia, fatigue, peripheral neuropathy and neutropenia. Ocular complications associated with bortezomib are less well described. We describe 6 patients with multiple myeloma who developed meibomitis, multiple chalazions and blepharitis after treatment with bortezomib containing regimens, resulting in delay and in some cases termination of the therapy. Methods: We reviewed the charts of forty patients who received induction chemotherapy for multiple myeloma between June 2013-June 2014 at Montefiore Medical Center, New York. Charts were reviewed for data pertaining to demographics, chemotherapy regimen and schedule as well as follow up of ocular symptoms. Results: Six of these forty (15%) patients complained about bilateral eye soreness, itching and redness. They did not have any evidence of viral or upper respiratory infections. Ophthalmology evaluation showed blepharitis, meibomitis and multiple chalazion. Majority of the patients were 60 years or greater, with 50% African-Americans. Half of the cases had stage 3 MM with a median duration of chemotherapy 8 weeks prior to onset of ocular symptoms. 4 of these 6 patients received VCD regimen (Bortezomib via subcutaneous route and Cyclophosphamide/ Dexamethasone as tablets) while the remaining 2 patients received VD and VCD-R (addition of Lenalidomide) via intravenous and subcutaneous route respectively. Ocular symptoms led to a 1-3 week delay in the next cycle of chemotherapy. These symptoms promptly responded to withdrawal of chemotherapy and other conservative measures. Chemotherapy was resumed in 4 out of 6 patients, with recurrence of chalazion in two patients within 3 weeks of starting Bortezomib. Conclusions: Ocular symptoms are commonly seen but rarely reported with bortezomib therapy. They can adversely affect patient's quality of life as well as lead to interruption in chemotherapy. Although these symptoms respond well to withdrawal of chemotherapy and conservative measures, the rate of recurrence is high once bortezomib is resumed. Awareness of these complications and early intervention can potentially avoid treatment delay. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Optimization of Plerixafor Utilization Based on Peripheral Blood CD34+ Count for Autologous Peripheral Blood Stem-Cell Collection

Blood ◽

10.1182/blood-2020-140171 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-41

Author(s):

Gaurav K. Gupta ◽

Sera Perreault ◽

Stuart Seropian ◽

Christopher A. Tormey ◽

Jeanne E. Hendrickson

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Medical Center ◽

Tertiary Care ◽

Peripheral Blood Cd34 ◽

Tertiary Care Medical Center ◽

Group 2 ◽

Group 1

Introduction: Peripheral CD34+ cells may be mobilized using filgrastim (G-CSF) alone or in combination with chemotherapy. However, some patients also require plerixafor, an inhibitor of C-X-C chemokine receptor type-4, for adequate mobilization. Given its cost, judicious utilization of plerixafor is warranted. Material and Methods: A retrospective analysis of autologous stem-cell mobilization was performed at a tertiary-care medical center in adult patients with multiple myeloma and lymphoma; here we will focus on the utility of repeat plerixafor dosing. Patients were mobilized at the treating physician's discretion with filgrastim plus plerixafor or chemotherapy plus filgrastim plus plerixafor. Collections were initiated once peripheral CD34+ counts reached 20/µL (or 10/µL if chemotherapy mobilized); plerixafor was administered if these counts were not reached after 4 or 8 days, respectively, of filgrastim treatment. Results: Patients with multiple myeloma (86) or lymphoma (30) were evaluated. One hundred five were mobilized by filgrastim plus plerixafor and 11 by chemotherapy plus filgrastim plus plerixafor. No patient that received plerixafor with a CD34+ count <5/µL after chemotherapy mobilized the next day. The end collection goal was achieved in 86 (81.9%) of the filgrastim plus plerixafor group and 7 (63.6%) of the chemotherapy plus filgrastim plus plerixafor group. Patients given at least one dose of plerixafor were divided into groups based on collection goal, peripheral blood CD34+ cell count after 1 dose and the first day collection yield: Group 1) Goal of 3x10^6/kg and CD34+ count ≥ 30 cell/µL vs < 30 cell/µL; Group 2) Goal of 6x10^6/kg and ≥ 50% of collection goal after 1 day of collection vs CD34+ count < 50 cell/µL or < 50% of collection goal. Forty of 42 (95%) patients in Group 1 with a CD34+ count ≥ 30 cell/µL achieved their end collection goal after one plerixafor dose. Eighteen of 19 (95%) patients in Group 1 with a CD34+ count <30 cell/µL received a second dose of plerixafor and 8 (44.4%) achieved their end collection goal. Twenty-eight of 32 (87.5%) patients in Group 2 with ≥ 50% of collection goal achieved on the first day of collection reached their end collection goal after one plerixafor dose. Nine of 12 (75%) patients in Group 2 with a CD34+ count of < 50 cells/µL or <50% collection goal received an additional dose of plerixafor and 6 (66.7%) achieved their end collection goal. Conclusion: Based on these data, we have developed the following repeat plerixafor dosing algorithm: 1) for a collection goal is 3x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is < 30 cell/µL, and 2) for a collection goal of 6x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is < 50 cell/µL or if the first day of collection yields <50% of the end goal. This algorithm optimizes pharmacy, apheresis and stem cell processing resources. Disclosures No relevant conflicts of interest to declare.

