Pursuing the curative blueprint for early myeloma

Treatment philosophies in multiple myeloma (MM) debate the relative merits of achieving the deepest possible remissions (“curative” doctrine) vs sequential delivery of antimyeloma agents (“control” doctrine). In this paper, we highlight the relevant strengths of each doctrine in the context of modern patient selection strategies, fresh biological insights on MM pathogenesis, agents with improved safety profiles, and emerging molecular and imaging tools. Paramount fundamental questions remain unanswered that require an intense research focus as we pursue a cure for this devastating disease

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection

Autologous Hematopoietic Stem Cell Transplantation Overcomes Primary Refractory Disease in Multiple Myeloma Patients Treated with Novel Agents

Abstract Introduction: Autologous hematopoietic stem cell transplantation (Auto HSCT) has been shown to prolong progression free (PFS) and overall survival (OS) in patients with multiple myeloma (MM), with the depth of response pre-transplant previously correlated with PFS, but not OS. Even in patients receiving proteasome inhibition and immunomodulatory agents as induction, up to 25% of newly diagnosed patients achieve less than a partial response (PR). We aimed to evaluate outcomes after Auto HSCT for patients with primary refractory MM. Methods: Between 1/2009 and 12/2012, we identified 95 newly diagnosed symptomatic MM patients treated at our institution with novel agent induction regimens and upfront Auto HSCT. Based on IMWG criteria, patients were separated into those achieving >= PR (CR, VGPR, PR) and those who are primary refractory (PrRef) as defined by stable or progressive disease (SD/PD) to first line therapy. Characteristics were compared by the Fisher's Exact test. PFS and OS were calculated in a landmark analysis from transplant and estimated by Kaplan-Meier methods and compared by the log rank test. Results: Sixteen patients (17%) had PrRef disease, with a median age of 53 vs 59 yrs in those who achieved >=PR (p=0.04). Demographic and clinical characteristics were otherwise not statistically different between the two groups: 56 vs 65% were male; 69 vs 80% Caucasian; 69 vs 48% had ISS Stage I disease with 19 vs 14% having high risk cytogenetics; 81 vs 84% had lytic lesions; and 31 vs 51% had extramedullary disease at diagnosis in PrRef pts vs >PR pts, respectively. All patients received induction regimens including either bortezomib (44 vs 38%), lenalidomide (31 vs 24%), or both (25 vs 37%) (p=0.68). Compared with 32% of >=PR pts, 94% of the PrRef pts were treated with additional therapy prior to Auto HSCT (p= PR patient. Response to Auto HSCT was a 38 vs 58%, 25 vs 25%, 38 vs 14%, and 0 vs 4% for CR, VGPR, PR, and SD/PD, in PrRef vs responding pts respectively (p=0.19). Maintenance therapy, primarily with lenalidomide, was given to 69 vs 78% (p=0.52). Median PFS from transplant was 41 months (95% CI 16 - not reached ) in PrRef pts compared to 53 months, (95%CI: 31 - not reached) in >=PR pts (p=0.51). With a median follow-up of 36.5 months (range 9.5-63 months) in surviving patients, median OS from transplant was not reached in either group (p=0.77)(Figures 1 and 2). For the PrRef pts, 3-yr OS from transplant was 77% (95%CI 43-92%) compared to 87% (95%CI 77-93%) in >=PR pts. Conclusion: A small portion of MM patients have primary refractory disease after induction therapy with bortezomib and lenalidomide. Demographic and disease characteristics, other than age, were not able to differentiate these patients. However, Auto HSCT was an effective therapy regardless of response to novel agent based induction therapy. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Hassoun: Celgene: Research Funding; Novartis: Consultancy; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Efranat: Consultancy; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Research Funding. Landgren:BMJ Publishing: Honoraria; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Onyx: Consultancy. Landau:Onyx: Honoraria, Research Funding; Spectrum Pharmaceuticals: Honoraria; Takeda: Research Funding; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Janssen: Consultancy. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding

Comparison of Standard Assays (Serum Immunofixation and Protein Electrophoresis) with Hevylite Assay in Patients with Multiple Myeloma

