Personalized Treatment with low doses of Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma in frail or Elderly Patients

Abstract Abstract 5049 Background. Treatment of frail or elderly patients with relapsing symptomatic/active Multiple Myeloma (MM) is very difficult due to concomitant diseases, impaired bone marrow reserve, systemic toxicity, relatively decreased renal function and general problems of old age. Dexamethasone and new agents (thalidomide, lenalidomide, bortezomib and bendamustine) have been used in this setting, in most cases with doses adapted to the clinical situation. Aims. To retrospectively analyze the management of frail and/or very elderly MM patients with relapsed and active disease treated with reduced doses of the aforementioned agents in five hospitals in Madrid, Spain. Methods. The files of this group of MM patients were studied. The most common treatment has been the combination of low doses of lenalidomide (len) and of dexamethasone (dex), whereas treatment with reduced doses of other agents has been anecdotal; therefore we analyzed the results of len/dex combinations. Len and dex have been used in lower than standard doses, adapted to the individual initial situation of the patients and tailored according to effect and toxicity throughout treatment. There was no specific protocol and the management of the patients has depended exclusively on the practice and criteria of the treating physicians. Patient risk was stratified following the Salmon and Durie (S&D) score and the International Staging System (ISS). Response was assessed with the IMWG criteria. The study has been approved by the Ethics Committee of Hospital Ramon y Cajal, as coordinating center. Results. 38 patients were included in the study. Mean age was 79 years (range 68–90). 30 pts (79%) were older than 75 years and 10 pts had over 85 years. More than half of the patients (21) had two or more comorbidities. Patients had previously received 1 to 5 (m=1. 8) different treatment modalities, including steroids, melphalan (25), bortezomib (20), thalidomide (6) (or their combinations), and others or even APBSCT (3). 23 pts (60%) had IgG (m=4087 mg/dl, range 868–13000); 13 (34%) IgA (m=2115, range 355–4930) and 2 (5%) only light chains. 22 had κ and 15 λ light chains. 19 (50%) had BJ proteinuria. Mean Hemoglobin level was 10. 7 gr/dl (7. 5–14. 1) and mean creatinine level 1. 3 mg/dl (0. 4–12. 9); 28 (74%) had bone disease. 3 pts had S&D stage I, 22 stage II, and another 13 stage III. 13 pts had ISS stage I, 17 had stage II and 7 stage III. Patients received between 1 and 30 cycles of len/dex (m= 8). Median initial Len dose was 10 mg, the majority between 5 and 15mg, although 4 received 25 mg that were rapidly reduced. Mean initial dex dose was 20mg/day for 4 days. 4 pts (10. 5%) achieved Complete Remission (CR) (3 with negative IF), 27 (71%) Partial Remission (PR) (5 with VGPR) and 2 (5%) a significant, but lesser than 50%, reduction of the M-component (Stable Disease, Std). Altogether, overall response (CR+PR+Std) occurred in 33 pts (86%). The best response occurred after 2 to 9 cycles (m=4) of len/dex. Treatment was stopped in 15 patients due to neurological (4) or hematological (1) toxicity, pulmonary embolism (1), unrelated causes (4) and after achieving a plateau response (5). Time to next treatment was 1–30 months, (m=8 mo). 7 pts relapsed after 3–21 months (m=7). 10 patients died, 5 of related (disease progression, cardiac amyloidosis, renal progression to ESRF) and 5 of unrelated (cancer, sepsis, myocardial infarction, congestive heart failure) causes. Grade III-IV bone marrow toxicity occurred in 9 pts and neurological toxicity (PNP) in 5 (all of them had previously been treated with bortezomib or thalidomide). Conclusions. Personalized low doses of len/dex have been the most common treatment for frail/very elderly patients with relapsed MM in our centers and it is an active and tolerable option in this setting. The haematological toxicity was expectable and manageable, but prior treatments with bortezomib or thalidomide were associated with limiting neurotoxicity. Disclosures: No relevant conflicts of interest to declare.

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Tailored Low Dose Lenalidomide with Low Dose Dexamethasone (len/dex) in Previously Treated Patients with Multiple Myeloma Older Than 70 Years Requiring Treatment.

