scholarly journals Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4452-4452
Author(s):  
Benedetta Dalla Palma ◽  
Valentina Marchica ◽  
Fabrizio Accardi ◽  
Daniela Guasco ◽  
Laura Notarfranchi ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Plasma Cells ◽  
Activin A ◽  
M Protein ◽  
Monoclonal Protein ◽  
Risk Of Progression ◽  
Standard Risk

Abstract The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients. We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis. With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001). In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

Metastatic Bone Survey in Monoclonal Gammopathy of Undertermined Significance: Useful or Not?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2728-2728
Author(s):  
Vrushali s Dabak ◽  
Esther Urbaez Duran ◽  
Muath Dawod ◽  
Amr Hanbali
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Calcium ◽  
Plasma Cells ◽  
Bone Marrow Aspiration ◽  
Hemoglobin Concentration ◽  
M Protein ◽  
Risk Of Progression ◽  
Male Sex

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a serum monoclonal protein &lt;3g/dl, with fewer than 10% plasma cells in bone marrow and absence of lytic bone lesions, anemia, hypercalcemia and renal insufficiency. Incidence increases with age, especially over 70 and its progression to malignant disease occurs at 1% per year. However, so far there are no studies which can reliably distinguish patients who would progress from those who would remain stable. Based on available literature, it is concluded that MGUS has low risk of progression when M-protein is less than 1.5 g/dl, with no reduction in polyclonal immunoglobulins and bone marrow plasma cells less than 5%. The recommended testing with suspected MGUS is hemoglobin concentration, protein studies, serum calcium, and creatinine. Metastatic bone survey (MBS) and bone marrow aspiration are felt unnecessary if M-protein is less than 1.5 g/dl. However literature to support the use of MBS at diagnosis based on the level of M-protein is limited. Also our observation has been that due to lack of clear guidelines, most physicians obtain a baseline MBS and some follow patients with yearly or every other year MBS irrespective of the level of M-protein. Hence, we decided to review patients diagnosed with MGUS at our institution to determine the importance of MBS and if possible identify risk factors like age, race, M-protein level, hemoglobin concentration, serum calcium or creatinine level, which would identify a subgroup of patients needing a MBS. In doing so we were hoping to separate out those patients in whom we could recommend against unnecessary use of the skeletal survey below a certain defined M protein level. Study: We reviewed charts on 1906 patients at Henry Ford hospital diagnosed with MGUS between 1990 and 2007. All patients with at least one M-protein and one MBS done were included in the analysis. We excluded patients with a level of M-protein &gt;3.0 g/dl, who never had a skeletal survey in our system, had a light chain myeloma, plasmacytoma, chronic lymphocytic lymphoma(CLL), amyloidosis or protein evaluation done for diagnosis other than MGUS. We had 620 such patients. We collected data regarding their age, sex, ethnicity, date of diagnosis, type and level of the M-protein, hemoglobin level, serum calcium and creatinine at baseline, result of the MBS, date of progression to multiple myeloma (MM) if any and the date of last follow up if they did not progress to MM. Positive MBS is defined as x ray findings consistent with myelomatous changes with bone marrow aspiration confirming diagnosis of MM. Results: Of 620 patients, 36 had a positive MBS and applying non parametric Mann Whitney test and a chi-squared test, positive results seemed to correlate with higher level of M-protein, IgG subtype, lower hemoglobin and higher creatinine. Male sex and older age were other risk factors. Using the LOES curve to graph the risk of a positive skeletal event with the level of M-protein, risk was noted to increase significantly with M-protein in the range of 1.8– 3.0 (odds ratio 8.84 compared with 1.31 if level was less than 1.8), which was highly statistically significant as shown in figure 1. Further for 97/620 who progressed to multiple myeloma, the risk of progression was significantly higher for males, younger age at diagnosis of MGUS, lower hemoglobin, higher level of M-protein, IgG subtype and a positive skeletal event. Discussion: Our study is a retrospective chart review with its own limitations. However to our knowledge this is the first study to define the level of M-protein in patients with MGUS above which obtaining a MBS may be of value. Our study identifies 1.8 as a cut off value of M-protein below which doing routine MBS without symptoms of bone pains or other laboratory features suggesting progression to multiple myeloma might be unnecessary. Other risk factors for a positive event and progression to MM like lower hemoglobin, higher creatinine, older age, male sex and IgG subtype in our study are in keeping with what has been described in the literature. Conclusion: Based on our study, obtaining baseline MBS in all patients with suspected MGUS was not beneficial. Hence, we would not recommend obtaining MBS in patients with M-protein &lt;1.8 g/dl in absence of other risk factors for progression to multiple myeloma. Figure 1: LOES curve showing increased likelihood of positive MBS for increasing MPEV level. Figure 1:. LOES curve showing increased likelihood of positive MBS for increasing MPEV level.