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Bortezomib Induction Followed by ASCT in Patients with Multiple Myeloma: Achievement of Response After Induction and Achieving CR Post-ASCT Are Both Important Prognostic Markers

Blood ◽

10.1182/blood.v118.21.1866.1866 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1866-1866

Author(s):

Min Kyoung Kim ◽

Chang-Ki Min ◽

Myung Soo Hyun ◽

Kihyun Kim ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Conflicts Of Interest ◽

Induction Treatment ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival

Abstract Abstract 1866 Background: In multiple myeloma (MM), the association between the response to induction before autologous stem cell transplantation (ASCT) and long-term outcome is less clear but the situation may change with the introduction of novel agents. We therefore assessed the clinical relevance of response of bortezomib induction treatment or post-ASCT response for patients who received bortezomib-combined induction chemotherapy followed by ASCT. Methods: We retrospectively assessed 183 MM patients who received bortezomib-containing induction therapy (BTZ-IT) followed by ASCT in 24 institutions throughout Korea between 2003 and 2010. Records of these patients were reviewed using the Korean Myeloma Registry database (www.myeloma.or.kr). Each institution was requested to reconfirm the data using additional case report forms. Patients who had overt MM based on International Myeloma Working Group diagnostic criteria were selected. Results: One-hundred seventy eight patients were eligible. Their median age was 56 years (range, 28–69 years) and 96 (53.9%) were male. Forty nine (27.5%) received bortezomib as front-line therapy and 129 (72.5%) as second-line treatment. All patients underwent ASCT and 22 (12.4%) were treated with tandem ASCT. Ninety-seven (54.5%) patients were treated with maintenance therapy after ASCT. After BTZ-IT, the response rates in this selected series of patients were 37.6% CR, 12.4% VGPR, 41.0% PR, 7.3% SD and 1.7% PD (Figure 1A, 1B, 1C); the corresponding post-ASCT rates were 69.2% CR, 14.0% VGPR, 11.0% PR, 2.9% SD and 2.9% PD. At a median follow-up of 46.6 months, the 3-year overall survival (OS) and event-free survival (EFS) rates were 70.0% and 31.9%, respectively. Multivariate analysis showed that factors independently predictive of OS and EFS included achievement of BTZ-IT response °Ã PR (P=0.025 and P=0.014, respectively) and the treatment with maintenance therapy (P=0.048 and P=0.001, respectively). Post-ASCT CR vs. °Â VGPR was also an independent prognostic factor for OS and EFS (P=0.0001 and P=0.002, respectively). Conclusion: At least PR to BTZ-IT and CR after ASCT were predictive of survival. These findings suggest that patients who responded to BTZ-IT may benefit from ASCT due to an enhanced quality of response. Maintenance therapy can also affect patient outcomes. Disclosures: No relevant conflicts of interest to declare.

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Venous Thromboembolism (VTE) In Hospitalized Patients: What Proportion Is Attributable to Malignancy?

Blood ◽

10.1182/blood.v118.21.5250.5250 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5250-5250

Author(s):

Frank Akwaa ◽

Alok Khorana

Keyword(s):