Abstract Background : TheHevylite assay (HLC Assay) is a novel assay using antibodies that recognize unique conformational epitopes presented by the association of the heavy and light chain constant regions of intact immunoglobulins (Ig) allowing quantitative measurement of each Ig class concentration and generating ratios for each pair (e.g. IgGK/IgGL). Recent studies indicate that HLC Assay can enhance the ability to detect and quantify monoclonal Ig, potentially providing greater sensitivity for detection of minimal residual disease or early relapse after treatment and providing a prognostic indicator of progression free survival (Ludwig, H. et al. Leukemia (2013) 27, 213-219; Kraj, M. et al. Adv Clin Exp Med 2014, 23, 1, 127-133). While HLC Assay could simplify and enhance the assessment of monoclonal protein response in multiple myeloma (MM), its utility as compared to standard assays (SA) (Serum Protein Electrophoresis (SPEP) and Immunofixation (IF)) is not well established. The goal of this retrospective study was to compare the performance of these tests in patients with MM seen at Memorial Sloan Kettering Cancer Center. Methods : We have previously reported on the patterns of relapse and/or progression (R/POD) in 179 patients with MM transplanted between 2001 and 2009 at MSKCC and determined the precise date of R/POD based on IMWG standard clinical criteria using serum and urine PEP and IF, as well as Free Light Chain Assay (FLCA) (Zamarin, Bone Marrow Transplant, 2013). Serum samples from 63 of these patients, collected at the time of R/POD and/or at time points preceding R/POD were analyzed by HLC Assay and compared to results obtained by SA. Results : Among the 63 patients, 22 had IgA and 41 had IgG isotype. Overall, 207 samples were available for all 63 patients, including 72 IgA and 135 IgG samples. Figure 1 shows the concordance of Hevylite ratio (on the Y-axis) with the results obtained by SA (on the X-axis), for IgA and IgG samples, respectively. These graphs reveal an excellent association between HLC Assay and SA results in the IgA samples: all IgA samples revealing an M spike by SPEP had an abnormal HLC ratio even for low M spike levels (between 0 and 0.5 g/dL). Among IgA samples with a monoclonal band detectable by IF, 43 out of 48 samples also had an abnormal ratio by HLC Assay; and among samples with no detectable band by IF, 18 out of 24 had a normal ratio by HLC Assay (sensitivity 90%, specificity 75%, p< 0.001) (Table 1, Panel 1). Interestingly, when looking at samples taken prior to relapse in IgA patients having achieved CR, HLC Assay was abnormal in 4 out of 7 patients while SA was still reported as normal. In contrast, the lack of association between the SA and HLC Assay is striking for the IgG samples, with poor sensitivity for the HLC Assay to detect monoclonal gammopathies with M spikes below 1 g/dL on SPEP. Among IgG samples with a monoclonal band detectable by IF, only 48 out of 89 samples also had an abnormal ratio by HLC Assay; while among samples with no detectable band by IF, 40 out of 46 had a normal ratio by HLC Assay (sensitivity 53% and specificity of 86% , p < 0.001) (Table 1, Panel 2). Conclusions: Although retrospective, this analysis suggests the following: 1) HLC Assay may be more sensitive than IF or SPEP in patients with IgA disease, as it can detect an abnormal HLC ratio at a time prior to relapse by SA, when IF and SPEP are still normal; 2) HLC Assay appears to be less useful in IgG patients, as its sensitivity in these patients appears much lower than IF; 3) There is a need for further detailed analysis on larger prospective cohorts to test the utility of HLC Assay compared to SA in the management of multiple myeloma patients, especially those with IgA disease. Figure 1 Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 1. Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 2 Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Figure 2. Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Disclosures Hassoun: Celgene: Research Funding; Binding Site: Research Funding; Novartis: Consultancy; Takeda: Consultancy, Research Funding. Kazunori:Binding Site: Research Funding. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korde:Medscape: Honoraria. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; BMS: Honoraria; Medscape Myeloma Program: Honoraria; Merck: Honoraria; Celgene: Honoraria, Research Funding

Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

© 2015 eLife Sciences Publications Ltd. All rights reserved.Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisit

Biomarkers of Cardiotoxicity Among Multiple Myeloma Patients Subsequently Treated with Proteasome Inhibitor Therapy

