Superior Rate of Complete Response with up-Front Velcade-Thalidomide-Dexamethasone Versus Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma Is Not Affected by Adverse Prognostic Factors, Including High-Risk Cytogenetic Abnormalities.

Abstract Complete response (CR) is an important objective of autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). In comparison with conventional induction treatments, newer combinations of novel agents may effect increased rates of CR and near CR (nCR), a benefit potentially translating into even higher frequencies of CR/nCR after ASCT and improved clinical outcome. We designed a phase III study to detect an increase in CR+nCR rates from 10–15% with conventional Thalidomide-Dexamethasone (TD) to 20–30% with Velcade added to TD (VTD) in newly diagnosed MM. Both TD and VTD were given as three 21-day cycles in preparation for double ASCT. In the present analysis, CR+nCR rates by the two induction treatments were examined in relationship to baseline prognostic variables in 399 evaluable pts aged ≤65 years, of whom 199 randomized to VTD and 200 to TD. All analyses were intent to treat. In comparison with TD, VTD effected higher rates of CR+nCR (12% vs 33%, P<0.001) and of ≥very good partial response (VGPR) (30% vs 61%, P<0.001). By univariate analysis, superiority of VTD to TD was maintained across all sub-group analyses according to standard prognostic factors, including β2-m, albumin, stage (ISS), Hb, PLTs, bone marrow PC, M protein isotype, LDH, CRP. In particular, the rates of CR+nCR with VTD vs TD in pts with standard poor prognostic factors were as follows: ISS stage 3 (23.5% vs 6%, P=0.03), Hb<10 g/dL (24% vs 4%, P=0.002), PLTs<150.000/μL (35% vs 4%, P=0.009), bone marrow PC ≥50% (31% vs 13%, P<0.001), IgA isotype (63% vs 15%, P<0.001), LDH >190 U/L (33% vs 9%, P<0.001), CRP ≥8 mg/L (29% vs 10%, P=0.004). We next examined CR+nCRs by treatment arms in relationship to cytogenetics (FISH data available in 93% to 99% of all pts). Superior CR+nCR rates were effected by VTD vs TD in the presence of high-risk cytogenetics, including del(13) (39% vs 10%, P<0.001), t(4;14) (39.5% vs 10%, P=0.002), combined t(4;14) and del(13) (32% vs 0%, P=0.001), and del(17p) (28.5% vs 0%, P=0.03). Remarkably, when examined in the context of the VTD arm, high-quality response rates were significantly higher for pts carrying del(13) and t(4;14) vs those who lacked these abnormalities [del(13): CR+nCR:39% vs 24%, P=0.03; ≥VGPR: 71% vs 48%, P=0.001] [t(4;14): ≥VGPR:79% vs 55%, P=0.007)]. An opposite trend was noted for pts in the TD arm, whose probability to attain ≥VGPR was adversely affected by the presence of del(13) (P=0.07) and del(17p) (P=0.03). Variables associated with achievement of CR+nCR in the two arms that retained statistical significance when assessed by multivariate Cox regression analysis included randomization to VTD (P<0.001), light chain only subtype (P<0.001), IgA isotype (P<0.001) and Hb>10 g/dL (P=0.01). In the VTD arm, a positive correlation was observed with del(13) (P=0.006) and t(4;14) (P=0.02). Response to first ASCT with melphalan 200 mg/m2 could be evaluated in 297 pts, of whom 145 randomized to VTD and 152 to TD. Randomization to VTD was closely associated with increased CR+nCR rates (54% vs 29% with TD, P<0.001) and remained statistically significant (P<0.001) also in the multivariate analysis. Additional factors predicting for superior post-ASCT CR+nCR rates in the multivariate setting included light chain only subtype (P<0.001) and IgA isotype (P=0.005). We conclude that randomization to up-front VTD was the strongest and independent factor associated with increased rates of CR+nCR before ASCT. Superiority of VTD to TD pertained in both low-risk and high-risk sub-groups, including the traditionally unfavorable sub-groups carrying del(13), t(4,14) and del(17p). Remarkably, in the VTD arm improved postinduction CR+nCR rates were significantly associated with the presence of del(13) and t(4;14) in the multivariate analysis. Benefit from VTD vs TD as primary induction therapy translated into significantly improved CR+nCR rates after the first ASCT and remained statistically significant when assessed by multivariate analysis.

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Prognostic Value of Bone Marrow Angiogenesis in Newly Diagnosed Multiple Myeloma: A Comparison with Conventional Prognostic Factors.