Blood ◽

10.1182/blood.v114.22.4950.4950 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4950-4950

Author(s):

Angel Ruedas ◽

Ricardo Perez ◽

Valentin Garcia ◽

Alicia Smucler ◽

Pilar Bravo ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Elderly Patients ◽

Low Dose ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Bone Marrow Toxicity ◽

Low Doses ◽

Previously Treated

Abstract Abstract 4950 Background & Aims The management of elderly patients with Multiple Myeloma (MM) previously treated requiring further therapy (although in most cases palliative) is very difficult due to the presence of concomitant diseases, decreased bone marrow reserve, systemic toxicity, relatively decreased renal function and general problems of old age. As in this setting the tolerability of standard doses of conventional chemotherapy, high doses of dexamethasone or IMiDs is a concern, we report the preliminary results of the combination of tailored low doses of lenalidomide (len) and low doses of dexamethasone (dex). Methods We retrospective analyze the results of the combination of low dose lenalidomide and low dose of dexamethasone (len/dex) in 14 patients aged over 70 years with pretreated MM and progressive disease. Low doses of len (5-10 mg daily for 21days) were initially given and flexibly modified in subsequent cycles according to response and toxicity, along with low doses of dex (20-40 mg/day for 4 days) in most (12) patients. G-CSF and red cell transfusions were used when needed. Patient risk was stratified following the Salmon and Durie (S&D) score and the International Staging System (ISS). Response was assessed with the IMWG criteria. Results Median age was 80 years (70-90). All patients had received between 2-5 different previous modality treatments (m=2), including bortezomib (7), thalidomide (4) or PBSCT (2). 11 pts had IgG, m=3397mg/dl (868-4990), 2 IgA m=1460 (1050-1870) and another one BJ. 9 pts had κ and 4 » light chains. Median Hemoglobin level was 10 gr/dl (7.2-11.4) and median creatinine level 1.19 mg/dl (0.75-1.63). 11 (78%) had bone disease. 9 pts had S&D stage II, 4 stage III and another one stage I. 7 pts had ISS stage II, 4 had stage I and 2 stage III. Patients received between 2 and 13 cycles of len/dex (m=6.8). 11 pts (78%) achieved Partial Remission (PR) and 2 (14%) achieved significant, but lesser that 50%, reduction of the M-component (Stable Disease: Std). Overall response (PR+Std) occurred in 13/14 patients (92.8%). The best response occurred between 2-12 cycles of len/dex. Grade III-IV bone marrow toxicity occurred in 5 pts (35 %) and neurological toxicity (PNP) in 5 pts (35%) (all of them had received previous bortezomib or thalidomide). Treatment was stopped in 6 pts: for unrelated causes (1), due to neurological (3) or haematological (1) toxicity and in 2 pts after achieving Std and both relapsed after 3 months. Conclusions Treatment with tailored low doses of lenalidomide and low doses of dexamethasone (len/dex) is an active and tolerable option for previously treated elderly patients with symptomatic MM. Low lenalidomide doses can be flexibly modified according to the quality of the response and the hematological toxicity that is expectable and manageable. Previous treatments with bortezomib or thalidomide is associated with neurotoxicity. Disclosures No relevant conflicts of interest to declare.

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The Role of18F-FDG PET/CT in Multiple Myeloma Staging according to IMPeTUs: Comparison of the Durie–Salmon Plus and Other Staging Systems

Contrast Media & Molecular Imaging ◽

10.1155/2018/4198673 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Shengming Deng ◽

Bin Zhang ◽

Yeye Zhou ◽

Xin Xu ◽

Jihui Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Prognostic Factors ◽

Staging System ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Newly Diagnosed ◽