Abstract BACKGROUND: Cardiovascular (CV) events are a known complication to proteasome inhibitor therapy in myeloma. Underlying mechanisms are unknown. We recently completed an investigator initiated, single institution Phase II study of high dose carfilzomib (56mg/m2) in patients with relapsed/refractory MM (NCT01351623). Among 42 response evaluable patients, 11 patients (25%) developed treatment-emergent heart failure of any grade, and 5 patients (11%) developed severe heart failure requiring mechanical ventilation. We undertook a study to identify potential biomarkers that may point to underlying mechanisms of CV events among multiple myeloma patients treated with carfilzomib therapy. METHODS: We performed a nested case-control study with 7 patients who experienced a CV event on our high dose carfilzomib study and had pre-treatment (baseline) plasma stored and 19 case matched controls treated on the same study who did not have a CV event. We screened for 90 proteins known to be associated with CV disease using O-linked glycosylation. We used the Proseek Multiplex CVD I 96x96 platform which is based on the Proximity Extension Assay (PEA) technique. PEA is a 96-plex immunoassay that allows high throughput detection of protein biomarkers in liquid samples. For each biomarker, a matched pair of antibodies linked to unique oligonucleotides (proximity probes) binds to the respective protein target. Upon binding, the unique proximity probes can hybridize to each other and subsequently be detected and quantified by real-time PCR. Mean biomarker levels were compared using a t-test. False discovery rate (FDR) was used for multiple comparisons adjustment. RESULTS: Using samples collected prior to initiation of carfilzomib therapy, in an agnostic statistical model we identified the following four proteins to have altered levels in myeloma patients who developed CV events (p=0.002-0.004, unadjusted; p=0.089, after FDR correction): matrix metalloproteinase-1 (MMP-1, heparin-binding EGF-like growth factor (HB-EGF), TNF-related apoptosis-inducing ligand (TRAIL), and myoglobin (MB). Myeloma patients who developed CV events had 37% lower MMP-1, 15% lower MB, and 4% lower HB-EGF, while TRAIL was 7% higher in patients who developed CV events. Matrix metalloproteinases are a family of proteolytic enzymes responsible, among other functions, for myocardial extracellular protein degradation. Interestingly, several MMP species, including MMP-1, have been identified within the human myocardium and are thought to be dysregulated in congestive heart failure. HB-EGF is a mitogenic and chemotactic glycoprotein that is essential for maintaining normal cardiac function and is known to play an important role in myocardial remodeling. CONCLUSIONS: We found that there was a trend towards lower MMP-1, HB-EGF, and MB levels and higher TRAIL levels in patients with CV events while receiving proteasome therapy. MMP-1 appears to be the most promising potential biomarker based on our data. Our study supports further investigation of these proteins as potential biomarkers for patients at risk of CV events when treated with carfilzomib. Table 1. CV event No CV event N=7 N=19 CKD Proteins1 Mean (SD) Mean(SD) Unadjusted P-value Adjusted P-value MMP_1 1.7 (0.5) 2.7 (0.9) 0.002 0.089 HB_EGF 6.9 (0.2) 7.2 (0.3) 0.004 0.089 TRAIL 8 (0.3) 7.5 (0.5) 0.004 0.089 MB 5 (0.5) 5.9 (0.8) 0.004 0.089 HSP_27 2.2 (0.3) 2.7 (0.8) 0.032 0.528 PDGF_subunit_B 4 (0.7) 5 (1.5) 0.036 0.528 CD40_L 3.4 (0.6) 4.2 (1.2) 0.042 0.533 EGF 3.7 (0.9) 4.7 (1.4) 0.053 0.592 CX3CL1 5.9 (0.2) 5.6 (0.6) 0.092 0.895 TRAIL_R2 4.2 (0.4) 4.6 (0.6) 0.101 0.895 1. Proteins are listed based on the p-value associated with the difference between patients who did and did not have CV events, with lowest p-value on the top. The top 10 biomarkers are shown. Disclosures Ekman: Olink Bioscience: Employment. Grundberg:Olink Bioscience: Employment. Hassoun:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Lesokhin:Aduro: Consultancy; Efranat: Consultancy; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Landau:Janssen: Consultancy; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Landgren:Onyx: Honoraria; Celgene: Honoraria; BMJ Publishing: Consultancy; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Honoraria; Onyx: Research Funding; Medscape: Consultancy; Medscape: Honoraria; BMJ Publishing: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy

No Risk of Arterial or Venous Thrombosis in Monoclonal Gammopathy of Undetermined Significance: Results from a Population-Based Study