Blood ◽

10.1182/blood.v106.11.5111.5111 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5111-5111

Author(s):

Shaji Kumar ◽

Jessica L. Haug ◽

Linda Wellik ◽

Thomas E. Witzig ◽

John A. Lust ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Prognostic Value ◽

Staging System ◽

Continuous Variable ◽

Newly Diagnosed ◽

Grade Group

Abstract Background: Abnormally increased tumor associated neovasculature plays an important role in tumor progression in solid tumors and hematological malignancies. In multiple myeloma (MM) bone marrow angiogenesis, measured in terms of microvessel density (MVD), has prognostic value, and appear to increase with disease progression from monoclonal gammopathy of undetermined significance to relapsed MM. We have shown that MVD has prognostic value in patients with newly diagnosed MM including patients undergoing upfront high dose therapy and stem cell transplantation, but comparison with other known prognostic factors has been limited by sample size. It is also not known whether the MVD adds prognostic value once the recently described International Staging System (ISS) is applied. The goal of this study was to determine the prognostic effect of bone marrow MVD in newly diagnosed MM relative to the ISS and other known prognostic factors. Methods: We studied 400 patients with newly diagnosed MM seen at the Mayo Clinic between March of 1988 and December 2001. Sections from bone marrow biopsy blocks from the time of initial diagnosis were studied by immunohistochemistry using antibodies against CD34 antigen to high light the endothelial cells. Under low power (100X); three areas with maximum number of microvessels (hotspots) were identified. Each of these areas was further studied at 400X magnification and the number of microvessels per high power field counted. The average of the three readings was taken as the MVD for the sample. In addition, the samples were graded as low, intermediate or high by using a visual estimate as previously described. Additional clinical data was extracted from medical records. Some of the patients have been included in previous studies related to angiogenesis. Results: A total of 400 patients in whom a bone marrow biopsy from within 30 days of diagnosis was available were studied. The pts were followed for a median of 37 months (Range: 1 month to 16.5 years) and 318 pts (80%) had died at the time of this analysis. The median MVD for the entire group was 14.7 (Range 0–168). The median overall survival for the three groups according to the MVD grade was lower for the high grade group (31.9 months) compared to the intermediate grade group (37.2 months) and the low grade group (not reached); P <0.029, log rank test. We examined this group of patients for other factors prognostic for overall survival. Factors significant on univariate analysis included ISS stage, platelet count (<150 vs. >= 150 X 106/L), and plasma cell labeling index (<1 vs >=1). In a multivariate analysis using these variables and MVD as a continuous variable, high MVD and the ISS staging system were significantly associated with poorer survival (Table). Conclusion: In this large group of pts with newly diagnosed MM, we confirm the prognostic value of increased bone marrow angiogenesis. We examined the MVD as a continuous variable in the multivariate analysis for a closer evaluation of this measure in this comparison. More importantly, the prognostic value appears to be independent of the ISS and other major prognostic factors. The resultsof this study reinforces the biological relevance of this finding in MM. HR 95% CI P value MVD 1.006 (1.001, 1.011) 0.0279 ISS Stage I 0.37 (0.25, 0.56) <0.001 ISS Stage II 0.58 (0.41, 0.83) 0.0025

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Development and Analysis of a Weighed Prognostic Model in Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood-2020-140464 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Xue-Han Mao ◽

Yan Xu ◽

Yuting Yan ◽

Jiahui Liu ◽

Huishou Fan ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Prognostic Model ◽

