A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Abstract Abstract 4051 Introduction: What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center's predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student's t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v114.22.4866.4866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4866-4866

Author(s):

Luciana Correa Oliveira de Oliveira ◽

Juliana Alves Uzuelli ◽

Ana Paula Alencar de Lima Lange ◽

Barbara Amelia Aparecida Santana-Lemos ◽

Marcia Sueli Baggio ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Prognostic Factors ◽

Bone Disease ◽

Cox Regression ◽

Conflicts Of Interest ◽

Newly Diagnosed ◽

Significant Difference ◽

The Impact

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

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Use of Plerixafor in Predicted and Proven Poor Mobilizer (according to GITMO criteria). Experience of Policlinico Universitario Tor Vergata

Blood ◽

10.1182/blood.v120.21.4415.4415 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4415-4415

Author(s):

Massimiliano Postorino ◽

Alessandro Lanti ◽

Eleonora Fiorelli ◽

Angelo Salvatore Ferraro ◽

Oana Marilena Chiru ◽

...

Keyword(s):

Side Effects ◽

Conflicts Of Interest ◽

Minimum Requirement ◽

Correct Definition ◽

Cd34 Cells ◽

Minimum Number ◽

Poor Mobilizer ◽

Operational Criteria ◽

Definition Of ◽

To Receive

Abstract Abstract 4415 BACKGROUND. Autologous stem cell transplantation (ASCT) of PBSCs has become a widely applied treatment for Multiple Mieloma (MM), non- Hodgking's lymphoma (NHL) and Hodgking's lymphoma (HL). Successful engraftment correlates with the number of CD34 hemopoietic progenitors cells infused. However, a part of MM or lymphoma patients (5% to 40%) fail to mobilize adequate numbers of PBSCs and thus cannot undergo to ASCT. The success of PBSCs mobilization is usually assessed by the total number of CD34+ stem cells collected, with a cutoff of 2.0–2.5 ×106 CD34+ cells/kg recipient body weight being considered as a minimum requirement for transplant. Poor mobilization of PBSCs is a major limitation to ASCT. Recently GITMO Working Group worked to define operational criteria for the identification/prediction of the poor mobilizer (PM) patients (Olivieri et al. 2011). Plerixafor, a CXCR4 chemochine antagonist, has been showed to improve significantly PBSC mobilization in PM patients. We present our experience using Plerixafor in PM patients classified according to GITMO criteria. METHODS. Between September 2009 and June 2012, a total of 17 patients (9F-8M) were enrolled. The diagnosis were: 10 MM (5F-5M), 1HL (1M), 6 NHL (4F-2M). The median age was 57 (range 15–66). 7 patients (3MM, 4NHL) were defined “Proven PM” and 10 patients (7MM, 2NHL, 1HL) “Predicted PM” according to GITMO criteria. The mobilization protocol included G-CSF, administered at a dose of 10μg/kg daily on 4 consecutive days. In the evening of the fourth day, patients received subcutaneous plerixafor at a dose of 0,24 mg/kg. Apheresis was initiated on the fifth day, 10–12 h after plerixafor and 1 h after G-CSF administration. Apheresis and daily administration of G-CSF and plerixafor continued until the patient collected enough CD34+ cells for auto- HSCT (> 2 ×106/kg; max 7 plerixafor injections if required). PBSC collection was initiated if peripheral CD34+ cells count was >10μl. A successful mobilization was defined as a total yeld of > 2×106/kg. RESULTS. 13 patients (76,5%) collected the minimum number of CD34 cells > 2×106/kg. The diagnosis were: 8MM, 1HL,1 NHL. 7 patients (2NHL; 4 MM; 1 LH; 7 predicted) were able to collect > 5×106/Kg. Only 4 patients (3 MM; 1 LNH; 4 proven) failed the mobilization because the numbers of cells CD34 were < 10μL and these patients did not undergo to apheresis procedures. The collection target of 2×106/Kg was reached in a median of 2 apheresis session (range 1–3). The technical characteristics of the procedures were (median value): blood volume processed 12 L (range 9–14), total CD34+/Kg collected 3,06 × 106(range 2,21-8,62), procedure efficiency 47,5% (range 35,3–79), duration of the procedure 261 minutes (range 210–309). Plerixafor was well tolerated and mild side effects were: reactions in the injection site, gastrointestinal disturbs, muscle pain. During administration of plerixafor we did not observe any significant laboratory abnormalities of liver or renal function. CONCLUSION. Unsuccessful mobilization represents an important limitation to ASCT in lymphoma and MM. In our experience plerixafor allowed to collect an appropriate amount of CD34 also in patients defined “proven PM” significantly reducing the percentage of patients that could not undergo ASCT (target value obtained in 43% of “proven PM”). Confirming the recent literature plerixafor is well tolerated with minimal side effects. We retrospectively applied GITMO criteria for PM patients and our experience, although limited, confirm that the use of a correct definition of PM allows the appropriate use of new mobilizing agents like plerixafor increasing significantly the therapeutic options also in patients who had no possibilities to receive an ASCT with the traditional mobilizing therapy. Disclosures: No relevant conflicts of interest to declare.