Deauville Score ◽

Staging Systems

We aimed at comparing the Durie–Salmon Plus (DS Plus) staging system based on Italian Myeloma criteria for PET USe (IMPeTUs) with other two staging systems in predicting prognosis of patients with all stages of newly diagnosed multiple myeloma (MM). A total of 33 MM patients were enrolled in this retrospective study. The variation between the DS Plus classification and Durie–Salmon staging system (DSS) or Revised International Staging System (RISS) classification was assessed. When staged by the DSS, patients in stage I and stage II did not reach the median overall survival (OS), and the median OS was 33 months for stage III (p=0.3621). When staged by the DS Plus, patients in stage I did not reach the median OS of stage I, and the median OS for stages II and III was 38 and nine months, respectively (p=0.0064). When staged by the RISS, patients in stage I did not reach the median OS, and the median OS was 33 and 16 months for stage II and stage III, respectively (p=0.0319). The concordances between two staging systems were 0.07 (DS Plus versus DSS) and 0.37 (DS Plus versus RISS), respectively. Multivariate analysis revealed that DS Plus stage III (HR: 11.539,p=0.021) and the Deauville score of bone marrow ≥4 (HR: 3.487,p=0.031) were independent prognostic factors associated with OS. Both the DS Plus based on IMPeTUs and RISS possessed a better potential in characterizing and stratifying MM patients compared with the DSS. Moreover, DS Plus stage III and the Deauville score of bone marrow ≥4 were reliable prognostic factors in newly diagnosed MM patients.

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Dynamic Changes in International Staging System As a Predictor of Survival Outcome in Patients with Advanced Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112134 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4438-4438

Author(s):

Jin-Liern Hong ◽

Victoria Crossland ◽

Aaron Galaznik ◽

Paul Dolin

Keyword(s):

Multiple Myeloma ◽

Mortality Rate ◽

Staging System ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Study Cohort ◽

Dynamic Changes ◽

Beta 2 Microglobulin ◽

Line Of Therapy

Abstract Background: The International Staging System (ISS) based on serum beta-2 microglobulin and serum albumin is a useful tool for risk stratification in patients with multiple myeloma. ISS is usually assessed at the time of diagnosis. Recent studies have suggested that risk stratification should be considered dynamic over the disease course. Our study aimed to describe dynamic changes in ISS over time and their impacts on mortality in patients with advanced multiple myeloma. Methods: This study included 417 patients with multiple myeloma from the Flatiron medical records database (Jan 2011- May 2018) who have received at least two lines of therapy and had data on ISS at the time of diagnosis (TDX) and at the time of initiating the second line of therapy (T2L). ISS stage was either abstracted from medical records or derived from the results of laboratory tests of serum beta-2 microglobulin and serum albumin. Patients were followed up from T2L until the earliest event of the last activity in database or death. We calculated mortality rates by TDX and T2L ISS stages, and generated Cox proportional hazard models to estimate the impact of TDX and T2L ISS stages on mortality. Additionally, in the subgroup of patients in ISS stage III at TDX, we used univariate logistic models to identify the predictors for downward shift to ISS stage I or II at T2L. Results: The study cohort had a median age of 70 (interquartile range: 61 to 77), and 59% were male. Based on ISS at TDX, 30%, 37%, and 33% of the study cohort were classified as stage I, II, and III with the mortality rate of 12, 11, and 24 deaths per 100 person-years, respectively. The hazard ratios were 0.95 (95% confidence interval (CI): 0.57-1.61) for patients in stage II and 1.96 (95% CI: 1.22-3.16) for patients in stage III, compared with patients in stage I. Based on ISS at T2L, 47%, 34%, and 20% were classified as stage I, II, and III, with the mortality rate of 7, 19, and 39 deaths per 100 person-years, respectively. The hazard ratios were 2.62 (95% CI: 1.61-4.25) for patients in stage II and 5.18 (95% CI: 3.10-8.64) for patients in stage III, compared with patients in stage I. Dynamic changes in ISS stages over time and mortality rates were depicted in the Table. Among patients in ISS stage I at TDX, about 25% shifted to higher stages at T2L, and had a higher mortality rate (26 per 100 person-years) than did patients remaining in stage I (8 per 100 person-years). For patients in ISS stage II at TDX, 43% stayed in Stage II at T2L, and 46% moved down to Stage I, with a mortality rate of 20 and 5 per 100 person-years, respectively. Among patients in ISS stage III at TDX, 58% moved down to lower stages at T2L. The mortality rate was 10, 21, and 40 per 100 person-years for patients moving down to Stage I and II at T2L and those remaining in Stage III, respectively. In the subgroup of patients in ISS stage III at TDX, strong predictors for shifting down to lower stages were younger age (odds ratio: 2.65; 95% CI:1.20-5.87 for age <65 vs ≥65 years) and serum creatinine ≤ 2 mg/dL at TDX (odds ratio: 2.26; 95% CI:1.03-4.92 for serum creatinine ≤ 2 vs >2 mg/dL), but not gender, race, or cytogenetic abnormality of del17p, t(4;14), and t(14;16). Conclusion: Large changes in ISS stages were observed in multiple myeloma patients when advancing the line of therapy. Changes in ISS stage were also associated with survival outcome. A downward shift to stage I was associated with substantially improved overall survival; in contrast, patients moving up to or remaining in higher stages had poor outcomes, especially for those remaining in ISS stage III. Our results suggest that re-evaluating ISS stage at the time of change in line of therapy can improve prediction of survival outcomes. Disclosures Hong: Takeda Pharmaceuticals International Co.: Employment. Crossland:Takeda Pharmaceuticals International Co.: Employment. Galaznik:Takeda Pharmaceuticals International Co.: Employment. Dolin:Shire: Other: PD holds shares in Shire ; GSK: Other: PD holds shares in GSK; Takeda Pharmaceuticals International Co.: Employment.

