Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 991-991 ◽  
Author(s):  
María-Victoria Mateos ◽  
Lucía López-Corral ◽  
Miguel Hernández ◽  
Pilar Giraldo ◽  
Javier De La Rubia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Phase Iii ◽  
Symptomatic Disease ◽  
Risk Of Progression ◽  
The Moment

Abstract Abstract 991 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist. In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide is not approved for smoldering myeloma. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Baquero:Celgene: Employment. Quintana:Celgene: Employment. García:Celgene: Employment.

Smoldering Multiple Myeloma (SMM) at High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) as Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1935-1935 ◽  
Author(s):  
María-Victoria Mateos ◽  
Lucía López-Corral ◽  
Miguel Hernández ◽  
Pilar Giraldo ◽  
Javier De La Rubia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Phase Iii ◽  
Symptomatic Disease ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

Abstract Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (>50% at 2 years): >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 10 out of these 21 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. In conclusion, this second interim analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma. De La Rubia:Celgene: Honoraria. Rosiñol:Celgene: Honoraria. Lahuerta:Celgene: Honoraria. Palomera:Celgene: Honoraria. Oriol:Celgene: Honoraria. Garcia-Laraña:Celgene: Honoraria. Hernández:Celgene: Honoraria. Leal-da-Costa:Celgene: Honoraria. Alegre:Celgene: Honoraria. Quintana:Celgene: Employment. Baquero:Celgene: Employment. García:Celgene: Honoraria. San Miguel:Celgene: Honoraria.

Maintenance Therapy With Bortezomib and Dexamethasone for Transplant-ineligible Patients With Multiple Myeloma

2021 ◽  
Vol 1 (2) ◽  
pp. 35-42
Author(s):  
YURIKA NOGUCHI ◽  
NORIYOSHI IRIYAMA ◽  
HIROMICHI TAKAHASHI ◽  
YOSHIHITO UCHINO ◽  
MASARU NAKAGAWA ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Survival Rates ◽  
Patient Characteristics ◽  
Newly Diagnosed ◽  
Estimated Glomerular Filtration Rates ◽  
Overall Survival Rates ◽  
Maintenance Group

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

Extensive Bone Marrow Infiltration and Abnormal Free Light Chain Ratio Identifies Patients with Smoldering Myeloma At High Risk for Progression to Symptomatic Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3926-3926
Author(s):  
Efstathios Kastritis ◽  
Lia A Moulopoulos ◽  
Maria Gkotzamanidou ◽  
Dimitra Gika ◽  
Maria Roussou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Light Chain ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Symptomatic Disease ◽  
Lytic Bone Lesions ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Substantial Risk