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A 15 Hour Dosing-Collection Interval for Plerixafor Is at Least as Effective as the Standard 10 Hour Interval.

Blood ◽

10.1182/blood.v114.22.2152.2152 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2152-2152 ◽

Cited By ~ 1

Author(s):

Eric R Rosenbaum ◽

Mayumi Nakagawa ◽

Gina Pesek ◽

John Theus ◽

Bart Barlogie ◽

...

Keyword(s):

Phase I ◽

Conflicts Of Interest ◽

P Value ◽

Number Of Patients ◽

Cd34 Cells ◽

Significant Difference ◽

The Difference ◽

Student’S T ◽

Age Range ◽

Total Average

Abstract Abstract 2152 Poster Board II-129 Introduction: Plerixafor (formerly AMD3100) is a reversible CXCR4 inhibitor used to mobilize CD34+ cells for collection and use in hematopoietic transplant. Since beginning phase I trials, the drug has been given at 10 pm and collection initiated 10h later at 8 am. After recent FDA approval, we examined use of a dosing-collection interval of 15h (5 pm administration/8 am collection) for patient (pt) convenience. Here we compare results retrospectively from phase I and II trials at our institution using the 10h interval with post-approval collections using the 15h interval. We also evaluated prechemotherapy platelet (plt) count as a predictor of response to plerixafor+G-CSF. Materials and Methods: We reviewed data for all pts (n=107) at our institution who received plerixafor using the 10h (n=79) and 15h (n=34) intervals. This group was reduced to only those who received 4 consecutive days of plerixafor (n=76), of which 67 had the 10h interval and 21 had the 15h interval. The age range of the 10h group was 30-79y (median 62) and the range of the 15h group was 45-78y (median 57). The primary disease in both groups was multiple myeloma, but included 2 NHL in the 10h group, and 5 NHL in the 15h group. Chemotherapy given prior to mobilization for both the 10h and 15h interval groups were similar and plerixafor was administered with G-CSF in all pts. CD34+ cells collected on days 1-4 were quantified by flow cytometry. Finally, some patients (n=9) underwent mobilization with plerixafor two or more times, of which 4 did so on both the 10h and 15h intervals. These instances were recorded as separate events. Prechemotherapy plt counts were also reviewed for each patient and subcategorized into 3 groups: <100, 100-150, and >150,000/uL. Mean CD34+ cells collected were compared between the plt subcategories for both the 10h and 15h groups. Results: The mean number of CD34+ cells collected for the 10h group on days 1-4 of plerixafor administration was 1.26, 1.04, 0.71, and 0.55 ×10e6 CD34+ cells/kg, respectively, with total average collection of 3.56 × 10e6 CD34+ cells/kg. For the 15h group, the average number of CD34+ cells collected on days 1-4 were 2.20, 1.61, 1.44, and 1.01 × 10e6 CD34+ cells/kg, respectively, with total average collection of 6.26 × 10e6 CD34+ cells/kg. The two groups were compared using two-tailed student's t-tests. There was no statistically significant difference between the quantity of CD34+ cells collected on days 1 or 2 for the 10h and 15h groups, however there was a statistically significant difference on days 3 and 4. On these latter two days, the 15h group collected a significantly higher number of CD34+ cells compared to the 10h group. The difference in average total collection for the two groups over all 4 days was statistically significant at an alpha level of 0.05 (p-value: 0.03). The different prechemotherapy plt groups were compared using one-way ANOVA statistical analysis. Within the 10h group the <100 group had the least amount collected (mean 2.46×10e6 CD34+/kg), the 100-150 had an intermediate amount (mean 3.30×10e6CD34+/kg), and the >150 group the most (4.30×10e6CD34+/kg; p-value 0.02). The same comparison within the 15h group showed similar findings but the number of patients in each subcategory was too small to be statistically significant. Conclusion: Administration of plerixafor with the 15h interval (5 pm dosing/8 am collection) appears to be equivalent to the standard 10h interval with regard to quantity of CD34+ cells collected over the first 2 days, and is superior to the 10 h schedule if the collection continues for 4 days. Further, prechemotherapy plt count is predictive of ability to mobilize CD34+ cells with perixafor+G-CSF for the 10h interval, as has been previously shown by our group for G-CSF alone in a similar population. Additional pts are needed to demonstrate conclusively the same finding for the 15h dosing/collection interval. Disclosures: No relevant conflicts of interest to declare.