Public Health ◽

New York ◽

Conflicts Of Interest ◽

Hematologic Malignancy ◽

Medical Center ◽

New York State ◽

Length Of Hospital Stay ◽

Cost Of Care ◽

Hospitalized Patients ◽

Public Health Burden

Abstract Abstract 5250 Background: VTE is a public health burden in hospitalized patients, affecting the length of hospital stay and overall cost of care. Recent studies suggest increasing incidence of VTE among cancer patients, but contemporary data regarding proportion of VTE attributable to cancer and non-cancer populations are lacking. Methods: Hospital-acquired VTE is a reportable event to New York State and we studied all reported VTE events among patients hospitalized at the University of Rochester Medical Center from January 2003 through April 2009. We utilized electronic medical records to identify additional information including demographics and diagnosis of malignancy. Results: We identified 2031 patients with 2185 documented VTE events during the study period. Of these, 1102 (54.3%) were men and 929 (45.7%) were women. VTE events included deep vein thrombosis (DVT) (N=1428, 65 %), pulmonary embolism (PE) (N=757, 34.6%), and concurrent DVT and PE (N=153, 7 %). Of the 2031 hospitalized patients with VTE, 492 (24.2%) had a concurrent diagnosis of cancer and 1539 (75.8%) did not. Of 492 cancer-related VTE, 167 (34%) were associated with hematologic malignancies, and 324 (66%) with solid tumors. The proportion of cancer-associated VTE varied by year, ranging from 21% to 31%. Conclusions: Approximately one-fourth of all VTE in hospitalized patients occurred in patients with cancer, including a substantial proportion with hematologic malignancy. Public health efforts to reduce hospital-associated VTE should focus on improving compliance with thromboprophylaxis for this population. Disclosures: No relevant conflicts of interest to declare.

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Evidence Based Recommendations for Supportive Care in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-110748 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1952-1952

Author(s):

Anum Qureshi ◽

Muhammad Junaid Tariq ◽

Zunairah Shah ◽

Muhammad Abu Zar ◽

Shehroz Aslam ◽

...

Keyword(s):

Quality Of Life ◽

Multiple Myeloma ◽

Supportive Care ◽

Conflicts Of Interest ◽

Control Group ◽

Cell Transplant ◽

Clodronic Acid ◽

Management Of Complications ◽

Reduced Risk

Abstract Introduction: Multiple myeloma (MM) is associated with end organ damage that negatively impacts the quality of life (QOL)and supportive care has a potential to improve symptoms. Methods: After detailed search on Pubmed, Cochrane, Embase and Clinical Trials.gov, we finalized total 36 articles on supportive care published after 2004. Results: Management of skeletal events: Mhaskar et al. (2017, n=3257) compared bisphosphonates (BPs) with placebo (PBO) in preventing pathological vertebral fractures, skeletal-related events (SRE), reported risk ratio (RR) of 0.74 in each; 95% CI 0.62-0.89 and 0.63-0.88 respectively. Both zoledronic acid (ZA) and clodronic acid prevent SRE, but mortality rate was better reduced with ZA (hazard ratio [HR]=0.84; p=0.0118), (Gareth et al. 2010, n=1960). In a study by Zuradelli et al. (2009, n= 240); hypocalcemia developed in 93 (38.8%) patients on ZA for a median of 2.3 months (range, 0-34.9). Vitamin D and calcium replacement is essential in patients developing hypocalcemia with BPs, (Kennel et al. 2009). Vertebral augmentation procedures improved pain after compression fracture (n=923) by 4.8, 4.6 and 4.4 points at 1 week, 1 year and beyond 1 year respectively, (Khan et al. 2014). Valerie et al. (2011, n=84) analyzed improvement in bone pain with radiotherapy (median 45 grays) in 92 % patients. Prophylaxis of infections: Leng et al. (2018, n=70,687) observed reduced risk of herpes zoster (HZ) reactivation in patients on bortezomib or carfilzomib + HZ prophylaxis (2.4%) vs 5.8% in non-prophylactic group, (attributable risk reduction: 0.42; 95% CI 0.31-0.56). Teh et al. (2016, n=199) reported reduced risk of varicella zoster virus reactivation with valacyclovir (500 mg) in patients on bortezomib based therapy and following autologous stem cell transplant (ASCT) vs no prophylaxis (HR=0.06 vs 16.9; p<0.01). Dimopoulos et al. (2016, n=569) found higher risk of pneumonia, 8.2% in daratumumab group (n=286) vs 7.8% in control group (n=283). Prophylactic trimethoprim-sulfamethoxazole reduced risk of PCP in 85% patients after ASCT (RR=0.15; 95% CI 0.04-0.62), Stern et al. (2014, n=1000). Incidence of Community-acquired pneumonia (CAP), noninvasive CAP and invasive pneumococcal disease in elderly population (≥65 years) was seen in 49, 33 and 7 patients on Pneumococcal polysaccharide conjugate vaccine group as compared to 90, 60 and 28 patients in placebo group respectively, (Bonten et al. 2015, n=84,496). Role of plasmapheresis in renal impairment (RI): Alkhatib et al. (2017) showed that plasmapheresis reduced dialysis dependency by removing serum free light chains (sFLC) in patients with RI (n=147), (RR 0.45; P = 0.02). Yu-X et al. (2015, n=147), showed lower 6-month dialysis dependency ratio with plasmapheresis and chemotherapy (PP + CTH) vs CTH alone, (15.6% vs 37.2%; RR=2.02; p = 0.04). High cut-off hemodialysis lowered sFLC level in 61% (n=42) and 63% patients at day 12 and 21 respectively. Out of these, 71% and 69% patients became dialysis independent, (Hutchison et al. 2012, n=67). Peripheral neuropathy (PN): Bortezomib caused PN in 124/331 (37%) patients (Richardson et al. 2009) whereas with thalidomide, the incidence of PN was 38% and 73% at 6 and 12 months, respectively, (Mileshkin et al. 2006, n=75). PN improved in 68% patients on bortezomib with dose modifications (n=72) vs 47% patients, without dose modification (n=19). (Table 1 and 2). Significant improvement in PN was seen with duloxetine vs placebo (1.06 vs. 0.34; p= 0.003), (Smith et al. 2013, n=231). Arbaiza et al. (2007, n=36) showed improvement in neuropathic pain with tramadol (p= < 0.001). Epoetin and derivates for anemia: Castelli et al. (2017, n= 31; median creatinine 1.2 mg/dL (0.8-3.0)) reported hemoglobin (Hb) increase of ≥1g/dL and ≥2g/dL in 71% and 31.7% patients respectively with epoetin α, transfusions requirement reduced from 2.39 ± 1.05 to 1.23 ± 1.36 (p < 0.001). Begiun et al. (2013, n= 72) compared the effect of darbepoetin (D) ± iron (Fe) vs placebo on erythroid recovery after ASCT. All patients receiving D + Fe achieved Hb ≥13 g/dL (p<0.0001). Tonia et al. (2012, n= 16,093) showed 35% decrease in transfusion need with erythropoietin stimulating agents (RR=0.65; 95% CI 0.62-0.68). (Table 3) Conclusion: Along with anti-myeloma chemotherapy therapy, management of complications (anemia, infections, renal insufficiency) and other associated symptoms is necessary to improve the quality of life. Disclosures No relevant conflicts of interest to declare.