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The Discriminatory Ability of the R-ISS Is Equivalent to the ISS in a Large Cohort of Newly Diagnosed Multiple Myeloma (NDMM) Patients

Blood ◽

10.1182/blood-2020-136996 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 46-47

Author(s):

Anaïs Schavgoulidze ◽

Valerie Lauwers-Cances ◽

Aurore Perrot ◽

Herve Avet-Loiseau ◽

Jill Corre

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Cox Model ◽

Intensive Treatment ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Discriminatory Ability ◽

Risk Of Death ◽

Significant Difference

Background In the era of personalized treatment in multiple myeloma, high-risk (HR) patients must be defined accurately more than ever. The International Myeloma Working Group (IMWG) recommends to use the Revised International Staging System (R-ISS) to identify HR patients. This score combines ISS, abnormal serum LDH level and 3 high risk chromosomal abnormalities (CA): del(17p), t(4;14) and t(14;16). However, with the advent of new tools in genomics, assessing only 3 abnormalities seems to be limited. Moreover, LDH level is impacted by various medical conditions; its relevance in the score is questionable. Aims The main purpose of our work was to assess the R-ISS on a multi-center cohort of transplant-eligible patients (1180 patients). To our knowledge, this is the first large scale study in Europe. Methods Data were collected from NDMM patients enrolled in 3 clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible to an intensive treatment. The overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method and compared using the stratified log-rank test. The hazard ratio (HR) for progression or death were estimated by a multivariate Cox regression analysis adjusted for age, sex and therapy. Discrimination was assessed by the Harrell's concordance index (C-index) which estimates the proportion of all pairs of patients in whom prediction and outcome are concordant and takes values from 0.5 (no discrimination) to 1.0 (perfect discrimination). Results Altogether, 1180 patients with MM were analysed. Median age of our cohort was 58 years. The majority of patients (78%) received an intensive treatment followed by an autologous stem-cell transplantation (ASCT). Median follow-up was 94 months for OS. Forty-three percent of patients had ISS stage I, 39% had ISS stage II and 18% had ISS stage III. In the multivariable Cox model, the risk of death was increased for ISS stage II versus I (HR, 1.8; P < 0.001), as well for R-ISS stage III versus I (HR, 2.1; P < 0.001). Thirty percent of patients had R-ISS stage I, 62% had R-ISS stage II and 8% had R-ISS stage III. In the multivariable Cox model, the risk of death was 1.8 times higher for R-ISS stage II versus I and 3.0 times higher for R-ISS stage III versus I. Then we compared patients between their couple ISS/R-ISS. Thirty-one percent of the patients from ISS I were upgraded in R-ISS II; 55% of ISS III patients were reclassified in R-ISS II. Patients from the ISS I/R-ISS II couple didn't have a higher risk of progression (HR, 1.02; P = 0.893) or death (HR, 1.36; P = 0.115) than patients in the ISS I/R-ISS I subgroup. We also focused on the patients classified in R-ISS stage II (736 patients). We compared several subgroups: high risk CA (defined by R-ISS) versus standard risk, del(17p) vs. no del(17p), t(4;14) vs. no t(4;14) and high LDH vs. normal LDH. In the multivariable Cox model for OS, the risk of death was increased for patients with del(17p) (HR, 2.14; P < 0.001), t(4;14) (HR, 2.06; P < 0.001) and any of the high risk CA (HR, 2.15; P < 0.001). Conversely, high LDH didn't have an impact neither on PFS (HR, 1.10; P = 0.333) nor OS (HR, 1.09; P = 0.540). Finally, we assessed the performance of the different prognostic models for discriminating patients who progressed from those who didn't (PFS) and patients who died from those who survived (OS) with the Harrell's C-index. The C-index for the R-ISS was the same than the ISS one for both PFS (0.56) and OS (0.61). R-ISS didn't give an additional prognostic value to the ISS. For every models, C-index were the same with or without LDH level; a LDH level upper than the upper limit of normal range didn't bring predictive gain on PFS or OS. C-index was better when we assessed each criteria of the R-ISS independently; this system presents the advantage of considering different prognostic weights and also different associations. Conclusion Our study confirms a significant difference for both PFS and OS between R-ISS stages I, II and III, but importantly, we show that the discriminatory ability of the R-ISS, assessed by the Harrell C-index, is equivalent to the ISS. Moreover, patients in stage R-ISS II have different prognosis depending on their cytogenetic while LDH level doesn't give any difference. Combining ISS, high risk CA and LDH level in only 3 categories induces a loss in the prognosis assessment. A model which assesses all the parameters in an independent way would be better. Figure 1 Disclosures Perrot: Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