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Pharmacokinetics and Tolerability of Etoposide in Newly Diagnosed Lymphoma Patients with Hepatic Impairment

Blood ◽

10.1182/blood.v124.21.4445.4445 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4445-4445

Author(s):

Catherine Lai ◽

Diane Cole ◽

Nicole Lucas ◽

Seth M. Steinberg ◽

Brigitte C Widemann ◽

...

Keyword(s):

Febrile Neutropenia ◽

Dose Reduction ◽

Hepatic Impairment ◽

Conflicts Of Interest ◽

Aggressive Lymphoma ◽

P Value ◽

Newly Diagnosed ◽

Aggressive Lymphomas ◽

Significant Difference ◽

Elevated Bilirubin

Abstract Background: The addition of etoposide to chemotherapy regimens (e.g.- CHOEP and EPOCH) may be beneficial for the treatment of aggressive lymphomas. Previous studies have shown decreased clearance of etoposide in hepatic impairment leading to a dose reduction or removal of drug. Total clearance of etoposide does not change significantly in patients with elevated bilirubin. However, free (or unbound) etoposide levels are a more accurate measurement of drug clearance (Stewart el al. Changes in the Clearance of Total and Unbound Etoposide in Patients with Liver Dysfunction. J Clin Oncol. 1990 Nov;8(11):1874-9.). No studies have analyzed etoposide pharmacokinetics and clinical toxicity in lymphoma patients with hepatic impairment. Methods: Patients with newly diagnosed aggressive lymphoma received 1 to 8 cycles of DA-EPOCH +/-R at the NCI. Of 56 pts studied, 48 had normal and 8 had elevated bilirubin (median 3.4mg/dL, range 1.4-22.5mg/dL). All patients received full dose etoposide at 200mg/m2 over 96-hours on cycle 1. Blood samples were collected at 0, 22 and 96 hours after infusion began. Results: There was no significant difference between free etoposide clearance (Cl) and the free etoposide concentration (Css) in patients with elevated versus normal bilirubin (see table below). In all patients, irrespective of bilirubin, there was no significant correlation between free etoposide Cl, free etoposide Css and creatinine clearance (CrCl) or age. Neutropenia and thrombocytopenia was higher in patients with elevated bilirubin. Complete response (CR) was achieved in 75% (6/8) versus 85% (41/48) and PR in 0% (0/8) vs 4% (2/48) of patients with elevated vs normal bilirubin. Conclusions: Etoposide pharmacokinetics were not altered in patients with abnormal versus normal hepatic function. Although there was an increase in hematologic toxicities, there was no difference in Css or Cl of etoposide. Importantly, there were no significant differences in febrile neutropenia or grade 3/4 toxicities. The toxicity difference is likely attributed to other drugs. Response rates were similar between the 2 groups. Our results do not support the empiric dose reduction of etoposide in patients with aggressive lymphomas receiving potentially curative treatment. Table Results Elevated Bilirubin Normal Bilirubin p-value Median age (yrs) 39 (17-59) 54 (20-75) 0.15 IPI (int hi/hi risk) 75% (6/8) 23% (11/48) 0.0070 ANC nadir < 500/mm3 (C1) 100% (8/8) 54% (26/48) 0.017 PLT nadir < 25x103/mm3 (C1) 38% (3/8) 4% (2/48) 0.017 Febrile Neutropenia (C1) 13% (1/8) 13% (6/48) 1.00 G3/4 GI and neuro tox (C1) 38% (3/8) 13% (6/48) 0.11 Median free etoposide clearance on C1 (ml/min/m2) 724 (438-1413) 663 (199-1148) 0.40 Median free etoposide concentration on C1 (μM) 0.082 (0.044-0.135) 0.089 (0.052-0.298) 0.44 Disclosures No relevant conflicts of interest to declare.