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Differential Downregulation of Telomerase Activity by Bortezomib in Multiple Myeloma Cells- Regulatory Pathways and Clinical Implications.

Blood ◽

10.1182/blood.v114.22.4917.4917 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4917-4917

Author(s):

Chana Weiss ◽

Orit Uziel ◽

Ofir Wollach ◽

Shlomo Bulvick ◽

Meir Lahav

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Conflicts Of Interest ◽

Medical Center ◽

Telomerase Activity ◽

Response To Treatment ◽

Clinical Implications ◽

Myeloma Cells ◽

Regulatory Pathways ◽

Kinetics Of

Abstract Abstract 4917 Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells- regulatory pathways and clinical implications C. Weiss1, O Uziel2, O. Wolach2, S. Bulvick1, and M. Lahav2 1Laniado Medical Center, Netania; 2Felsenstein Medical Research Center, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel. Background The proteasome inhibitor bortezomib is an effective drug in Multiple Myeloma (MM). However, its exact mechanism of action is not yet fully understood. The importance of telomerase in the biology and prognosis MM is well established, but its response to bortezomib has not been assessed yet. In light of common signaling pathways of connecting telomerase regulation and bortezomib known mechanisms of action, we surmised that the drug may affect the activity of telomerase in MM cells. Results Bortezomib downregulated telomerase activity in all MM cell lines. However, the kinetics of this downregulation varied between the two cell lines examined. Whereas in ARP-1 cells telomerase activity decreased 24 hours after bortezomib treatment, in CAG cells the effect was observed only after 48 hours. These finding imply different regulatory mechanisms between these lines. In both lines bortezomib transcriptionally downregulated telomerase activity by inhibiting hTERT expression. ChIP (Chromatin Immune Precipitation) analysis showed that SP-1 and C-Myc transcription factors mediate this transcriptional downregulation of telomerase. Interestingly, the binding of NFkB to hTERT promoter is enhanced in response to the drug, consistent with a recent study reporting upregulation of NFkB by bortezomib. We are currently looking in depth at the pathways leading to these phenomena. However, the two lines differed in the post translational modification of AKT, which phosphorylates telomerase post-translationally. Whereas in ARP-1 cells the phosphorylated form of AKT is downregulated in response to bortezomib, the drug did not affect AKT phosphorylation in CAG cells. These findings explain the different kinetics of telomerase downregulation and are in keeping with previous data showing different AKT response between these two cell lines. Conclusions and future studies Our results shed light on the effects and mechanism of bortezomib on telomerase activity in MM. Te differential response of pAKT pathway is in keeping with recent studies suggesting differential dependency of MM cells on pAKT. Telomerase inhibition by bortezomib may be of varying efficacy in subsets of MM patients in relation to their pAKT dependency. A correlation may also be found between the effect of bortezomib on telomerase activity and resistance to bortezomib in MM. As such, the ex vivo assessment of telomerase activity response to treatment may serve as a prognostic feature and add to therapeutic armamentarium by addition of telomerase inhibitors in defined subsets of patients. Disclosures No relevant conflicts of interest to declare.