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Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-003-0432-z ◽

2003 ◽

Vol 129 (4) ◽

pp. 234-238 ◽

Cited By ~ 25

Author(s):

Kathrin Niemöller ◽

Christian Jakob ◽

Ulrike Heider ◽

Ivana Zavrski ◽

Jan Eucker ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stage I ◽

Stage Ii ◽

Disease Characteristics ◽

Versus Stage

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International Staging System Is Useful for Predicting Survival in Patients with Multiple Myeloma Treated with Chemotherapy ± Interferon vs Intensive Treatment.

Blood ◽

10.1182/blood.v106.11.5177.5177 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5177-5177

Author(s):

Luis Villela ◽

Agustin Avilés-Miranda ◽

Manuel A. López-Hernández ◽

Maria J. Nambo ◽

José R. Borbolla-Escoboza

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Intensive Therapy ◽

Autologous Transplantation ◽

Risk Groups ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Cell Transplant ◽

Intensive Chemotherapy

Abstract The survival of patients with multiple myeloma (MM) varies widely from months to years. This heterogeneity is usually related to the characteristics of the disease and the patient. The identification of the factors which influence the prognosis is very important to predict outcomes, assist in the choice of the treatment and adequately stratify the patients in clinical studies. The Durie-Salmon staging is the classification most used. Recently, the International Myeloma Working Group identified 3 risk groups. They evaluated this system in patients with standard chemotherapy vs. intensive chemotherapy (autologous transplantation) but lacked to mention the paper of interferon (Griepp P. JCO 2005). We analyzed retrospectively 274 patients treated with chemotherapy (CT) ± interferon (INF) or intensive chemotherapy (CT+ autologous transplantation), during a period of 8 year (from 1997 to 2004) and compared overall survival depending of ISS risk groups among different types of treatment. Two hundred and seventy-four patients with the diagnosis of MM within the period of 1997 to 2004 at four Mexican hospitals with available data on albumin and ß2 microglobulin were stratified according to the ISS. A total of 118 patients received chemotherapy [VAD: 104, MEL-PDN: 7, others: 7]; eighty one patients received chemotherapy plus INF as induction (n= 70) or VAD + INF in manteinance (n=11) and 75 received CT + Autologous Stem Cell Transplant (ASCT like intensive therapy) as initial therapy (No tandem transplantations were performed). The survival was estimated using the Kaplan-Meier method with differences in survival examined using the log-rank test. The median age of the patients was 61 years (range: 31– 88), 53% female (n= 146) and 47% male (n=128). Type of MM was: IgG 66 % (n=180), IgA 19% (n=51), light-chains myeloma 13% (n=36), IgD 2% (n=7). Median monoclonal peak was 5.8 g/dL (range: 1.7–13). Whole group (n=274) was in stage I (n=49) with overall survival (OS) of 77.5%, in stage II (n=89) OS 64% and in stage III (n=136), 55.8% (p<0.024). When analyzed patients without INF or ASCT (n=118) the OS was for stage I 56.52%, Stage II 52.5%, Stage III 36.3% (p=0.21). The OS of patients that received INF or ASCT was for stage I 97%, stage II 73%, stage III 69% (p=0.009). The OS for INF group was for stage I 86%, stage II 64%, stage III 48% (p=0.006). When analyzed ASCT vs non-ASCT in whole series with or without INF we found that ASCT is better (90% vs. 56% vs. 46.6%, respectively; p<0.000) This new system of staging for multiple myeloma (ISS) is simple, is based on variables easy to be performed, and it makes it possible to identify different overall survival in patients who were treated with CT ± INF vs. Intensive chemotherapy. As of now, the results in our study group are clearly favorable for patients treated with intensive chemotherapy followed by patients using INF and could be possible modify OS in MM, keeping inmind that our series do not use MEL+PDN as primary treatment.