Abstract Abstract 3926 Asymptomatic/smoldering multiple myeloma (SMM) is a proliferative plasma cell disorder characterized by a substantial risk of progression to symptomatic myeloma. According to current recommendations, patients with SMM should be followed without treatment until they develop symptomatic disease. However, the risk of progression to symptomatic myeloma varies between different series and for individual patients; thus, significant effort is needed in order to identify factors that could discriminate those who are at high risk for progression. Such patients should be followed closer and should be considered candidates for clinical trials. In order to evaluate previously recognized risk factors and study patterns of progression we analyzed our series of patients with SMM, who have been diagnosed and followed in the Department of Clinical Therapeutics in Athens, Greece. SMM was defined as serum monoclonal (M) protein (IgG or IgA) level of ≥3 g/dL and/or bone marrow plasma cells ≥10%, absence of end-organ damage, such as lytic bone lesions, anemia, hypercalcemia, or renal failure, that can attributed to a plasma cell proliferative disorder (IMWG criteria, Br J Haematol 2003;121:749–57). Progression to symptomatic myeloma was defined as per the IMWG proposed criteria. We analyzed 95 patients with SMM, 53% of whom were females, 70% had IgG heavy chain, 22% had IgA, 5% had a biclonal SMM and 3% had light chain only SMM, while 65% had a kappa light chain and 35% a lambda light chain. Median infiltration by clonal plasma cells in BM trephine biopsy was 20% (range 10–90%), 10% of patients had ≥60% clonal plasma cells in BM biopsy. Fifty patients had MRI of the spine at the time of diagnosis of SMM and 19.5% had an abnormal pattern of BM infiltration (diffuse, focal or variegated pattern). In patients with available bone marrow immunohistochemistry data, 61% had clonal plasma positive for CD56, 17% for CD20 and 19% for cyclin D1. The median follow up of the cohort was 27 months (range 1–253 months) and 23 (24%) patients have progressed to symptomatic myeloma. The one-year, 2-year and 3-year cumulative probability of progression was 7%, 12% and 20% respectively. Nine patients (9.5%) progressed within the first two years from the diagnosis of SMM. All these patients had an M-protein of ≥1 g/dl (10 g/L), 67% had bone marrow plasma cells >60% and 80% had an abnormal MRI pattern of BM infiltration. The 3-year probability of progression to symptomatic myeloma was 4%, 18% and 87% for patients with <20%, 20–59% and ≥60% clonal plasma cells in bone marrow biopsy (P<0.001). The 2-year probability of progression to symptomatic myeloma was 0%, 13% and 60% for patients with <20%, 20–59% and ≥60% clonal plasma cells in BM biopsy (P<0.001). Patients with significantly abnormal free light chain ratio (either kappa/lambda ≥8 or kappa/lambda ≤0.125, according to Dispenzieri et al, Blood 2008;111:785–9) had a 3-year probability of progression to symptomatic MM of 41% vs. 15% (p=0.07). There was no significant difference in the risk of progression to symptomatic MM for patients with IgA vs. IgG myeloma. In multivariate analysis, abnormal FLC ratio less than 0.125 or more than 8 (HR: 6.4, 95% CI 1.3–34.5 p=0.032) and BM clonal plasma cells infiltration ≥60% (HR: 23, 95% CI 5–125, p<0.001) were independent risk factors for progression to symptomatic myeloma. Progression to symptomatic MM was manifested by the development of anemia in 52% of patients who progressed to symptomatic MM, development of lytic bone lesions or pathologic fracture in 48%, an increase of serum creatinine to ≥2 mg/dl in 13%, development of a soft tissue plasmacytoma in 4% and development of hypercalcemia in 4%. In conclusion, in our series of patients the 3-year probability of progression to symptomatic myeloma is about 20%, but there is a subgroup of patients with extensive bone marrow infiltration (≥60%) and highly abnormal FLC ratio, who have a substantial risk of progression to symptomatic disease within the first two years from the diagnosis of SMM. These high risk patients may also have other features such as abnormal MRI of the spine. Patients at high risk for progression should be considered for clinical trials evaluating the role of treatment before the development of symptomatic disease, which in most cases is manifested with anemia and/or lytic bone disease or pathologic fractures. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

scholarly journals Bence Jones Proteinuria in Smoldering Multiple Myeloma As Predictor Marker of Progression to Symptomatic Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3369-3369 ◽  
Author(s):  
Veronica Gonzalez de la Calle ◽  
Ramon Garcia-Sanz ◽  
Eduardo Sobejano ◽  
Enrique M. Ocio ◽  
Noemi Puig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Light Chain ◽  
Plasma Cells ◽  
Symptomatic Disease ◽  
Risk Of Progression ◽  
Bone Marrow Plasma ◽  
Active Disease ◽  
Bence Jones Proteinuria

Abstract BACKGROUND Smoldering multiple myeloma (SMM) is a plasma cell proliferative disorder with no related organ or tissue impairment. It is associated with a risk of progression to symptomatic multiple myeloma (MM) of approximately 10% per year. Several prognostic factors for the progression to active disease have been identified, such as those defined by the Mayo Clinic including the proportion of bone marrow plasma cells, the serum monoclonal protein level at diagnosis and the serum immunoglobulin free light chain ratio (FLC); or those defined by the Spanish Group including the proportion of bone marrow aberrant plasma cells assessed by flow cytometry plus immunoparesis. The presence of Bence Jones (BJ) proteinuria is a myeloma feature associated with renal function and tumor burden as well. There is lack of evidence about the role of BJ proteinuria in SMM as predictor marker of progression to symptomatic disease. AIMS The goal of the present study was to investigate the role of the presence of Bence Jones proteinuria at diagnosis in SMM as predictor of progression to symptomatic disease. METHODS We reviewed 147 medical records of SMM patients from area of Castilla y León (Spain), diagnosed between 1983 and 2013, according to the criteria of the International Myeloma Working Group. The primary endpoint was time to progression to active multiple myeloma (hypercalcemia, renal insufficiency, anemia or bone lesions). RESULTS 147 patients with SMM were included in the analysis. The median age at diagnosis was 69 years-old (range: 34-90).The serum M-protein at diagnosis ranged from 1 to 26 g/l (median,25). 70% of SMM were Ig G subtype. The proportion of bone marrow plasma cells ranged from 1% to 55% (median, 14). In 64 % of SMM, the percentage of aberrant plasma cells assessed by flow cytometry was superior to 95% and 51% had immunoparesis. Bence Jones proteinuria was detected at diagnosis in 40 patients (27%) and the average amount of urinary monoclonal light chain was 236 mg per 24h. Of those patients, 58% had a monoclonal kappa light chain. The FLC ratio was assessed in 18 patients and it was abnormal (<0.26 or >1.65) in 83% of them. The median level of involved Immunoglobulin was 88.5 mg/l (range, 13-1200) and the median ratio of involved to uninvolved was 10.8 (range, 2.2-3360). In 4 patients, FLC ratio was greater than 100. At a median follow-up of 54 months, progression to active disease occurred in 49%. Anemia was the most common CRAB feature at the time of progression. Median time to progression (TTP) to symptomatic disease in the whole series was 63 months. SMM with BJ proteinuria had a significantly shorter median TTP to active disease as compared with patients without BJ proteinuria (21.7 months vs 82.9 months ;HR: 2.44, IC 95%: 1.48-4.02; p<0.001). The progression risk at 2 years in the BJ group of SMM was 53%. Multivariate analysis selected BJ proteinuria at diagnosis as an independent variable for progression to symptomatic MM (HR: 2.47, IC 95%: 1.32-4.63; P=0.005). Using this independent variable, we identified 4 risk categories according to amount of urinary monoclonal light chain: 0 mg per 24h; 1-250 mg/24h; 251-500 mg/24h ; or more than 500 mg/24h, with a median TTP of 83, 37, 16 and 7 months, respectively; p <0.001. CONCLUSIONS The presence of Bence Jones proteinuria at diagnosis in SMM patients is associated with significantly higher risk of progression to active MM (53% risk of progression at 2 years). Moreover, the presence of more than 500 mg of BJ proteinuria can be considered as a marker for the identification of ultra high risk SMM. Disclosures No relevant conflicts of interest to declare.