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Induction Therapy With Continuous Alternate-Day Low Dose Lenalidomide Combined With Low-Dose Prednisone In Octogenarian Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.5394.5394 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5394-5394

Author(s):

Luca Pezzullo ◽

Bianca Serio ◽

Raffaele Fontana ◽

Idalucia Ferrara ◽

Mariarosaria Sessa ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Low Dose ◽

Nk Cell ◽

Conflicts Of Interest ◽

Performance Status ◽

Progressive Increase ◽

Hematologic Toxicity ◽

Dose Prednisone

Abstract About 30% of patients with newly diagnosed multiple myeloma (NDMM) are older than 75 years. Immunomodulatory drugs (IMIDs) have improved response rates and outcomes of NDMM, except for patients older than 75 years more vulnerable to side effects of IMIDs because of their frailty and comorbidities. We evaluated efficacy, toxicity and health-related quality of life (HRQOL) associated with continuous alternate-day low dose lenalidomide (LD-R, 10 mg on alternate days) and low dose prednisone (15 mg/day) (LD-RP) in 7 octogenarian NDMM patients (5 males and 2 females) with a median age of 82 years (range 80-87). All octogenarian patients had IgG MM, except 1 oligosecretory lambda chain MM; all were in Durie-Salmon stage III, except 1 in stage II, and had poor WHO performance status (median: 2, range 1-3). Patients were evaluated at baseline and every 6 months for HRQOL according to MM-specific questionnaire QLQ-MY20 of European Organisation for Research and Treatment of Cancer (EORTC). All patients received aspirin thromboprophylaxis, 57% of them requiring from diagnosis erythropoietin and zoledronic acid treatment. In these 7 octogenarian NDMM patients completing at least three months of therapy, the overall response rate (ORR) was 86%, including 1 complete remission (CR), 2 very good partial remission (VgPR) and 3 PR. After a median follow-up of 12 months (range 3-24), the quality of response improved with continuous LD-RP treatment with a cumulative median reduction in monoclonal protein levels of 85% (range 20-100%); none of the patients required discontinuation of treatment secondary to specific hematologic and/or extra-hematologic toxicity. In addition, QLQ MY-20 questionnaires revealed that 70% of patients treated with continuous LD-RP reported improvements of QOL scores. Two out of 7 octogenarian patients died (1 for progression after 12 months and 1 for sepsis no treatment-related), and 2-year overall survival and progression-free survival estimates were 41% and 75%, respectively. Noteworthy, all patients treated with continuous alternate-day LD-RP showed a progressive increase in the percentage of CD3+ CD56+ NK cells during the first 6 months of LD-RP therapy reaching a plateau maintained until +12 months after initiation of therapy: the median percentage of NK cells was 4% before LD-RP treatment versus 10%, 13%, 30%, 31%, and 27% at +1, +3, +6, +9 and +12 months, respectively. Mean fold increase of NK cells during LD-RP therapy was 1.5, 2.5, and 6.5 at +1, +3 and +6 months, respectively. Progressive increase of NK cells was concomitantly associated with reduction in tumor-linked monoclonal immunoglobulin in all patients and increased circulating NK cells further support that this drug may mediate its anti-MM effect, at least in part by modulating NK-cell number and function. Our data provide evidence that continuous alternate-day low dose lenalidomide is a manageable and effective frontline treatment for octogenarian NDMM patients and increases circulating NK cells. These preliminary results require further validation in prospective larger studies. Disclosures: No relevant conflicts of interest to declare.