scholarly journals Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3192-3192 ◽  
Author(s):  
Theresia Akhlaghi ◽  
Even H Rustad ◽  
Venkata D Yellapantula ◽  
Neha Korde ◽  
Sham Mailankody ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Ultra High Risk ◽  
Risk Of Progression ◽  
Equity Ownership ◽  
M Spike ◽  
Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals Evaluation of Current Clinical Models for Risk of Progression from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma or Related Malignancies in 2028 Persons Followed in the Czech Republic

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3376-3376 ◽  
Author(s):  
Viera Sandecka ◽  
Zdenek Adam ◽  
Ivan Spicka ◽  
Vlastimil Scudla ◽  
Evzen Gregora ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mayo Clinic ◽  
Plasma Cells ◽  
Reference Group ◽  
Low Risk ◽  
M Protein ◽  
The Czech Republic ◽  
Risk Of Progression ◽  
Clinical Models

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition associated with a risk of progression to multiple myeloma (MM) or related disorders. There are currently 2 clinical models predicting progression from MGUS to MM. The Mayo Clinic model uses levels and type of serum monoclonal protein (M-protein) and serum free light chain ratio (sFLC). The Spanish PETHEMA model uses flow cytometry of bone marrow plasmocytes (BMPC) and the presence of DNA aneuploidy. Purpose: The primary end point was to estimate the cumulative risk of hematologic disorders occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models suggested by the Mayo Clinic group and the Spanish PETHEMA group for the risk of progression from MGUS to MM or related malignancies and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of low-risk MGUS group. Group: Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. MGUS diagnosis was made according to IMWG criteria. In total, 2028 persons with MGUS were enrolled in the RMG study from May 2007 to June 2013. A total of 93% (1887/2028) of persons were evaluated. Results: 1887 MGUS persons were followed with median 4 years. Malignancies developed in 8.6% (162/1887) cases; MM occurred in 77.2% (125/162) of persons. The risk of progression was 1.5% at 1 year, 7.6% at 5 years and 16.5% at 10 years after diagnosis. The key predictors factors of progression were as follows: age ≥ 69 years, serum M- protein concentration ≥ 1.5 g/dL, BMPC > 5%, pathological sFLC ratio (< 0.26 or >1.65), immunoparesis of polyclonal immunoglobulins, levels of serum hemoglobin at baseline < 12.0 g/dL and the presence of normal plasma cells (nPC) in bone marrow ≤ 5 % identified by multiparametric flow cytometry techniques. Distribution of MGUS persons according to risk groups based on the Mayo Clinic