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Bortezomib: Once-Weekly 1.6mg/m2 Maybe a Better Choice Compared with Twice-Weekly 1.3mg/m2 in Newly Dignosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-125714 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5558-5558

Author(s):

Yubin Li ◽

Fangfang Li ◽

Wangshan Song ◽

Zhumei Zhan ◽

Xiangxin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Statistical Difference ◽

Clinical Observation ◽

Conflicts Of Interest ◽

Combined Chemotherapy ◽

Newly Diagnosed ◽

Nccn Guidelines ◽

Significant Difference ◽

Induction Regimen

Background: The first-in-class proteasome inhibitor, Bortezomib - based chemotherapy significantly improved the symptoms of multiple myeloma and delayed disease progression. Although the NCCN guidelines recommend twice-weekly 1.3mg/m2, the most appropriate dosage and interval still need to be further observed to improve the tolerability and patients outcomes. Methods: Part I Clinical Observation of MM Therapy in real world The effectiveness and toxicity of bortezomib containing regimen on multiple myeloma (MM) were analyzed retrospectively. From August 2006 to July 2012, 113 MM patients(77 newly diagnosed, and 36 relapsed or refractory patients ) had previously received at least 2 courses of different combined chemotherapy regiments, including 2 patients relapsed after ASCT). Classification: The clinical charateristics of all the 113 MM patients were shown inTable 1. They had received minimal 2 cycles of either Classical VDT regimen (bortezomib 1.0-1.3mg/m2, d1, d8, d15, d22; thalidomide 100-200 mg/d, d1-d14; dexamethasone 20 mg d1, d2, d4, d5, d8, d9, d11, d21; 21 days per cycle) or VDT-A regimen (VTD regimens like the previous; Epirubicin 10mg/d, d1-d4; 21 days per cycle) or modified VTD regimen (bortezomib 1.6mg/m2, d1, d8, d15, d22; thalidomide 100-200 mg/d, d1-d21; dexamethasone 20 mg d1, d2, d8, d9, d15, d16, d22, d23; 35 days per cycle). Results: Of all the patients, 76 were treated with classical VDT regimen, 21 patients treated with VDT-A regimen, 16 patients treated with modified VTD regimen. All were assessed every 2 cycles. After the treatment of four cycles,the rates of overall response ( ORR) and the complete rate ( CR) for the above three regimens of bortezomib with thalidomide and dexamethasone were 77.9% and 28% respectively. As shown in Figure 1, there was no statistical difference of ORRs (77.9% vs 78.3% vs 71%) and CRs (28% vs 26.4 vs 30%) among our single-central (Qilu) and other two international clinical trials ( WOBS and VISTA). Part II Clinical observation of once-weekly 1.6mg/m2 and the twice-weekly 1.3mg/m2 bortezomib in BCD regimen. In the subsequent study, the effectiveness and toxicity of once-weekly 1.6mg/m2 and the twice-weekly 1.3mg/m2 bortezomib of BCD regimen on MM were analyzed retrospectively. From January 2016 to December 2018, 34 NDMM patients (the median age of 58 (35-78) years old) received minimal 4 cycles of 1.6mg/m2 bortezomib, d1, d8, d15, d22; cyclophosphamide 300 mg/m2 d1, d8, d15; dexamethasone 20 mg d1, d2, d8, d9, d15, d16, d22, d23; 35 days per cycle. 32 NDMM patients (the median age of 58.5 (27-74) years old) received minimal 4 cycles of 1.3mg/m2 ( bortezomib 1.3mg/m2, d1, d4, d8, d11; cyclophosphamide 300 mg/m2 d1, d15; dexamethasone 20 mg d1, d2, d4, d5, d8, d9, d11, d12; 21 days per cycle). All were assessed every 2 cycles. The clinical charateristics were shown inTable 2. Results: As shown in Table 3 and Figure 2, the analysis showed that there is no significant difference of effectiveness ORR (=1.941,P=0.164) and CR (=0.289,P=0.591) between the 1.6 mg/m2 group and the 1.3 mg/m2 group after 2 cycles of treatments, which 88.24% (30/34) patients achieved ORR and 5.88% (2/34) patients got CR in the 1.6 mg/m2 group and 75.0%(24/32) patients achieved ORR with 3.1% (1/32) patients in CR in the 1.3 mg/m2 group. After 4 cycles of treatment, the 1.6 mg/m2 group showed significantly higher CR as compared to the 1.3 mg/m2 group (44.1% vs 18.75%, =4.890, p=0.027), however with no statistical difference of ORRs between the two groups (82.35% vs 87.59%, =0.340, P=0.560). In the adverse events, there is no significant difference of peripheral neuropathy (PN) between the 1.6 mg/m2 group and the 1.3 mg/m2 group after 2 cycle treatments (=0.068, p=/0.794). However, the incidence of PN in 4 cycle assessment is lower significantly in the 1.6mg/m2 group than in the 1.3mg/m2 group (5.88% vs 31.25%, =7.131, p=0.008). In respect to hematologic, infective, gastrointestinal toxicities, no significant difference was observed between the two groups. Conclusions: In summary, the 1.6 mg/m2 group achieved deeper and quicker response with reduced PN than the 1.3mg/m2 group in after 4-cycle induction regimen, suggesting more effective and safer outcomes with the treatment of the 1.6mg/m2 BCD regiment on MM. Disclosures No relevant conflicts of interest to declare.