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Validation of International Staging System (ISS) for Multiple Myeloma: A Retrospective Analysis of 487 Patients at 8 Brazilian Centers.

Blood ◽

10.1182/blood.v106.11.5069.5069 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5069-5069

Author(s):

Vania T.M. Hungria ◽

Angelo Maiolino ◽

Gracia Martinez ◽

Gisele Colleoni ◽

Luciana Oliveira ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Median Survival ◽

Staging System ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

High Dose ◽

International Staging System ◽

New System

Abstract Introduction: The survival of patients with multiple myeloma varies from a few months to more than 10 years. This heterogeneity is related to the characteristics of the myeloma itself and of the host. The identification of the factors which influence the prognosis is very important to predict the result, assist in the choice of the treatment and adequately stratify the patients in clinical studies. Many prognostic factors have been identified in patients with multiple myeloma, such as anemia, renal failure, ß2 microglobulin, albumin and chromossomic alterations. Some authors have combined prognostic factors and proposed various systems of staging. However, none of them have yet substituted the Durie-Salmon staging system. Recently, the International Myeloma Working Group, with the objective of developing a simple and reliable staging system, which can be internationally applied to classify and stratify patients with multiple myeloma, identified 3 risk groups. This new system of staging, the “International Staging System” (ISS), consists of stage I: ß2 microglobulin < 3.5 mg/L plus albumin ≥ 3.5 g/dL (median survival: 62 months); stage II: neither I nor III (median 44 months); stage III: ß2 microglobulin > 5.5 mg/L (median 29 months). This study included sites in North America, Europe and Asia, but the sites in Latin America were not included. Objective: To validate the ISS in patients with multiple myeloma at Brazilian centers. Patients and Methods: Four hundred and eighty-seven patients with the diagnosis of multiple myeloma within the period of 1998 to 2004 at Santa Casa de São Paulo, Hospital Universitário Clementino Fraga Filho do Rio de Janeiro, Hospital das Clínicas de São Paulo, Hospital São Paulo, Hospital das Clínicas de Ribeirão Preto, HEMOPE, Hospital Prof. Edgar Santos de Salvador and Hospital de Clínicas de Porto Alegre, with available data on albumin and ß2 microglobulin, were stratified according to the ISS. A total of 339 patients received standard therapy and 148 received high-dose therapy as initial therapy. The survival was estimated using the Kaplan-Meier method with differences in survival examined using the logrank test. Results: The median age of the patients was 60 years, 52% male and 48% female. In Stage I (n=104), the global median survival was not reached, the survival at 60 months was 60%, in stage II (n=264), the global median survival was 61 months and in stage III (n=119), 19 months (p<0.001). Conclusion: The new system of staging for multiple myeloma (ISS) is simple, based on variables easy to be applied and was possible to be validated in patients with multiple myeloma in Brazilian centers.

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Usefulness of Biochemical Markers of Bone Turnover in the Evaluation of Venezuelan Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.5003.5003 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5003-5003 ◽

Cited By ~ 1

Author(s):

Eugenio Ionescu ◽

Edmundo Martinez ◽

Leonor Cardenas ◽

Dalal Zoghbi

Keyword(s):

Multiple Myeloma ◽

Alkaline Phosphatase ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Specific Alkaline Phosphatase ◽