model confirmed predictive power of Mayo Clinic model based on our data although isotype of M- protein was not found as independent predictor. At 10 years, no-risk group had 4.9% risk of progression compared to 16.3%, 24.6%, and 54.9% in groups with 1, 2 or 3 risk factors, respectively (p< 0.001). MGUS group with 1, 2 and 3 risk factors in comparison to the reference group without any risk factor had HR( 2.59 [95% CI: 1.39- 4.84]; p= 0.003, HR 4.79 [95% CI: 2.56-8.93]; p< 0.001, HR 12.97 [95% CI: 5.52-30.48];p< 0.001), retrospectively. Immunoparesis instead of DNA aneuploidy was used together with the presence of abnormal plasma cells (aPCs) to validate the modified PETHEMA model. The rates of progression at 3 years were 2.5%, 8.1% and 28.0% for groups with neither, one or both risk factors, respectively (p< 0.001). MGUS group with 1 and 2 risk factors in comparison to the reference group without any risk factor had HR (3.98 [95% CI: 1.60-9.91]; p= 0.003, HR 14.23 [95% CI: 2.86-70.76]; p< 0.001), retrospectively. Based on the 5 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥ 1.5 g/dL, BMPC > 5%, abnormal sFLC ratio and serum level of hemoglobin < 12.0 g/dL) we proposed a new CMG model. The created CMG model clearly detected MGUS persons at low risk 86.6% (828/956) with the risk of progression 5.6% at 5 years better than previously described models. As expected, the number of MGUS persons with the highest risk of progression was limited to 3.7% only (35/956), with the risk of progression 31.9% at 5 years. The MGUS group with 5 risk factors had 63 times higher hazard of progression compared to reference MGUS group (HR 63.17 [95% CI: 13.99-285.36]; p< 0.001). Conclusion: In the large cohort of MGUS persons, we confirmed validity of previously considered clinical models for the risk of progression from MGUS to MM by the Mayo Clinic group and the Spanish PETHEMA group (model used for SMM). New CMG model for the risk of progression from MGUS to MM or related malignancies was established with an advantage for better identification of MGUS persons at low risk (87% of persons with risk of progression below 10% in 5 years) as well as few persons at the highest risk of progression. As a consequence, limited evaluation and visits can be planned in majority of MGUS persons in follow-up. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n° 278570. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prevalence of Smoldering Multiple Myeloma: Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 151-151
Author(s):  
Sigrun Thorsteinsdottir ◽  
Gauti Kjartan Gislason ◽  
Thor Aspelund ◽  
Sæmundur Rögnvaldsson ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Population Based ◽  
M Protein ◽  
Screening Study