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The Chronic Kidney Disease-Epidemiology Collaboration-Cystatin C (CKD-EPI-CysC) Equation Has an Independent Prognostic Value for Overall Survival in Newly-Diagnosed Patients with Symptomatic Multiple Myeloma: Comparison with 3 Other Equations for GFR Estimation

Blood ◽

10.1182/blood.v120.21.1849.1849 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1849-1849

Author(s):

Meletios A Dimopoulos ◽

Efstathios Kastritis ◽

Eirini Katodritou ◽

Anastasia Pouli ◽

Eurydiki Michalis ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Cystatin C ◽

Prognostic Value ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

P Value ◽

Newly Diagnosed ◽

Number Of Patients ◽

Ckd Stage

Abstract Abstract 1849 Renal impairment (RI) is a frequent complication in multiple myeloma (MM). The estimation of glomerular filtration rate (GFR) is based on equations that use serum creatinine (sCr) as a marker of RI (i.e. MDRD or CKD-EPI). The IMWG has recommended the use of the MDRD formula for the estimation of GFR in MM patients with stabilized sCr, while the classification of RI is based on the 5 stages of the KDIGO classification (Dimopoulos et al, JCO 2010;28:4976–84). However, the equations based on sCr are imprecise and thus novel markers of renal injury have been used in patients with renal damage, including cystatin-C (CysC). CysC is considered as a more sensitive marker of GFR than sCr. Recently, the CKD-EPI investigators have reported that a combined sCr-CysC (CKD-EPI-sCr-CysC) equation correlated better with GFR than equations based on either of these markers alone (CKD-EPI or CKD-EPI-CysC; Inker et al, NEJM 2012;367:20–9). Although cysC has been reported by our group to be elevated in MM patients, the CKD-EPI equations and their value on MM patients' survival have never been evaluated. Therefore, we studied 220 newly-diagnosed, previously untreated, symptomatic MM patients. The median age was 69 years (range: 36–94 years) and 16% had sCr ≥2 mg/dl. Serum CysC was measured on the BN ProSpec analyser using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). Serum CysC was increased in MM patients compared to 52 age- and gender-matched controls [median: 1.07 mg/l vs. 0.72 mg/l, p<0.0001]. The median values for eGFR calculated by the MDRD, CKD-EPI, CKD-EPI-CysC and CKD-EPI-sCr-CysC equations were 63.45 ml/min/1.73m2, 68.13 ml/min/1.73m2, 68.11 ml/min/1.73 m2, and 64.87 ml/min/1.73 m2, respectively (p<0.01). Patients were divided in the 5 CKD stages of KDIGO classification, according to eGFR (stage 1: eGFR >90 ml/min/1.73 m2; stage 2: 60–89 ml/min/1.73m2; stage 3: 30–59 ml/min/1.73 m2; stage 4: 15–29 ml/min/1.73 m2; stage 5: <15 ml/min/1.73 m2 or on dialysis). For each studied equation, the number of patients with RI stage 3–5 (i.e. eGFR <60 ml/min/1.732) was 39.5% for MDRD vs. 42.2% for CKD-EPI vs. 43.1% for CKD-EPI-CysC vs. 45% for CKD-EPI-sCr-CysC (p<0.01; see also the table). Concordance for CKD stage allocation for the 4 equations of estimating eGFR was 97% for MDRD vs. CKD-EPI, 60% for MDRD vs. CKD-EPI-CysC and 84% for MDRD vs. CKD-EPI-sCr-CysC. A significant correlation was found between ISS stage and all studied equations (p<0.01 for all). The median overall survival (OS) for all patients was 52 months. In the univariate analysis per CKD stage, the 4 equations could predict for OS (the higher CKD stage had poorer survival) with the following significance: MDRD (p=0.057), CKD-EPI (p=0.01), CKD-EPI-CysC (p<0.0001), and CKD-EPI-sCr-CysC (p=0.006). When we tested the 4 equations as continuous variables, all had prognostic value for OS but the CKD-EPI-CysC had the strongest prognostic value (p<0.0001 and Wald=24.0 vs. p<0.0001 and Wald=19.7 for CKD-EPI-sCr-CysC, p=0.003 and Wald=8.9 for CKD-EPI and p=0.005 and Wald=7.7 for MDRD). In the multivariate analysis, that included ISS stage, LDH ≥300 U/l and eGFR for each different equation (as a continuous variable) only eGFR that included CysC but not sCr (CKD-EPI-CysC and not CKD-EPI-sCr-CysC) had independent significance (p=0.013) along with high LDH (p=0.029). Our data suggest that the CKD-EPI-sCr-CysC equation for the estimation of GFR detects more MM patients with stage 3–5 RI than the MDRD, CKD-EPI or CKD-EPI-CysC equations. However, CKD-EPI-CysC was the only equation that could predict for OS, possibly due to the very strong correlation of CysC with ISS (as myeloma cells produce CysC also). The confirmation of these data will lead to the broader use of equations based on CysC (CKD-EPI-CysC with or without sCr) for the evaluation of RI in patients with MM, as it has been suggested for patients with several other renal disorders. Table. Evaluation of Renal Function Stage by Different Equations CKD stage MDRD equation CKD-EPI equation CKD-EPI-CysC equation CKD-EPI-sCr-CysC equation p-value 1 60 (27%) 57 (26%) 67 (30%) 44 (20%) 2 73 (33%) 70 (32%) 58 (26%) 77 (35% Friedman-test 3 53 (24%) 55 (25%) 57 (26%) 62 (28%) p<0.01 4 21 (9.5%) 25 (11%) 27 (12%) 24 (11%) 5 13 (6%) 13 (6%) 11 (5%) 13 (6%) Disclosures: No relevant conflicts of interest to declare.