A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4706-4706 ◽  
Author(s):  
Manfred Hensel ◽  
Mathias Witzens-Harig ◽  
Peter Dreger ◽  
Anthony D. Ho ◽  
Daniel Thurley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Induction Therapy ◽  
Randomized Trials ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries. Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years. The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population. Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =&gt;CR) after induction therapy will be evaluated.

MAGE-A3 or NY-ESO1 Expression and Spontaneous Antibody Responses to NY-ESO1 in Newly Diagnosed Multiple Myeloma Patients Are Associated with Worse Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5110-5110
Author(s):  
Adam D Cohen ◽  
Ping Lu ◽  
Sacha Gnjatic ◽  
James Hoffman ◽  
Erika Ritter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Soft Tissue ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Prognostic Significance ◽  
Antibody Responses ◽  
Newly Diagnosed ◽  
Bone Marrow Plasma

Abstract The cancer-testis antigens (CTA) are highly immunogenic antigens expressed in various tumors but not in normal tissues (except during gametogenesis), making them an attractive target for cancer immunotherapy. Expression of CTAs such as MAGE-A3, MAGE-C1 (CT7), MAGE-C2 (CT10), NY-ESO1 and the SSX antigens has been previously reported in multiple myeloma (MM). To date, however, these reports have included a heterogeneous group of newly diagnosed and relapsed/refractory patients, all in different stages of treatment. Therefore, the extent and prognostic significance of CTA expression, and of de novo immune responses against CTA in newly-diagnosed MM patients are not known. We now report on both CTA expression and antibody responses in MM patients at diagnosis and on their prognostic significance. From 8/00-11/04, we treated 67 newly-diagnosed, symptomatic patients with a thalidomide, doxorubicin, and dexamethasone-based induction regimen. (Brit J Haematol2006;132:155). Median age was 58; 54% were ISS stage I, 28% ISS II, and 18% ISS III. Nine of 63 tested (14%) had deletion 13q by FISH, while 24% had soft tissue involvement by MM. Responses to induction therapy included 10 (15%) CR, 16 (24%) VGPR, 26 (39%) PR, 6 (8%) stable or progressive disease, and 9 (13%) inevaluable. Post-induction 54 underwent autoSCT and 9 also underwent alloSCT.. Median overall survival (OS) has not been reached with 61% alive at median follow up of 65 months. Cryopreserved pre-treatment bone marrow plasma cells were used to assess CTA expression by RT-PCR. Pre- and post-treatment sera were used to assess antibody (Ab) responses against CTA proteins by ELISA. Fifty-two patients had sufficient RNA for PCR, and 46 had baseline serum for ELISA. OS of these groups did not differ significantly from the entire cohort. At least 1 CTA was expressed in 77% of cases, including MAGE-A3 (52%), SSX1 (40%), CT7 (29%), CT10 (25%), NY-ESO1 (21%), and SSX5 (17%). Three or more CTA were expressed in 29% of cases. Individually MAGE-A3 or NY-ESO1 expression at diagnosis conferred a poorer prognosis (MAGE-A3: median OS 66 mos. vs. not reached, p=0.02 by log-rank; NY-ESO1: median OS 65 mos. vs. not reached, p=0.09). These poorer outcomes were independent of ISS stage, presence of del 13q, or response to induction therapy. No other CTA was associated with an OS difference, nor was the total number of CTA expressed prognostically significant. Baseline Ab responses, all at titers &gt; 1:1600, were noted to NY-ESO1 in 6/46 (13%) patients, 5 of whom also had Ab to the NY-ESO1 homologue LAGE-1. Ab responses were also noted to CT7 (n=2), CT10 (n=1) and SSX4 (n=1). No Ab responses were noted to MAGE-A3. The effect of induction therapy on antibody titers was inconsistent, with increases, decreases, and no changes seen. Interestingly, 2 of the 6 NY-ESO1 Ab+ patients had no NY-ESO1 expression in bone marrow plasma cells. Both, however, had extensive soft tissue (ST) plasmacytomas, suggesting another source of NY-ESO1 antigen. Presence of NY-ESO1 Ab correlated significantly with baseline ST involvement, with 67% of Ab+ patients having ST disease compared with 20% of Ab− patients (p=0.05). NY-ESO1 Ab+ patients also had significantly poorer OS (med 21 mos. vs. not reached, p=0.009), independent of other prognostic factors. In sum, CTA expression is frequent in newly diagnosed MM patients, and expression of MAGE-A3 or NY-ESO1 is associated with worse long-term survival. Spontaneous antibody responses against NY-ESO1 are seen in untreated patients, and are associated with ST involvement and poorer survival. Further exploration of biologic differences between CTA+ and CTA-MM, as well as immunotherapeutic strategies which target these antigens, are warranted.