Abstract Background Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). Emerging data from clinical trials indicate that - compared to watchful monitoring - initiation of therapy at the SMM stage might be indicated. Currently, there is no established screening for SMM in the general population and therefore patients are identified incidentally. Here, we define for the first time, epidemiological and clinical characteristics of SMM in the general population based on a large (N&gt;75,000) population-based screening study. Methods The iStopMM study (Iceland Screens Treats or Prevents Multiple Myeloma) is a nationwide screening study for MM precursors where all residents in Iceland over 40 years of age and older were invited to participate. Participants with a positive M-protein on serum protein electrophoresis (SPEP) or an abnormal free light chain (FLC) analysis entered a randomized controlled trial with three arms. Participants in arm 1 continued care in the Icelandic healthcare system as though they had never been screened. Arms 2 and 3 were evaluated at the study clinic with arm 2 receiving care according to current guidelines. In arm 3 bone marrow testing and whole-body low-dose CT (WBLDCT) was offered to all participants. SMM was defined as 10-60% bone marrow plasma cells on smear or trephine biopsy and/or M-protein in serum ≥3 g/dL, in the absence of myeloma defining events. Participants in arm 3 were used to estimate the prevalence of SMM as bone marrow biopsy was performed in all participants of that arm when possible. The age- and sex-specific prevalence was determined with a fitted function of age and sex, and interaction between those. Diagnosis at baseline evaluation of the individuals in the study was used to define the point prevalence of SMM. Results Of the 148,704 individuals over 40 years of age in Iceland, 75,422 (51%) were screened for M-protein and abnormal free light chain ratio. The 3,725 with abnormal screening were randomized to one of the three arms, and bone marrow sampling was performed in 1,503 individuals. A total of 180 patients were diagnosed with SMM, of which 109 (61%) were male and the median age was 70 years (range 44-92). Of those, a total of 157 (87%) patients had a detectable M-protein at the time of SMM diagnosis with a mean M-protein of 0.66 g/dL (range 0.01-3.5). The most common isotype was IgG in 101 (56%) of the patients, 44 (24%) had IgA, 2 (1%) had IgM, and 5 (3%) had biclonal M-proteins. A total of 24 (13%) patients had light-chain SMM. Four patients (2%) had a negative SPEP and normal FLC analysis at the time of SMM diagnosis despite abnormal results at screening. A total of 131 (73%) patients had 11-20% bone marrow plasma cells at SMM diagnosis, 32 (18%) had 21-30%, 9 (5%) had 31-40%, and 8 (4%) had 41-50%. Bone disease was excluded with imaging in 167 (93%) patients (MRI in 25 patients, WBLDCT in 113 patients, skeletal survey in 27 patients, FDG-PET/CT in 1 patient), 13 patients did not have bone imaging performed because of patient refusal, comorbidities, or death. According to the proposed 2/20/20 risk stratification model for SMM, 116 (64%) patients were low-risk, 47 (26%) intermediate-risk, and 17 (10%) high-risk. A total of 44 (24%) had immunoparesis at diagnosis. Using the PETHEMA SMM risk criteria on the 73 patients who underwent testing with flow cytometry of the bone marrow aspirates; 39 (53%) patients were low-risk, 21 (29%) patients were intermediate-risk, and 13 (18%) patients were high-risk. Out of the 1,279 patients randomized to arm 3, bone marrow sampling was performed in 970, and 105 were diagnosed with SMM (10.8%). The prevalence of SMM in the total population was estimated to be 0.53% (95% CI: 0.49-0.57%) in individuals 40 years of age or older. In men and women, the prevalence of SMM was 0.70% (95% CI: 0.64-0.75%) and 0.37% (95% CI: 0.32-0.41%), respectively, and it increased with age in both sexes (Figure). Summary and Conclusions Based on a large (N&gt;75,000) population-based screening study we show, for the first time, that the prevalence of SMM is 0.5% in persons 40 years or older. According to current risk stratification models, approximately one third of patients have an intermediate or high risk of progression to MM. The high prevalence of SMM has implications for future treatment policies in MM as treatment initiation at the SMM stage is likely to be included in guidelines soon and underlines the necessity for accurate risk stratification in SMM. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Janssen: Other: IDMC; Celgene: Research Funding; Takeda: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