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Response Kinetics of Daratumumab-Based Regimens in Patients with Newly Diagnosed or Refractory/Relapsed Multiple Myeloma

Blood ◽

10.1182/blood-2021-149315 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3806-3806

Author(s):

Jiasheng Wang ◽

Raul Arroyo-Suarez ◽

William Tse

Keyword(s):

Multiple Myeloma ◽

Clinical Outcomes ◽

Median Time ◽

Conflicts Of Interest ◽

Residual Disease ◽

Late Response ◽

Cell Transplant ◽

Newly Diagnosed ◽

Hematopoietic Cell Transplant ◽

Significant Difference

Abstract Background: It is controversial in multiple myeloma (MM) whether early and late responders to therapies have similar clinical outcomes. Daratumumab (DARA) is a human anti-CD38 antibody that has been increasingly used in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The association between response kinetics to DARA and clinical outcomes remains unexplored. Methods: Individual-participant data were obtained from phase 3 trials: POLLUX (Dimopoulos, NEJM, 2016), CASTOR (Palumbo, NEJM, 2016), and MAIA (Facon, NEJM, 2019). Patients were divided into early and late response groups based on the median time to the response of interest. Modified PFS (mPFS) and OS (mOS) were calculated from the time of first response of interest. Minimal residual disease (MRD) negativity was defined as less than 10 5 tumor cells by NGS assays. Results: After a median follow up of 16.1 months, 670 patients achieved a response of very good partial response (VGPR) or better, and 213 achieved MRD negativity. The median time to achieving VGPR or better was similar between NDMM and RRMM (86 vs. 84 days, respectively), while the median time to MRD negativity was longer among NDMM than RRMM (407 vs. 197 days, respectively). Among patients achieving VGPR or better, there was no significant difference of mPFS (HR 1.00, 95%CI 0.69 to 1.44) (fig. a), duration of response (DOR) (HR 1.02, 95%CI 0.68 to 1.53) (fig. b), or mOS (HR 0.98, 95%CI 0.54 to 1.75) (fig. c) between early and late responders. In the subgroup analysis, no significant difference of DOR was observed across all prespecified groups, including sex, age, cytogenetic risk groups, lines of previous therapy, types of measurable disease, NDMM vs. RRMM, prior treatment with autologous hematopoietic cell transplant, immunomodulatory drugs, or proteasome inhibitors. Among patients with NDMM achieving MRD negativity, there was no significant difference of mPFS (p=0.66) (fig. d), DOR (p=0.21) (fig. e) or mOS (p=0.87) (fig. f) between early and late responders. However, among patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS (p=0.038) (fig. g) and DOR (p=0.043) (fig. h) than early responders; mOS was not significantly different (fig. i). In the multivariable Cox analysis among patients achieving MRD negativity, only lower baseline LDH level, NDMM, and IgG type MM were independently associated with later response. Conclusions: For patients with NDMM or RRMM achieving VGPR or better, early and late responders had similar survival; for patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS and DOR. Our data support that in patients who failed to achieve an early or deep response to daratumumab based regimens, therapies should be continued with the goal of achieving ongoing and stepwise improvement of response. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A Comparison of Efficacy Following Two Different Doses of Granulocyte Colony Stimulating Factor (G-CSF) Alone for Mobilization of Peripheral Blood Stem Cells in 221 Multiple Myeloma Patients