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Huachansu Injection Combined With Cemt Regimen On Patients With Relapsed Or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5384.5384 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5384-5384

Author(s):

Qingchi Liu ◽

Huimin Zhang ◽

Xinwang Feng ◽

Shujie Wang

Keyword(s):

Quality Of Life ◽

Multiple Myeloma ◽

Complete Remission ◽

Conflicts Of Interest ◽

Life Quality ◽

Control Group ◽

Short Term Treatment ◽

European Organization ◽

Refractory Multiple Myeloma

Abstract Objective To observe the short-term treatment effect of Huachansu Injection combined with CEMT regimen on patients with relapsed or refractory multiple myeloma and evaluate the quality of life of the patients. Methods The 40 patients of relapsed or refractory multiple myeloma were divided into two groups, 20 patients were in the Chinese and western medicine treatment group, the rest in the control group. The patients in the control group received the CEMT regimen (Carboplatin, Etoposide, Methotrexate, and Thalidomide);and those in the Huachansu group received Huachansu injection on the basis of the CEMT treatment. The Huachansu injection in the 500ml 5% Glucose injection was given by intravenous drop once daily, 10'20ml for each time. The general treatment lasted 3 months and one treatment period was 4 weeks,during each period the patients received the medicine treatment for 7 days and had a rest for 2 days. The patients in each group were given the syndrome differentiation type of traditional chinese medicinal broth,decoction, once a day. The QLQ-C30 Quality of Life Questionaire(Chinese Version V3.0for clinical use) worked out by EORTC(European Organization For Research And Treatment Of Cancer) was adopted to evaluate and research the patients’ quality of life before and after the treatment. Results 5 cases had complete remission,6 had part remission, 2 had stable and 7 cases had progresss and the total effectiveness reaches 65.0% in the Huachansu group group. In the control group, 3 cases had complete remission,4 had part remission, 1 had stable and 12 had progress and the total effectiveness reaches 40.0%. The effective rate of Huachansu group is higher than the control group,and the differences was statistically significant(P<0.05). The quality of life questionaire result also shows that the overall health status and the overall life quality of the patients in both groups have been improved as well as the patients’ physical and mental status. The difference in the patients’ life quality is less obvious in both groups. The 3-month treatment on their role functions and social functions have no outstanding effects after comparation. Conclusion The Huachansu Injection combined with CEMT regimen not only has excellent effect on on patients with relapsed or refractory multiple myeloma,but also improves the quality of life of patient. Disclosures: No relevant conflicts of interest to declare.

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Resequencing Analysis of the Human Candidate Ras and Receptor Tyrosine Kinase Gene Family In Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.301.301 ◽

2010 ◽

Vol 116 (21) ◽

pp. 301-301

Author(s):

Vishwanathan Hucthagowder ◽

Chelsea D. Mullins ◽

Rekha Meyer ◽

Rakesh Nagarajan ◽

John F. DiPersio ◽

...

Keyword(s):