Osteoblastic Activity ◽

Bone Specific Alkaline Phosphatase ◽

Average Value ◽

Osteoclastic Activity

Abstract Abstract 5003 Multiple Myeloma is a neoplastic disease of B-lymphocyte that invariably mature into plasma cells, synthesizing abnormal amounts of immunoglobulin or their fragments. Bone destruction is a relevant clinical finding and is responsible for the major signs of the disease. Since the osteolytic lesions of Multiple Myeloma do not heal rapidly, imaging studies and changes in the levels of monoclonal proteins cannot reflect the progress or regression of the bone disease during the anti-myeloma treatment. The purpose of this study is to establish the Profile of Biochemical Markers of Bone Turnover present in Venezuelan patients with Multiple Myeloma. The study was carried out in patients diagnosed with Multiple Myeloma that attended, during the year 2009, the Hematology Service of the “Dr. Miguel Pérez Carreño” General Hospital in Caracas, Venezuela. Methods: A descriptive, transversal, unicentric study was carried out in a single auto-comparable group. Urinary NTx osteoclastic activity biomarkers (Reticulated Collagen-type I N-telopeptides) and serum CTx (C-terminal telopeptide of type I collagen) were processed, as well as the osteoblastic activity biomarkers osteocalcin and bone specific alkaline phosphatase. Results: A total of 34 patients were included: 68% males and 32% females. By the International Staging System (ISS) 45% were stage I; 23 % stage II, 32% stage III. The average value of osteocalcine was the following: 15. 1 ± 9. 5 in stage I; 20. 9 ± 14. 5 in stage II and 25. 2 ± 23. 3 in stage III. The average value of bone specific alkaline-phosphatase was: 19. 1 ± 7. 7 in stage I; 20. 9 ± 8. 4 in stage II and 18. 4 ± 5 in stage III. The average value of CTx was: 2 ± 0. 6 in stage I; 2. 5 ± 0. 7 in stage II and 3. 3 ± 2. 5 in stage III. The average value of urinary NTx was: 48. 3 ± 21. 7 in stage I; 56 ± 22. 9 in stage II and 58. 7 ± 19. 2 in stage III. Discussion: It can be seen that the average value of serum CTx was elevated in all the states of the disease, regardless of the classification used to study the patients. It was also found that this value increases as the disease becomes more severe; that is to say, the more advanced the stage of the patient's disease. This is more significant when using the ISS to study the patients. The value of the urinary NTx osteoclastic activity was never high or outside its reference range. The osteoblastic activity markers osteocalcin and bone specific alkaline-phosphatase never appeared outside their average reference value. Conclusion: Serum CTX osteoclastic activity biomarker is useful to establish the severity of the bone disease in patients with Multiple Myeloma. The urinary NTX osteoclastic activity biomarker and the osteoblastic activity markers osteocalcin and bone specific alkaline-phosphatase do not appear to be useful to establish the severity of the bone disease in patients with Multiple Myeloma. Disclosures: No relevant conflicts of interest to declare.

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Serum Total-RANKL Is Elevated in Patients with Multiple Myeloma, Increases with ISS Stage and Decreases after Induction Therapy.

Blood ◽

10.1182/blood.v106.11.2511.2511 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2511-2511

Author(s):

Christian Jakob ◽

Jan Sterz ◽

Lorenz Kleeberg ◽

Ivana Zavrski ◽

Martin Kaiser ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Serum Levels ◽