Blood ◽

10.1182/blood.v128.22.5732.5732 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5732-5732

Author(s):

Soufi Osmani ◽

Mohamed Brahimi ◽

Souad Talhi ◽

Kamila Amani ◽

Hafida Ouldjeriouat ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Growth Factors ◽

Growth Factor ◽

Conflicts Of Interest ◽

Peripheral Blood Stem Cells ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Significant Difference

Abstract Introduction: Intensive chemotherapy followed by autologous stem cell transplantation (ASCT) is currently the treatment of choice in multiple myeloma (MM). Mobilization of hematopoietic stem cell blood (HSCs) can be achieved either by the combination of chemotherapy plus growth factors or by growth factors alone. However, there is no consensus concerning the dose of growth factor alone that should be administered, with ranges varying from 5 microgr to 16 microgr/kg body weight. In this context, we report our experience in mobilization of HSCs using growth factor alone at the dose between 15 microgr /kg and 10 microgr /kg in MM. Patients and methods: A total of 340 ASCT were performed in our center, from May 2009 until June the 31st 2016. These concerned 221 patients with MM. Patients were hospitalized at day -5 on which mobilization started with G-CSF alone (filgrastim) at the dose of 15 microgr /kg/daily subcutaneously for 5 days from May 2009 to October 2012 and at the dose of 10 microgr /kg from November 2012 to June 2016. The white blood cell count was assessed daily. Apheresis was performed at day -2 and day -1 using a Spectra Optia CMN device, and the CD34+ count was assessed by flow cytometry. A single leukapheresis was performed if the number of CD34+ cells was above 2.106/kg. Failure of mobilization was defined as a level of CD34+ less than 2.106/kg, after two leukapheresis. In our study patients were divided into two groups: Group1 (G-CSF=15 microgr /kg) and Group 2 (G-CSF=10 microgr /kg) and the number of CD34+ were divided into three groups: optimal (³5.0 x 106 CD34+ cells/kg), suboptimal (2.0Ð5.0 x 106 CD34+ cells/kg) and poor (<2.0 x 106 CD34+ cells/kg) mobilization. Intensification was done using melphalan 200 mg/m2 on day -1. Results: Patient's characteristics are shown in Table 1. No significant difference was observed between the 2 groups. In this study, we found no significant difference in terms of optimal (p= 0.73), sub-optimal (p= 0.19) or poor (p= 0.11) harvest of stem cells between the 2 groups (table 2). Among the poor mobilizators with G-CSF, only 4 of them had a level of CD34+ harvest less than 0.5 x 106/kg. These patients did not receive an ASCT. 1,3% (4) of all apheresis failed to achieve acceptable harvest level. Conclusion: Our study showed that the mobilization regimen with G-CSF alone at the doses of 10 microgr/kg have the same efficacy as the doses of 15 microgr/kg and is interesting alternative to chemotherapy and G-CSF in patients with MM because it can be administered as an outpatient and is not associated with the risk of febrile neutropenia. Disclosures No relevant conflicts of interest to declare.