scholarly journals The Poor Prognosis of High Cytogenetics Abnormalities in Elderly Patients Might be Overcome with an Optimized Total Therapy Approach Including Proteasome Inhibitors, Imid's Compounds and Alkylators

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5688-5688 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Norma C Gutierrez ◽  
María-Luisa Martín ◽  
Joaquín Martínez-López ◽  
Miguel-T Hernandez ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Fish Analysis ◽  
Advisory Committees ◽  
The Poor ◽  
Standard Risk

Abstract Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (CA) has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

scholarly journals Identifying a Gene Expression (GEP)-Based Model Predicting for Progression from AMM to Cmm Requiring Therapy in S0120 Patients Treated at Mirt

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2078-2078
Author(s):  
Rashid Z Khan ◽  
Christoph Heuck ◽  
Adam Rosenthal ◽  
Caleb K Stein ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Effect ◽  
M Protein ◽  
Proliferation Index ◽  
Q Value ◽  
Advisory Committees ◽  
Cut Point ◽  
Risk Of Progression

Abstract Background: The definition of high risk smoldering multiple myeloma (HR-SMM) is in flux. There are several models using serologic, bone marrow and radiologic data that predict for time to progression (TTP) to clinical myeloma (CMM). Lenalidomide and Dexamethasone in HR-SMM is reported to delay onset of end organ damage and improve overall survival, stressing the clinical utility of early intervention. We previously reported a GEP70 based score cutoff (<-0.26), when applied to the S0120 population, that improved the predictive power (R2) of standard clinical variables by 11%. The combination of GEP70 score >-0.26, serum M spike ≥3g/dL, and involved SFLC >25 mg/dL identified a subset of patients with 67% risk of progression at 2 years. With longer follow up, we now examine whether unique gene probe sets can be identified at the AMM stage that portend an earlier time to therapy (TTT). Patients and Methods: We identified 105 patients with AMM who had baseline GEP data on our S0120 protocol, after IRB approval for retrospective data review, and evaluated each of 54,675 Affymetrix gene probes for their potential to predict TTT. Probes were ranked by their q-values; we found 40 probes with q-value < 0.05 and 7 probes with q-value < 0.01; the top probe had a q-value of 0.00066. Scores based on the number of significant probes at these cut-points were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes. Results: In the GEP40 model, an optimal cut-point for risk of progression was identified at 7.05. The 3-year TTT probability was 83% with scores >=7.05 and only 11% for patients with values under this threshold (Figure 1A; p<0.0001). TTT probabilities also differed markedly when examined by score quartiles, attesting to a gene dose effect (Figure 1B). For the Q1 subset of 26 patients, only 4% required therapy in 3 years. Univariate Cox analysis for TTT yielded age>65 (HR: 2.3), Albumin<3.5g/dl (HR: 3.7), M-protein>3g/dl (HR: 4.99), BM plasmacytosis>=10% (HR: 12.2), GEP70>-0.26 (HR: 3.4), GEP40>=7.05 (HR: 16.41), GEP proliferation index > -0.26 (HR: 2.8), GEP PR subgroup (HR: 9.4) and GEP PolyPC >11.6 (HR: 0.22) to be significant. In the multivariate model, GEP40>=7.05 was the most significant (HR: 13.7), followed by SFLC>10mg/dl and M-protein>3g/dl. GEP40 score positively correlated with proliferation index (R: 0.804), and showed no correlation with GEP polyPC score (R: -0.156). Next, we used recursive partitioning on data from 72 patients and identified 23 patients with GEP40 score >=7.05 of whom 22 suffered TTT by 3 years (87%). Among the remaining 49 patients with GEP40 <7.0325, a further cut-point of age >59 years identified 24 patients, of whom 11 suffered progression with a 3 year TTT estimate of 25%. In the 25 patients with GEP40 <7.0325 and age <59 years, no patient progressed to CMM, with a 3 year TTT estimate of 0%. The GEP7 and GEP1 models, at optimal cut-offs, yielded equivalent positive and negative predictive values compared to the GEP40 model, albeit with less power. Conclusion:Gene expression profiling can readily identify a subset of AMM patients who are high risk for progression to CMM. Further refinement of GEP based risk scoring can be achieved by combining clinical and correlative variables to select the super HR-SMM for intervention trials. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dhodapkar:Celgene: Research Funding. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

Clinical Course and Prognosis of Smoldering (Asymptomatic) Waldenstrom’s Macroglobulinemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2709-2709
Author(s):  
Robert Kyle ◽  
Joanne Benson ◽  
Dirk Larson ◽  
Terry Therneau ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Serum Albumin ◽  
Hemoglobin Level ◽  
M Protein ◽  
Waldenström’S Macroglobulinemia ◽  
Monoclonal Protein ◽  
Risk Of Progression ◽  
Lymphoplasmacytic Infiltration ◽  
Waldenström's Macroglobulinemia