Conventional Radiography ◽

Elisa Test ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Bone Lesions ◽

Serum Samples

Abstract Enhanced osteolytic bone resorption is a hallmark of multiple myeloma. Several studies demonstrated an elevation of RANKL levels in the bone marrow microenvironment in multiple myeloma, but serum levels of soluble RANKL (sRANKL) revealed controversial results. One study reported elevated sRANKL in serum in myeloma patients, but using the same test, the levels in the majority of the patients were below the detection limit in the hand of other groups. Thus, a novel test was developed which measures both soluble and OPG-bound RANKL (total-RANKL, tRANKL). The objective of the present study was to investigate the clinical significance of circulating levels of tRANKL in monoclonal gammopathies of undetermined significance (MGUS) or multiple myeloma (MM). Serum levels of tRANKL were analyzed by ELISA in 128 individuals: 20 healthy donors, 20 with MGUS and 88 newly diagnosed patients with multiple myeloma. Multiple myeloma patients had significantly (P<0.001) higher serum tRANKL values (median 7.01 μmol/L, range < 2 – 57.6) than healthy controls (median < 2 μmol/L) and individuals with MGUS (median < 2 μmol/L). Serum tRANKL levels increased significantly (P<0.001) from Durie & Salmon stage I to stage III (median values: stage I = 2.98, stage II = 4.61, stage III = 10.45 μmol/L) und from ISS stage I to stage III (median values: stage I = 4.64, stage II = 7.98, stage III = 23.12 μmol/L). Furthermore the serum tRANKL concentrations were significantly elevated in MM Durie & Salmon stage I versus MGUS (P=0.01). Multiple myeloma patients with osteolytic bone lesions in conventional radiography had significantly higher tRANKL levels than those without bone lesions (median 8.34 vs. 4.02 μmol/L, P=0.01). In 32 patients with multiple myeloma in stages II and III, who received chemotherapy and a monthly bisphosphonate treatment with zoledronic acid or pamidronate additional serum samples after 3 months were available. There was a significant (P<0.001) decrease from pre- to post-treatment tRANKL concentrations after three months of treatment. Our study shows that serum tRANKL levels are detectable in the majority of myeloma patients using this novel ELISA test. Advanced disease stages and osteolytic bone lesions in multiple myeloma patients are associated with increased serum tRANKL levels. The decrease of tRANKL after 3 months of induction therapy and bisphosphonates suggest a positive effect of anti-myeloma treatment on RANK ligand expression in multiple myeloma patients.

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The Role of Bone Marrow Examination in the Initial Evaluation of Pediatric Hodgkin’ Disease: The Canadian Perspective.

Blood ◽

10.1182/blood.v110.11.2326.2326 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2326-2326

Author(s):

David C. Simpson ◽

Jun Gao ◽

Conrad V. Fernandez ◽

Margaret Yhap ◽

Victoria E. Price ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Involvement ◽

Stage Iv ◽

Bone Marrow Examination ◽

Pet Scan ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Significant Difference ◽

The Impact

Abstract Hodgkin’s Disease (HD) is the most common lymphoma affecting young adults and teenagers. Bone marrow involvement is rare but if present, infers Stage IV disease and an inferior outcome. Adult studies have suggested that bone marrow examination (BME) may not be necessary unless certain risk factors are present. However, some pediatric centers continue to perform BME routinely on all children with HD. BME is invasive and generally performed under conscious sedation in children. We validated and administered an internet-based survey to examine the practice of all Canadian pediatric oncologists regarding BME in children with HD. We also retrospectively evaluated the impact of routine BME on the HD patients treated at our institution over the past 27 years. Forty-three percent of eligible physicians (n=93) completed the survey and 16 of a total of 17 Canadian pediatric oncology centers were represented. BME universally consisted of bilateral bone marrow aspirates and trephine biopsies. Routine BME for Stage III and IV disease was consistently practised nationally (by 92% and 97% of respondents, respectively). By contrast, 54% and 70% of respondents reported performing routine BME in low stage (Stage I and II) disease, respectively. Respondents were more likely to report performing routine BME in low stage patients, if their pediatric hematology/oncology training was entirely outside Canada (p=0.04 for Stage I and p=0.07 for Stage II) and if they practiced at smaller centers (p=0.05 for Stage I and p=0.03 for Stage II). There were no differences in practice regarding BME associated with the number of years in practice or the number of patients seen annually by the respondent. If not part of routine staging for all patients, BME was more likely performed if there were “B” symptoms, cytopenias, and/or bulky disease. Most respondents (95%) would proceed with BME following a positive PET scan. In the review of local institutional practice, 62 patients with HD and BME were eligible for analysis. Only 4 patients (6.5%) had a positive BME. No patient with otherwise low stage disease was found to have bone marrow involvement. Two patients, who would have been assigned as Stage III disease, were upstaged to Stage IV due to their BME. Comparison of staging with and without BME demonstrated no significant difference. Hemoglobin level was found to be the to be the only significant risk factor for marrow involvement based on univariate analysis(put in statisticp=0.006). Age, gender, histologic subtype, presence of “B” symptoms, and other blood parameters (white count, platelets, ESR and transaminases) were not significant factors. Practice regarding BME in children with low stage HD is highly variable across Canada. Bone marrow examination in pediatric patients with low stage HD should be abandoned, unless there is a specific indication to do so (for example positive PET scan or unexplained anemia). Moreover, BME does not appear to add any additional therapeutic direction for higher stage patients.

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