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Differences in the Original Diagnostic Markers Including the "CRAB" Criteria in Multiple Myeloma Patients from Different Ethnicities: A Single Center Experience

Blood ◽

10.1182/blood.v124.21.5673.5673 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5673-5673

Author(s):

Ahmad Hatem Mattour ◽

Joshua Vollstaedt ◽

Philip Kuriakose

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Final Analysis ◽

Epidemiological Studies ◽

Study Data ◽

Diagnostic Markers ◽

Newly Diagnosed ◽

Chi Square ◽

Single Center Experience ◽

Significant Difference

Abstract LEARNING OBJECTIVES: Determine if there are any differences in the original diagnostic markers, including the “CRAB” criteria, in Multiple Myeloma patients from different ethnicities. BACKGROUND: About 24,050 new cases of Multiple Myeloma are expected to be diagnosed in 2014. In a metropolitan institution, such as Henry Ford Hospital, newly diagnosed patients are drawn from multiple ethnic backgrounds. While several epidemiological studies have demonstrated a positive correlation between race and values of several diagnostic markers (such as hemoglobin, creatinine and albumin), most of the research focused on molecular and genetic, as opposed to clinical, differences in patients from multiple ethnicities. Our study, therefore attempted to offer a more customized diagnostic approach to patients with newly diagnosed Multiple myeloma, based on their ethnicity, and to determine if there was a correlation between the patients' races and common diagnostic elements, including the CRAB criteria, at time of diagnosis. METHODS: We conducted a retrospective study. Data from 300 patients over 5 years (2007-2012) with newly diagnosed with Multiple myeloma was collected. Only 197 patients fulfilled the diagnostic criteria and were included in the final analysis. The following data was extracted: Age at diagnosis, gender, diagnostic elements according to the CRAB criteria (serum Calcium, serum Creatinine, Anemia, Bone lytic lesions) at date of diagnosis, serum beta-2-microglobulin level, M-protein serum concentration, and whether Urine monoclonal protein excretion was present. The patients were divided into two groups by race: African American and Caucasian. An overall score was created by summing the incidence of each diagnostic marker. RESULTS: Categorical data was compared between the two groups using chi-square tests, and CRAB score was compared using a Wilcoxon rank-sum test due to its ordinal nature. Our study demonstrated that there were no statistically significant differences between the two groups in any of the components collected, or in the final total score CONCLUSIONS: Our study demonstrated that there was no statistically significant difference in the original diagnostic markers, including the CRAB criteria, in Multiple Myeloma Patients from Different Ethnicities presenting to our Institution.The effect of baseline cytogenetic characteristics on the diagnostic markers between multiple myeloma patients from different ethnicities is still not fully understood, and might be a factor that needs to be studied further. Disclosures No relevant conflicts of interest to declare.

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Effect of Ranibizumab Treatment in Cases of Choroidal Neovascular Membranes Secondary to Pathological Myopia versus Age-Related Macular Degeneration

QJM ◽

10.1093/qjmed/hcaa058.011 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

M S Abdaltawab ◽

Z F Ismail ◽

W M A Ebeid ◽

S M Fawzy

Keyword(s):

Visual Acuity ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Intravitreal Injections ◽

P Value ◽

Newly Diagnosed ◽

Pathological Myopia ◽

Age Related ◽

Significant Difference ◽

The Mean

Abstract Aim of the Work The aim of this work is to compare the response of treatment with ranibizumab in terms of visual acuity in cases of CNV secondary to pathological myopia versus CNV secondary to age-related macular degeneration. Methods This prospective, comparative study included ten eyes newly diagnosed as having CNV secondary to pathological myopia, and 10 eyes newly diagnosed as having subfoveal active CNV secondary to AMD. All patients had 3 monthly intravitreal Injections of 0.50 mg (in 0.05 ml of solution) ranibizumab with monthly evaluation of best corrected visual acuity (BCVA) by Landolt C chart, and also calculated in Logarithm of Minimum Angle of Resolution (Log MAR). Results pretreatment there was no significant difference between the two groups as the mean VA (Log Mar) was 1.31 ± 0.2 in AMD group and 1.17 ± 0.3 in MCNV group of P value = 0.431 and also post three IVI of ranibizumab showed no significant difference between the two groups as the mean VA (Log Mar) was 1.22 ± 0.2 for AMD and 1.22 ± 0.5 for MCNV of P value = 0.635. Conclusion there was no significant difference in BCVA between AMD and MCNV groups after three intravitreal injections of ranibizumab.

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