Abstract Smoldering Waldenström’s Macroglobulinemia (SWM) is defined as a serum IgM monoclonal protein ≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration but no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity. Forty-eight patients with SWM were identified at Mayo Clinic from 1974 to 1995. Patients with a diagnosis of chronic lymphocytic leukemia or lymphoma or history of any antineoplastic therapy before diagnosis of SWM were excluded. The median age at diagnosis was 63 years (range 39–87 years). Only one patient (2%) was &lt; 40 years of age, but 14 percent were &lt; 50 years old. Thirty-two (67%) were men, and 16 (33%) were women. At diagnosis, hepatomegaly was noted in 10%, splenomegaly in 4%, and lymphadenopathy in 8%. The initial hemoglobin level ranged from 8.7 to 15.3 g/dL (median 11.8). The anemia in all 4 patients with an initial hemoglobin &lt; 10 g/dL was due to other causes such as myelodysplastic syndrome, bronchopleural fistula, Barrett’s esophagus, and Coumadin administration. The initial leukocyte level ranged from 3.2 to 13.2 × 109/L (median 5.7), and platelets ranged from 101 to 578 × 109/L (median 285.5). Only one patient had a serum creatinine &gt; 2.0 mg/dL and it was unrelated to SWM. The serum monoclonal protein level at the time of diagnosis ranged from 1.5 to 5.2 g/dL (median 3.3); 12 (25%) were &lt; 3 g/dL, while 10 (21%) were ≥4 g/dL. IgM kappa accounted for 75%, IgM lambda 21%, and 2 (4%) were biclonal. Immunofixation of the urine was positive in 97% (kappa 80%, lambda 17%, indeterminate 3%) of those tested. The size of the urine M protein ranged from unmeasurable to 1.4 g/24h (median 0.04 g/24h). Serum albumin ranged from 2.5 to 4.3 g/dL (median 3.6). Five patients (10%) had an albumin value &lt; 3 g/dL. Ten (26%) had a reduction of 1 uninvolved immunoglobulin, while 8 (21%) had a reduction of both IgG and IgA immunoglobulins. Lymphoplasmacytic infiltration of the bone marrow ranged from 3% to 80%, (median 30%). Three (6%) had less than 10% infiltration, while 13 (27%) had 50% or greater infiltration. The 48 patients were followed for a total of 292 (range 0.5 to 22.6 years; median 3.7) person-years, during which time 33 progressed to symptomatic WM and one to AL amyloidosis. The expected number of WM based on the SEER data was 0.004 cases. Thus, relative risk of progression to WM was increased 7,586-fold (95% CI, 5,083 to 10,373). The median time to progression was 4.6 years. The absolute risk of progression to WM was 6% at 1 year, 39% at 3 years, and 55% at 5 years. The median survival after progression to symptomatic WM was 5.1 years. Seventy-three percent of patients died, indicating a robust follow-up. We evaluated sex, hemoglobin level, size of serum M protein, reduction of uninvolved immunoglobulins, presence of urinary monoclonal light chains, serum albumin level, and the proportion of lymphoplasmacytic infiltration of the bone marrow as risk factors for progression. Significant risk factors for progression with univariate analysis included size of the serum M protein, hemoglobin level, reduction in uninvolved immunoglobulins, and degree of bone marrow lymphoplasmacytic cell infiltration. Multivariate modeling revealed that the size of the M protein and the degree of bone marrow infiltration were the most important risk factors. We conclude that smoldering WM is a distinct clinical entity that needs to be differentiated from IgM MGUS and symptomatic Waldenstrom’s Macroglobulinemia.

scholarly journals A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1649-1649
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Michael Z. Koontz ◽  
Jeffrey V. Matous ◽  
Andrew J. Yee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Bone Marrow Plasma

Abstract Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as &lt;10% bone marrow plasma cells and &lt;3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of &lt;0.26 or &gt;1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio &lt;0.125 or &gt;8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Prediction of Progression of Smouldering into Therapy Requiring Multiple Myeloma By Easily Accessible Clinical Factors [in 527 Patients]

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2071-2071 ◽  
Author(s):  
Roman Hajek ◽  
Viera Sandecka ◽  
Anja Seckinger ◽  
Ivan Spicka ◽  
Vlastimil Scudla ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Plasma Cells ◽  
Risk Model ◽  
Validation Cohort ◽  
M Protein ◽  
Tumour Mass ◽  
Clinical Parameters ◽  
Clinical Factors ◽  
Risk Of Progression

