MDR-1 expression and response to vincristine, doxorubicin, and dexamethasone chemotherapy in multiple myeloma refractory to alkylating agents.

1994 ◽  
Vol 12 (1) ◽  
pp. 115-119 ◽  
Author(s):  
J J Cornelissen ◽  
P Sonneveld ◽  
M Schoester ◽  
H G Raaijmakers ◽  
H K Nieuwenhuis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Plasma Cell ◽  
Multiple Drug Resistance ◽  
Labeling Index ◽  
Cell Labeling ◽  
Survival Duration ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
Mdr 1

PURPOSE To assess whether the presence of enhanced multiple drug resistance (MDR)-1 gene expression in multiple myeloma (MM) patients predicts survival, as well as response to vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy. PATIENTS AND METHODS Sixty-three MM patients refractory to alkylating therapy were studied. The presence of the MDR-1 gene product, a 170-kd glycoprotein (P-170), was analyzed in bone marrow plasma cells by means of the alkaline phosphatase (APAAP) technique using the P-170-specific monoclonal antibody (MoAb) C219. The prognostic value of MDR-1 gene expression, examined before VAD treatment, was compared with other established prognostic factors including beta 2-microglobulin, albumin, lactate dehydrogenase (LDH), and the plasma cell labeling index. RESULTS Fifty-nine percent of all samples were P-170-positive. No association could be demonstrated between response to VAD and MDR-1 gene expression (chi 2 P = .359), in contrast to high serum beta 2-microglobulin levels, which were positively correlated with response (P = .006). P-170-positive and -negative patients showed a median survival duration of 23 and 22 months, respectively, a difference that was not statistically significant (P = .9). beta 2-microglobulin, LDH, albumin, and the plasma cell labeling index were all significantly correlated with survival. CONCLUSION These results indicate that other mechanisms of resistance must be involved in MM apart from MDR. The role of MDR status at this stage of disease may be biased by the major contribution of dexamethasone to induction of response by VAD in MM patients.

Plasma cell labeling index, beta 2-microglobulin, and C-reactive protein: what is the best combination for myeloma prognosis? [letter; comment]

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3507-3508 ◽  
Author(s):  
M Boccadoro ◽  
G Gallone ◽  
R Frieri ◽  
A Pileri ◽  
R Bataille ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Labeling Index ◽  
Cell Labeling ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Letter Comment ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.

1991 ◽  
Vol 9 (3) ◽  
pp. 444-448 ◽  
Author(s):  
M Boccadoro ◽  
F Marmont ◽  
M Tribalto ◽  
G Avvisati ◽  
A Andriani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Median Overall Survival ◽  
Cell Labeling ◽  
Induction Treatment ◽  
Treatment Groups ◽  
Significant Difference ◽  
Risk Patients ◽  
Beta 2 ◽  
Beta 2 Microglobulin

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

Incorporation of the plasma cell labeling index into the international staging system of multiple myeloma: Impact on prognostic value

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 8591-8591 ◽  
Author(s):  
P. Kapoor ◽  
C. Snozek ◽  
C. L. Colby ◽  
D. R. Larson ◽  
J. A. Katzmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Prognostic Value ◽  
Staging System ◽  
Labeling Index ◽  
Cell Labeling ◽  
International Staging System

scholarly journals The plasma cell labeling index: a valuable tool in primary systemic amyloidosis

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 1108-1111
Author(s):  
MA Gertz ◽  
RA Kyle ◽  
PR Greipp
Keyword(s):  
Multiple Myeloma ◽  
Median Survival ◽  
Plasma Cell ◽  
Poor Prognosis ◽  
Systemic Amyloidosis ◽  
Labeling Index ◽  
Cell Labeling ◽  
Plasma Cell Dyscrasia ◽  
Response To Chemotherapy

The plasma cell labeling index (LI) is of value in predicting prognosis in multiple myeloma. Primary systemic amyloidosis (AL) is a plasma cell dyscrasia that shares many features with myeloma. We obtained bromodeoxyuridine LI on 125 patients who presented with AL, 22 of whom also had overt multiple myeloma. Forty-six patients had a plasma cell LI greater than 0%. Of the 46 patients with an elevated LI, 19 (41%) had multiple myeloma as compared with three (4%) of the 79 patients with an LI = 0 (P less than .0001). A response to chemotherapy was seen in 14 (30%) of 46 patients with an LI greater than 0, as compared with ten (13%) of 79 patients with an LI of 0 (P = .015). The median survival of the high LI group was 14.6 months v 29.8 months for the low LI group (P = .02). In the low LI group, 29% are projected to be alive at 60 months, as compared with 20% in the high LI group. When patients with myeloma were excluded from the analysis, the LI did not predict response but continued to indicate a survival disadvantage (P less than .05). The major utility of the LI was in identifying those patients most likely to have multiple myeloma and those AL patients with a poor prognosis (median survival, 14.1 months).