Rising Plasma Cell Proliferation By Ki67/CD138 Ratio at Relapse Is a Marker of High Risk Disease in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2991-2991
Author(s):  
Peter A. Forsberg ◽  
Tomer M Mark ◽  
Sujitha Yadlapati ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Initial Therapy ◽  
First Line ◽  
High Risk Disease

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) for years but utilization remains limited. We recently developed a novel immunohistochemical (IHC) co-staining technique for CD138 and Ki67 expression to quantify plasma cells in active cycling. Previously presented results from newly diagnosed patients demonstrate that having an elevated ratio of plasma cells in active cycle by co-expression of CD138 and Ki67 (>5%) is associated with aggressive disease and poor outcomes including shorter overall survival (OS). The expansion of subclones with higher proliferative capacity following initial therapy may be an indicator of a higher risk relapse event and indicate poor prognosis. Here we assess MM patients (pts) with Ki67/CD138 co-staining on bone marrow samples both at diagnosis and relapse to assess the impact of changes in cell cycling ratio on outcomes with subsequent therapy and overall clinical course. Methods: A retrospective cohort study of pts with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts must have had bone marrow evaluation with double-staining for Ki67 and CD138 by immunohistochemistry both at diagnosis and relapse. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The Ki67% was calculated as the ratio of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on alterations in Ki67% between diagnosis and relapse. Results: We identified 37 pts with bone marrow sampling that was evaluated for CD138 and Ki67 co-expression both at diagnosis and at the time of relapse. These pts had undergone a median of 2 lines of prior treatment at the time of relapse bone marrow biopsy (range 1-7). 19 pts were identified to have a rising Ki67% between diagnosis and relapse defined at a 5% or greater increase, the other 18 pts had stable or decreased Ki67%. Pts with a rising Ki67% at relapse had a shorter OS with a median of 72 months vs not reached (p=0.0069), Figure 1. Pts who had rising Ki67% at relapse had shorter progression free survival (PFS) on first line treatment with a median of 25 vs 47 months (p=0.036), Figure 2. Additionally pts with rising Ki67% had a trend towards shorter PFS with the treatment they received after relapse with median of 12.5 vs 3.5 months (p=0.09). Relapse regimens were most commonly carfilzomib (n=9), pomalidomide (5) or ixazomib (4) based. 37% of pts (7/19) with rising Ki67% achieved PR or better on relapsed treatment vs 67% (12/18) with stable Ki67%. Discussion: The presence of clonal evolution and selection of higher risk clones under therapeutic pressure in multiple myeloma is a key feature of disease progression. The ability to improve risk stratification at the time of relapse may help guide clinical decision making to best suit individual patient needs. We have identified rising plasma cell proliferation through quantification of Ki67/CD138 co-expression at relapse to be a useful marker of high risk disease evolution. This appears to help identify the emergence of higher risk clones which are ultimately responsible for treatment resistant disease. Patients with rising Ki67% were more likely than patients with stable Ki67% to have early relapses to initial therapy, were less likely to achieve responses to relapse regimens or to maintain their response and had shorter overall survival. Further evaluation is needed to identify if different approaches to patients with increasing proliferation may improve outcomes in these patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau.

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