Abstract Background Several models predict the progression from smouldering multiple myeloma (SMM) to therapy requiring multiple myeloma (MM). Three models comprise the assessment of tumour mass by different clinical parameters to stratify in risk groups: 1) the Mayo Clinic model uses bone marrow plasma cells percentage (BMPC) and serum monoclonal protein (M-protein), 2) the PETHEMA model uses immunoparesis and the percentage of abnormal plasma cells by flow cytometry, 3) the Heidelberg group assesses tumour mass by either the percentage of malignant plasma using iFISH or the Mayo assessment depicted above, and the presence of chromosomal aberrations associated with adverse prognosis. Besides tumor mass, they find the number of focal lesions in whole body MRI (>1) as strong prognostic factor. Aim To assess a combination of easily accessible clinical factors identifying patients at ≥ 80% risk of progression to MM requiring treatment within two years from the diagnosis of SMM. Methods Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic for 287 SMM patients enrolled from May 2007 to June 2013. A cohort comprising 240 SMM patients from Heidelberg, Germany was used for validation (Neben et al. JCO 2013). Results During the follow up period (median 2.4 years; range 0.6 - 18.0) progression to MM was observed in 51.9% (149/287) patients in the study cohort, representing 16% risk of progression at 1 year, 31.2% at 2 years, 54.8% at 5 years and 73.4% at 10 years. In univariate analysis factors significantly associated with progression were as follows: serum free light chain (iFLC/uFLC) ratio > 30 (HR 2.4 [95% CI: 1.4 - 4.1]; p< 0.001) plasma cell infiltration in bone marrow cytology ≥ 15% (HR 2.1 [1.5-3.0]; p< 0.001), immunoparesis (HR 2.0 [1.3-2.9]; p< 0.001), M - protein concentration ≥ 2.3 g/dL (HR 2.00 [1.4-2.7]; p< 0.001), beta2 microglobulin ≥ 2.0 mg/l (HR 1.8 [1.2-2.7]; p= 0.001), and thrombocyte count ≤ 250 x 109/l (HR 1.7 [1.1-2.4]; p= 0.005). In multivariate analysis, 3 parameters showed independent predictive value (immunoparesis, serum M-protein quantity ≥ 2.3 g/dL and iFLC/uFLC > 30). Combining these factors, we proposed a new risk model for SMM patients (CMG model). The risk of progression from SMM to MM at 2 years was 18.5%, 20.9%, 41.9% and 78.7% if 0 (reference group), 1, 2 or 3 risk factors are present (p< 0.001) (Figure 1) with HR of 1.5 [0.7-2.9]; p=0.283, 2.5 [1.3-5.0]; p= 0.008, 6.8 [3.0-15.2]; p<0.001, n=139), respectively. The CMG model was validated on 240 SMM patients from Heidelberg published in 2013. The risk of progression from SMM to MM at 2 years was 5.3%, 7.5%, 44.8% and 81.3% if 0, 1, 2 or 3 risk factors were present, respectively (p< 0.001) (Figure 1) with HR of 4.2 ([0.5-36.1]; p=0.189), 21.5 ([2.9-159.1]; p= 0.003, HR 38.6 [4.7- 317.7]; p<0.001, n=113). Conclusion We propose and validate a new risk model for SMM patients with prediction of 80% (78.7% on our CMG model; 81.3% on data from Heidelberg) risk of progression to therapy requiring myeloma within two years based on easily accessible clinical parameters (CMG model). The model could especially be used to identify high-risk patients to be included in early treatment clinical trials. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n°278570 and “OverMyR”, as well as the Deutsche Forschungs-Gemeinschaft (DFG) SFB/TRR79. Figure 1: CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Figure 1:. CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Disclosures Seckinger: Novartis: Research Funding.

Efficacy and Safety of Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Endeavor (NCT01568866)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 30-30 ◽  
Author(s):  
Wee-Joo Chng ◽  
Hartmut Goldschmidt ◽  
Meletios A. Dimopoulos ◽  
Philippe Moreau ◽  
Douglas Joshua ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Plasma Cells ◽  
Risk Group ◽  
High Risk Group ◽  
Advisory Committees ◽  
Risk Status ◽  
Grade 3 ◽  
Standard Risk ◽  
Support Research