scholarly journals Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma [see comments]

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3382-3387 ◽  
Author(s):  
PR Greipp ◽  
JA Lust ◽  
WM O'Fallon ◽  
JA Katzmann ◽  
TE Witzig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Thymidine Kinase ◽  
Prognostic Significance ◽  
Cell Labeling ◽  
C Reactive Protein ◽  
Prognostic Information ◽  
Reactive Protein ◽  
Beta 2 ◽  
Beta 2 Microglobulin

The plasma cell labeling index (PCLI) and serum beta 2-microglobulin (beta 2M) are independent prognostic factors in multiple myeloma (MM). Recently, levels of thymidine kinase (TK) and C-reactive protein (CRP) have been shown to have prognostic value. We studied 107 patients with newly diagnosed myeloma to determine whether TK and CRP values added prognostic information not already available using the PCLI and beta 2M. Univariate survival analysis showed prognostic significance for the PCLI, TK, beta 2M, age, serum albumin, and CRP. Multivariate analysis showed that only PCLI and beta 2M have independent prognostic significance. The survival curves were better separated using the PCLI and beta 2M than with other combinations of variables. Among nine patients under age 65 with low PCLI and low beta 2M, eight were alive almost 6 years after starting chemotherapy. These good-risk patients could not be identified by standard clinical features. Although creatinine and calcium were normal, other features such as bone lesions, osteoporosis, fracture, and anemia were present and stage distribution was similar to other patients in the study. In conclusion, PCLI and beta 2M measured at diagnosis are independent prognostic factors. They must be considered when interpreting the results of clinical trials and should be helpful in counseling patients and in designing new trials. When the PCLI and beta 2M values are known, the TK and CRP values do not add useful additional prognostic information.

scholarly journals Value of beta 2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 219-223 ◽  
Author(s):  
PR Greipp ◽  
JA Katzmann ◽  
WM O'Fallon ◽  
RA Kyle
Keyword(s):  
Prognostic Factor ◽  
Creatinine Level ◽  
Median Survival ◽  
Plasma Cell ◽  
Cell Labeling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Significant Prognostic Factor ◽  
Newly Diagnosed ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Beta 2-microglobulin (beta 2M) has been proposed as a prognostic factor in multiple myeloma (MM), but beta 2M levels are reported to correlate with other prognostic indicators such as stage and creatinine level. This study addressed the independent prognostic values of these and other variables, including plasma cell labeling indices (LI), in patients with newly diagnosed MM. beta 2M levels were measured with an enzyme-linked immunosorbent assay. LI were determined with a [3H]thymidine autoradiography method. By multivariate analysis and Kaplan-Meier survival analysis, the uncorrected beta 2M level remained the most significant prognostic factor after adjustment for age. Stage and creatinine level were closely related to beta 2M level and were no longer predictive of outcome after adjustment for age and beta 2M. Plasma cell LI varied independently of beta 2M level and remained predictive. A subset of patients with plasma-blastic myeloma had poor survival since beta 2M level and plasma cell LI were high. By using beta 2M level and LI, three risk groups were defined: low (beta 2M less than 4 micrograms/mL and LI less than 0.4%, median survival 48 months); intermediate (beta 2M less than 4 micrograms/mL and LI greater than or equal to 0.4%, median survival 29 months); and high (beta 2M greater than or equal to 4 micrograms/mL, median survival 12 months). Such grouping may better identify MM patients who might benefit from new treatment regimens.

A high bone marrow plasma cell labeling index in stable plateau–phase multiple myeloma is a marker for early disease progression and death

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2522-2523 ◽  
Author(s):  
David P. Steensma ◽  
Morie A. Gertz ◽  
Philip R. Greipp ◽  
Robert A. Kyle ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Group Versus ◽  
Labeling Index ◽  
Cell Labeling ◽  
Plateau Phase ◽  
Bone Marrow Plasma ◽  
High Bone

Abstract The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain–restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P < .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.

scholarly journals Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma [see comments]