Multiple Myeloma ◽

Tyrosine Kinase ◽

Structural Changes ◽

Somatic Mutations ◽

Conflicts Of Interest ◽

Human Cancer ◽

Medical Center ◽

Mutation Screening ◽

Kinase Gene ◽

Data Set

Abstract Abstract 301 Multiple myeloma (MM) is an incurable B-cell malignancy characterized by the clonal proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the growing number of sequencing studies, the comprehensive view of somatic mutations in multiple myeloma is far from clear. One of the most frequently altered gene families in most human cancer is the Ras and the tyrosine kinase (TK) genes, which encode for important regulators of various signal transduction pathways. To uncover the somatic mutation profile of Ras gene and TKs in myeloma, we performed a systematic mutation screening from a selected group of 10 candidate genes in 42 primary myeloma patients. The candidate gene selections were based on the highly altered genes extracted from GEO data sets using Function Express, a data mining and viewer for microarray data. The sequencing of the entire gene region including the promoter and the 3`UTR was performed in the Genome sequencing center at Washington University medical center using the standard resequencing pipeline, from the design of the primers to data output. These data were analyzed with a clinical resequencing pipeline and visualized using the Mutation Viewer software (MV v5.1). We identified 24 nonsynonymous alterations in five genes (KRAS2, PIK3CA, INSR, LTK and MERTK) in our myeloma cohort (Table 1). In particular, we identified the previously reported pathogenic mutation in a KRAS gene and novel somatic mutations in the Kinase family (PIK3CA) that would be expected to cause structural changes. We assessed the frequency plots of the known variants and most but not all are significantly different from the normal data set. The overall results suggest that the germline genetic background besides the somatically acquired mutations may exert an important influence on the prognosis and outcome of the myeloma patient. Our genome-wide resequencing approach thus revealed previously known and novel oncogenic mutations in multiple myeloma, but its relevance needs to be considered in the context of other genetic abnormalities. Table 1: DNA alterations in candidate ras and TK genes in primary multiple myeloma Gene Gene IDa Nucleotide changeb Amino acid change Zygosityc PolyPhen COSMIC KRAS2 3845 c.35 G>A p.G12D Hetero P. Dam Yes KRAS2 3845 c.34 G>T, c.33 T>C p.G12C, A11A Hetero Benign Yes KRAS2 3845 c.183 A>C p.Q61H Hetero P. Dam Yes KRAS2 3845 c.186_194 del p.E62_Y64 Homo PIK3CA 5290 c.928 C>T p.R310C Hetero Yes PIK3CA 5290 c.1173 A>G p.I391M Hetero Benign INSR 3643 c.356 C>T p.A119V Hetero INSR 3643 c.2243 C>T p.S748L Hetero INSR 3643 c.3034 G>A p.V1012M Hetero P. Dam LTK 4058 c.125 G>A p.R42Q Hetero Benign LTK 4058 c.680 C>T p.P227L Hetero LTK 4058 c.728 G>A p.R243Q Hetero LTK 4058 c.1603 G>A p.D535N Hetero MERTK 10461 c.60 A>T p.R20S Hetero Benign MERTK 10461 c.1552 A>G p.I518V Hetero, Homo Benign MERTK 10461 c.1397 G>A p.R466K Hetero, Homo Benign MERTK 10461 c.353 G>A p.S118N Hetero, Homo Benign MERTK 10461 c.2608 G>A p.V870I Hetero Benign MERTK 10461 c.844 G>A p.A282T Hetero Benign MERTK 10461 c.1493 A>G, c.1494 C>T p.N498S Hetero Benign MERTK 10461 c.878 G>A p.R293H Hetero Benign MERTK 10461 c.2593 C>T p.R865W Hetero P. Dam MERTK 10461 c.2069 C>T p.T690I Hetero Benign MERTK 10461 c.2467 G>C p.E823Q Hetero Benign a Gene ID at National center for biotechnology information (http://www.ncbi.nlm.nih.gov/sites/entrez) b del., deletion c Homo, homozygous; hetero, heterozygous Disclosures: No relevant conflicts of interest to declare.

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A Fully Automated Method for Isolating Highly Enriched Population of Multiple Myeloma Plasma Cell From Whole Bone Marrow for Enhanced Sensitivity in Downstream Assays

Blood ◽

10.1182/blood.v118.21.5064.5064 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5064-5064

Author(s):

Hossein Mossafa ◽

Sabine Defasque ◽

Hamid Belaouni ◽

Adrian Arechiga

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Dna Extraction ◽

Mononuclear Cells ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Snp Array ◽