Abstract Introduction: Single-agent carfilzomib has previously shown activity in patients with relapsed and refractory multiple myeloma (MM) who have high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). In the randomized phase 3 study ENDEAVOR (NCT01568866; N=929), carfilzomib plus dexamethasone (Kd) demonstrated a clinically meaningful and statistically significant 2-fold improvement in median progression-free survival (PFS) compared with bortezomib plus dexamethasone (Vd; 18.7 vs 9.4 months; hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.44-0.65; P<.0001) (Dimopoulos et al, J Clin Oncol 2015;33:abstr 8509; Dimopoulos et al, Haematologica 2015;100[s1]:abstr LB2071). Herein we present results of a preplanned subgroup analysis of the efficacy and safety of Kd vs Vd in the ENDEAVOR study based on baseline cytogenetic risk status. Methods: Adult patients with relapsed MM (RMM; 1-3 prior lines of therapy) were eligible. Patients in the Kd arm received carfilzomib (30-minute intravenous [IV] infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Patients in the Vd arm received bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection) on days 1, 4, 8, and 11 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Cycles were repeated until disease progression, withdrawal of consent, or unacceptable toxicity. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), rate of grade ≥2 peripheral neuropathy (PN), and safety. Fluorescence in situ hybridization was used to assess cytogenetic risk status. The high-risk group was defined as those patients with the genetic subtypes t(4;14) or t(14;16) in ≥10% of screened plasma cells, or deletion 17p in ≥20% of screened plasma cells based on central review of bone marrow samples obtained at study entry; the standard-risk group consisted of patients without these genetic subtypes. Results: A total of 929 patients were randomized (Kd: 464; Vd: 465). Baseline cytogenetic risk status was well-balanced between the treatment arms (high-risk: Kd, 20.9%; Vd, 24.3%; standard-risk: Kd, 61.2%; Vd, 62.6%; unknown: Kd, 17.9%; Vd, 13.1%). Efficacy end points by baseline cytogenetic risk status are presented in the Table; Kaplan-Meier PFS curves by baseline cytogenetic risk status are shown in the Figure. Median PFS in the high-risk group (n=210) was 8.8 months (95% CI: 6.9-11.3) for Kd vs 6.0 months (95% CI: 4.9-8.1) for Vd (HR: 0.646; 95% CI: 0.453-0.921). Median PFS in the standard-risk group (n=575) was not estimable for Kd (95% CI: 18.7-not estimable) vs 10.2 months (95% CI: 9.3-12.2) for Vd (HR: 0.439; 95% CI: 0.333-0.578). ORRs (≥partial response) were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ≥CR. Median DOR in the high-risk group was 10.2 months for Kd vs 8.3 months for Vd. Median DOR in the standard-risk group was not estimable for Kd vs 11.7 months for Vd. Grade ≥3 adverse events (AEs) were reported at higher rates with Kd vs Vd in the high- and standard-risk groups (70.1% vs 63.1% and 73.9% vs 68.3%). Rates of grade ≥3 AEs of interest by baseline cytogenetic risk status are shown in the Table. Grade ≥2 PN was reported at lower rates with Kd vs Vd in the high-risk group (3.1% vs 35.1%; odds ratio: 0.059; 95% CI: 0.018-0.198) and also in the standard-risk group (6.4% vs 33.4%; odds ratio: 0.135; 95% CI: 0.079-0.231). Conclusion: As expected, median PFS for patients with high-risk cytogenetics was lower compared with the overall population; however, patients treated with Kd had a clinically meaningful improvement in PFS compared with Vd in patients with high- or standard-risk cytogenetics. Higher response rates, a greater depth of response, and longer DOR were also observed with Kd vs Vd across cytogenetic subgroups. Kd had a favorable benefit-risk profile in patients with high-risk relapsed MM, and was superior to Vd, regardless of baseline cytogenetic risk status. Disclosures Goldschmidt: BMS: Consultancy, Research Funding; Amgen, Takeda: Consultancy; Onyx: Consultancy, Honoraria; Janssen, Celgene, Novartis: Consultancy, Honoraria, Research Funding; Chugai, Millennium: Honoraria, Research Funding. Dimopoulos:Onyx: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Moreau:Novartis, Janssen, Celgene, Millennium, Onyx Pharmaceuticals: Consultancy, Honoraria. Joshua:Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Facon:Onyx/Amgen: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Takeda: Research Funding. Niesvizky:Celgene, Millennium, Onyx: Consultancy, Speakers Bureau. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Rosinol:Celgene, Janssen: Honoraria. Gaidano:Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory Boards; Celgene: Research Funding. Weisel:Takeda: Other: Travel Support; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Noxxon: Consultancy. Gillenwater:Onyx, Amgen: Employment, Other: Stock. Mohamed:Onyx/Amgen: Employment, Other: Stock. Feng:Amgen/Onyx: Employment, Equity Ownership. Hájek:Janssen-Cilag: Honoraria; Celgene, Amgen: Consultancy, Honoraria.

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