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3382-3387 ◽  
Author(s):  
PR Greipp ◽  
JA Lust ◽  
WM O'Fallon ◽  
JA Katzmann ◽  
TE Witzig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Thymidine Kinase ◽  
Prognostic Significance ◽  
Cell Labeling ◽  
C Reactive Protein ◽  
Prognostic Information ◽  
Reactive Protein ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract The plasma cell labeling index (PCLI) and serum beta 2-microglobulin (beta 2M) are independent prognostic factors in multiple myeloma (MM). Recently, levels of thymidine kinase (TK) and C-reactive protein (CRP) have been shown to have prognostic value. We studied 107 patients with newly diagnosed myeloma to determine whether TK and CRP values added prognostic information not already available using the PCLI and beta 2M. Univariate survival analysis showed prognostic significance for the PCLI, TK, beta 2M, age, serum albumin, and CRP. Multivariate analysis showed that only PCLI and beta 2M have independent prognostic significance. The survival curves were better separated using the PCLI and beta 2M than with other combinations of variables. Among nine patients under age 65 with low PCLI and low beta 2M, eight were alive almost 6 years after starting chemotherapy. These good-risk patients could not be identified by standard clinical features. Although creatinine and calcium were normal, other features such as bone lesions, osteoporosis, fracture, and anemia were present and stage distribution was similar to other patients in the study. In conclusion, PCLI and beta 2M measured at diagnosis are independent prognostic factors. They must be considered when interpreting the results of clinical trials and should be helpful in counseling patients and in designing new trials. When the PCLI and beta 2M values are known, the TK and CRP values do not add useful additional prognostic information.

MYC Activation Is a Common Transformation Event in Myeloma and Associated with Poor Prognosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 834-834
Author(s):  
Wee-Joo Chng ◽  
Gaofeng Huang ◽  
Siok-Bian Ng ◽  
Marta Chesi ◽  
Leif Bergsagel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Plasma Cell ◽  
Poor Prognosis ◽  
Gene Set Enrichment Analysis ◽  
Labeling Index ◽  
Cell Labeling ◽  
Validation Dataset ◽  
Newly Diagnosed ◽  
Ras Mutation

Abstract Abstract 834 Multiple myeloma (MM) is an incurable bone marrow cancer. Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to MM is unknown. We analyzed 2 gene expression datasets generated on the Affymetrix U133 platform. The test set consisted of 22 MGUS and 101 MM (GEO Accession GSE6477) and the validation set 50 MGUS and 351 MM (GEO Accession GSE2658 and GSE5900). The gene expression profiles of MM were compared to MGUS using gene-set enrichment analysis. Genes over-expressed in MM were enriched for cell cycle, proliferation and MYC activation gene-sets. We dissected the relationship between MYC and cell cycle, and identified a MYC activation signature dissociated from proliferation. We validated our MYC signature in publicly available mouse and human cell line gene expression dataset (GEO Accession GSE3151 and GSE3158 respectively), showing specific expression of our MYC signature in cell lines forced to expressed MYC but not when over-expressing other oncogene such as E2F, HER2. In these analyses, we noted that tumors with RAS mutation also consistently express this signature. Applying this signature to the test dataset, we showed that MYC is activated in 60% of myeloma but none of MGUS. This pattern is reproduced in an independent validation dataset. In order to validate the hypothesis that RAS mutation may also lead to the MYC activation signature, we correlated RAS mutation with MYC activation as measured by a MYC index calculated from the median expression of genes that constitute the MYC activation signature, and showed that almost all cases with RAS mutation have a high MYC index. Together with samples with very high expression of MYC mRNA corresponding to those with MYC translocations, these 2 mechanisms account for 67% of cases with MYC activation. To further confirm MYC activation, we performed immunohistochemistry using a validated MYC antibody together with CD138 double-staining. We can clearly identify CD138 positive plasma cells with and without nuclear MYC expression and found that nuclear expression of MYC, a marker of MYC activation, correlated strongly with the MYC signature, therefore providing clear evidence that MYC activation is present in majority of newly diagnosed MM but not in MGUS. MYC activation is not very well correlated with proliferation as assessed by the plasma cell labeling index. Among newly diagnosed myeloma patients with plasma cell labeling index less than 1, those with nuclear MYC expression have significantly shorter survival than those without (Median survival 77.7 months versus 37.9 months, log-rank p-value 0.04). Multiple pathways converge on MYC activation, which is a common transforming event in MM associated with poor prognosis. MYC nuclear staining by IHC can be a useful clinical surrogate. Targeting MYC can be a chemoprevention strategy. Disclosures: Fonseca: Amgen: Consultancy; Medtronic: Consultancy; Celgene: Consultancy; Bristol Mayor Squibs: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy.

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