Cytogenetic Abnormalities ◽

Total Score Range ◽

Prognosis Model

Background and Objective: Multiple myeloma (MM) is characterized with significant cytogenetic changes and complex tumor microenvironment, thus patient survival is extremely heterogeneous. Various disease-related or patient-related factors affect the prognosis of patients. This study tried to analyze the prognostic indicators of patients with newly-treated MM, especially explored the prognosis of multiple cytogenetic abnormalities and the ratio of lymphocytes to monocytes (LMR). Additionally, we established a comprehensive prognostic model to help determine the patient prognosis. Methods: After screening, 603 patients of untreated MM from January 2008 to June 2017, with complete baseline indicators were enrolled into the study. By univariate and multivariate Cox analysis, risk factors related to the prognosis of patients were evaluated, and a weighted prognosis model was established to compare the survival differences of patients in each risk stratification. Result: Optimal thresholds of ALC, LWR, NLR and LMR were determined by ROC curve and Youdex index: ALC = 1.415, LWR = 0.325, NLR = 1.935, LMR = 2.95. Survival analysis showed that patients with LMR ≤ 2.95, ALC ≥ 1.415 and LWR ≥ 0.325 had significantly better survival compared with their respective control groups. Cox multivariate analysis showed that among the four indicators, only LMR≤2.95 was an independent adverse prognostic factor for overall survival (OS)(Figure 1A). 17p deletion, 1q21 amplification, t (4; 14) / t (14; 16) were define as high-risk cytogenetic abnormalities (HRA). Of the 603 patients, about 60% were associated with at least one high-risk cytogenetic event. Among them, the occurrence of cumulative 0, 1, 2, and 3 HRA were 39.6% (239/603), 42.5% (256/603), 16.6% (100/603), and 1.3% (8/603), respectively. There was no significant difference in survival among patients with same number of HRAs. The median OS of patients with 0, 1 and ≥ 2 HRA were not reached, 62.1 months (95% CI, 49.3-74.9) and 30.4 months (95% CI, 24.5-36.3), respectively (p <0.001)(Figure 1B).Final Cox regression model showed that age 65 ~ 74 (HR=1.77, 95%CI, 1.24-2.51, p=0.001), age ≥75 (HR=2.46, 95%CI, 1.69-3.58, p < 0.001), LDH≥247 U/L (HR =1.65, 95%CI, 1.07-2.51, p=0.023), ISS stage III (HR=1.76, 95%CI, 1.24-2.50, p=0.002), LMR≤2.95 (HR=1.53, 95%CI, 1.08-2.18, p=0.017), 1 HRA (HR=1.87, 95%CI, 1.27-2.75, p=0.002) and ≥2 HRA (HR=3.48, 95%CI, 2.22-5.45, p<0.001) are independent adverse prognostic factors for OS. Then weighted risk factors were summed to establish a comprehensive prognosis model, with a total score range of 0-6 points. Accordingly, the whole cohort was divided into low risk (0-1 points, 45.4%), intermediate risk (2 points, 27.9%), high risk (3 points, 19.2%) and ultra-high risk (4-6 points, 7.5 %) groups. The median OS of the four risk groups were 85.8 months (67.1-104.5), 49.0 months (44.7-53.3), 35.4 months (31.3-39.5), and 23.2 months (18.8-27.6), respectively (p<0.001). The C-statistics of this prognostic model is 0.68 (95% CI, 0.64-0.71), which is significantly better than the D-S stage (C-statistics = 0.52, 95% CI, 0.50-0.55, p <0.001), ISS (C-statistics = 0.60, 95% CI, 0.57-0.64, p <0.001) and R-ISS stage (C-statistics = 0.60, 95% CI, 0.57-0.63, p <0.001). Bootstrap resampling and calibration curve showed that the model has an accurate predictive effect on both short-term and long-term prognosis of patients(Figure 1C). Conclusion: In our analysis, ALC, LWR, LMR were associated with poor prognosis in NDMM patients, while NLR had no significant prognostic significance. Among the four indicators, LMR≤2.95 was the only independent prognostic factor. In NDMM patients, survival of patients with the same number of high-risk cytogenetic abnormalities were comparable with each other, regardless of whichever combination of HRA. Higher number of high-risk cytogenetic abnormalities were associated with worse prognosis. Cox multivariate analysis showed that, old age (65-74 years old, ≥75 years old), increased LDH (≥247 U/L), decreased LMR (≤2.95), ISS III, 1 HRA and ≥ 2 HRA were independent adverse prognostic factors that affect the OS of MM patients. 4. A comprehensive weighted prognostic model was established with the above factors, which was proved to effectively distinguish different prognosis of patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018022806 ◽

2019 ◽

Vol 3 (5) ◽

pp. 744-750 ◽

Cited By ~ 4

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

S. Vincent Rajkumar ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Light Chain ◽

Progression Free Survival ◽

Early Response ◽

Stage Iii ◽

Newly Diagnosed ◽

Best Response ◽

Light Chain Disease ◽

The Impact

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and <VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P < .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

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Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

Blood ◽

10.1182/blood.v88.5.1780.1780 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1780-1787 ◽

Cited By ~ 85

Author(s):

TE Witzig ◽

MA Gertz ◽

JA Lust ◽

RA Kyle ◽

WM O'Fallon ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

High Risk ◽

Plasma Cell ◽

Plasma Cells ◽

Cell Labelling ◽

Newly Diagnosed ◽

C Reactive Protein ◽

Reactive Protein ◽

Beta 2 Microglobulin

Abstract The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.

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Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Blood ◽

10.1182/blood-2002-01-0335 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1168-1171 ◽

Cited By ~ 183

Author(s):

Maurizio Zangari ◽

Eric Siegel ◽

Bart Barlogie ◽

Elias Anaissie ◽

Fariba Saghafifar ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

High Risk ◽

Doppler Ultrasonography ◽

Standard Dose ◽

Single Agent ◽

Cytotoxic Chemotherapy ◽

Newly Diagnosed ◽

Statistical Association ◽

Increased Risk

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos- phanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P = .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing DVT.

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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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The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽

10.1182/blood.v118.21.1823.1823 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1823-1823

Author(s):

Kevin D Boyd ◽

Fiona M Ross ◽

Mark T Drayson ◽

Roger G Owen ◽

Alex J Szubert ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Induction Therapy ◽

Response Rates ◽

Phase Iii ◽

Prognostic Impact ◽

Cell Transplant ◽

Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

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Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽

10.1182/blood.v120.21.5036.5036 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5036-5036 ◽

Cited By ~ 1

Author(s):

Beihui Huang ◽

Juan Li ◽

Junru Liu ◽

Dong Zheng ◽

Mei Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Light Chain ◽

Conflicts Of Interest ◽

Complete Response ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Hematologic Response ◽

Best Response ◽

Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

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The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2016-2016

Author(s):

Tomer M Mark ◽

Peter Forsberg ◽

Ihsane Ouansafi ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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