Fish Analysis ◽

Automated Method

Abstract Abstract 5064 Introduction, Multiple myeloma (MM) is characterized by a huge clinical heterogeneity despite the homogenous morphologic appearance of malignant plasma cells (PCs). The advent of interphase fluorescence in situ hybridization (FISH) or MicroArrays (MA) allows an increased rate of aberration detection and identification of some recurrent cryptic changes, which have been increasingly implemented as additional diagnostic and prognostic factors. To heighten sensitivity of Single Nucleotide Polymorphism (SNP) arrays, or FISH it is necessary to have a purified population of cells as starting material. Screening must be performed systematically on the purified CD138+ PCs. After testing different systems for cell purification, we encountered some challenges. We didn't obtain enough PCs for FISH and SNP array studies. This was due to excess M-protein accumulating in the blood stream, increasing hyper viscosity and also due to the morphology and size variations of PCs at various stages of differentiation. Additionally, downstream DNA extraction can be a challenge since EDTA found in most buffers is an inhibitor for chemical PCR reaction for some MA chips. Given the challenges, CERBA laboratory and Miltenyi Biotec GmbH have developed a fully automated process (FAP) for purification for CD138+ PCs. In a study of 100 BM patient samples, we compared the specificity, efficiency, performance, purity, ease of use, technologists' time and the quality of DNA after CD138+ PCs purification. Two methods were compared. In the first method, cells were directly purified from bone marrow samples by FAP using Automated Magnetic Cell Sorter (AMCS). In the second method, mononuclear cells from fresh whole bone marrow (WBM) were enriched by Ficoll, followed by cell selection procedure with anti-CD138+ MicroBeads using the AutoMACS®. Before separation and following the separation, the percentage of PCs was determined by Flow cytometry (FC) on WBM by multiparameter FC (MFC) for CD138/CD38 expression. Additionally, DNA quality on separated cells was assessed by Nanodrop. A fraction of the CD138+ PCs were used after hypotonic shock and Carnoy fixation, applied to glass slides for FISH application and another fraction for DNA extraction for MA (SNP.6 Affymetrix®) FISH was performed with the recommended unbalanced alterations & reciprocal rearrangements: del(13) (q14)(D13S25), del(17)(p13)(TP53),+3(D3Z), +9(D9Z1), +15(D15Z14), t(4;14)(p16;q32)/IGH-FGFR3. Results, the specificity and purity were the same for both process but the efficiency and performance were considerably better for FAP than mononuclear cells enriched by Ficoll (MCEFicoll) process. With FAP, in 95% of the MM cases we obtained enough PCs for performance of the recommended panel of FISH and for 50% of them we could extract DNA for SNP array. For the MCEFicoll, we observed inferior performance, with very few plasma cells after isolation. Having enough PSc for only 65% of the cases and we could only extract DNA for 28% of them. The quality of DNA was the same for both process and the technologists' time was longer by 30' /patient for MCEFicoll process than for FAP. Currently in CERBA lab, we realize more than 20 plasma cells isolation per week for patients with MM and from October 2007 to July 2011 we have separated more than 5.000 specimens using CD138 Whole Blood MicroBeads (CD 138 WBMB) from Miltenyi Biotec, in combination with the AMCS. This has allowed isolation directly from WBM without any sample preparation required, such as density gradient centrifugation (ficoll) or erythrocyte lysis. The detection rate of chromosomal abnormalities and the number of abnormalities per case in MM and PCs dyscrasia significantly improves when there are enough CD138+PCs for analysis. Conclusion, in this report we describe the benefits of fully automated isolations of CD138+ cells from WBM. We have developed an SOP for an automated reliable and standardized method which allows the processing of multiple samples in a single day, while maintaining sample integrity and increasing sensitivity of FISH analysis and WG arrays for a diagnosis lab. Disclosures: No relevant conflicts of interest to declare.

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Burden of Healthcare-Associated Viral Respiratory Infections in Children’s Hospitals

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piw072 ◽

2016 ◽

Vol 7 (1) ◽

pp. 18-24 ◽

Cited By ~ 5

Author(s):

Caroline Quach ◽

Rita Shah ◽

Lorry G Rubin

Keyword(s):

New York ◽

Intensive Care ◽

Respiratory Infections ◽

Medical Center ◽

Incidence Rates ◽

Children's Hospitals ◽

Children’S Hospitals ◽

Viral Respiratory Infections ◽

Healthcare Associated ◽

Viral Respiratory

Abstract Objective Although healthcare-associated (HA) viral respiratory infections (VRIs) are common in pediatrics, no benchmark for comparison exists. We aimed to determine, compare, and assess determinants of unit-specific HA-VRI incidence rates in 2 children’s hospitals. Methods This study was a retrospective comparison of prospective cohorts. The Montreal Children’s Hospital and the Cohen Children’s Medical Center of New York perform prospective surveillance for HA-VRI using standardized definitions that require the presence of symptoms compatible with VRI and virus detection. Cases detected between April 1, 2010, and March 31, 2013, were identified using surveillance databases. Annual incidence rates were calculated, and a generalized estimating equation model was used to assess determinants of HA-VRI rates. Results The overall HA-VRI rate during the 3-year study period was significantly higher at Montreal Children’s Hospital than that at Cohen Children’s Medical Center of New York (1.91 vs 0.80 per 1000 patient-days, respectively;P < .0001). Overall, the HA-VRI incidence rate was lowest in the neonatal intensive care unit. Rates in the pediatric intensive care, oncology, and medical/surgical units were similar. The most common etiology of HA-VRI at both institutions was rhinovirus (49% of cases), followed by parainfluenza virus and respiratory syncytial virus. Hospitals with less than 50% single rooms had HA-VRI rates 1.33 (95% confidence interval, 1.29–1.37) times higher than hospitals with more than 50% single rooms for a given unit type. Conclusions HA-VRI rates were substantial but different among 2 children’s hospitals. Future studies should examine the effect of HA-VRI and evaluate best practices for preventing such infections.

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