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma (MM) and other lymphoproliferative disorders. Patients with MM have an increased risk of venous and arterial thrombosis. Results from previous studies have also shown an increased risk of thrombosis in MGUS. However, these studies have been performed on clinically established cohorts, and no previous study has examined the risk of thrombosis in light chain MGUS (LC-MGUS). Methods We performed a population-based study on the longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Through screening all participants with free light chain analysis and serum protein electrophoresis, MGUS and LC-MGUS were identified in 299 and 52 individuals, respectively. The outcome was first incidence/occurrence of venous or arterial thrombosis, as diagnosis or as cause of death. Information on outcomes was supplemented by health care records, available from nine years prior to study baseline and for a median follow-up time of 8.8 years. Through logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate history of arterial and venous thrombosis, respectively, at study baseline. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% CIs for the risk of first incidence of thrombosis during follow-up. Results A history of any thrombosis during the nine years prior to diagnosis was present in 30 (10.0%) of individuals with MGUS, 13 (25.0%) of individuals with LC-MGUS, and 643 (12.0%) of individuals without MGUS. In a model adjusting for age, sex, smoking, serum cholesterol levels, diabetes, hypertension, and family history of thrombosis, the odds of having had a thrombosis was not significantly different for neither MGUS (OR = 0.75, 95% CI 0.50-1.12) nor LC-MGUS (OR = 1.81, 0.92-3.58), compared to those without MGUS. During a median follow-up time of 8.8 years, 80 (26.8%) of individuals with MGUS, 14 (26.9%) of individuals with LC-MGUS, and 1,344 (25.0%) of individuals without MGUS were diagnosed with thrombosis. Individuals with MGUS and with LC-MGUS had no increased risk of arterial thrombosis, when adjusted for age, sex, cholesterol, diabetes, hypertension, smoking, and family history of thrombosis (HR 1.04, 0.82-1.32). Similarly, no increased risk was found in MGUS or LC-MGUS for venous thrombosis, in a model adjusted for age, sex, body mass index, and previous or current cancer (HR 0.89, 0.41-1.89). Excluding individuals with a diagnosis of thrombosis occurring before baseline, or adjusting for a personal history of thrombosis, did not affect the results. Summary and conclusions In this large, population-based, screening cohort study, we found no increased risk of arterial or venous thrombosis in MGUS. A history of thrombosis was more common in individuals with LC-MGUS, which might be an effect of higher age in LC-MGUS individuals. To our knowledge, this is the first study to investigate risk of thrombosis in LC-MGUS. The results from our screened study contradict previous findings from clinically established cohorts. Future work is needed to better understand observed differences between studies and across populations. For example, potential underlying factors may include aggregation of underlying comorbidities in clinically diagnosed MGUS patients, and biological variations (shared germline genetic susceptibility) by ethnic groups. Table. Risk of thrombosis in individuals with MGUS and LC-MGUS, compared to individuals without MGUS. MGUS LC-MGUS No MGUS No. HR (95% CI) No. HR (95% CI) No. HR (95% CI) Any thrombosis* 80 (26.76%) 1.01 (0.80-1.26) 14 (26.92%) 1.13 (0.80-1.26) 1,344 (25.02%) 1.00 (Reference) Arterial thrombosis† 76 (25.42%) 1.04 (0.82-1.32) 14 (26.92%) 1.16 (0.67-2.01) 1,240 (23.08%) 1.00 (Reference) Venous thrombosis†† 7 (2.34%) 0.89 (0.41-1.89) 0 (0.0%) - 151 (2.81%) 1.00 (Reference) *Results adjusted for age and sex. † Results adjusted for age, sex, smoking, hypertension, cholesterol, diabetes, and family history of arterial thrombosis. †† Results adjusted for age, sex, body mass index, and previous or current cancer. MGUS: monoclonal gammopathy of undetermined significance, LC-MGUS: light-chain monoclonal gammopathy of undetermined significance. HR: hazard ratio, CI: confidence interval. Disclosures Landgren: Celgene: Consultancy; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Consultancy; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; BMJ Publishing: Honoraria; Onyx: Consultancy; Medscape: Consultancy

Immunophenotypic Evidence for Reactive Polyclonal Marrow Plasmacytosis in Multiple Myeloma Patients Receiving Long-Term Lenalidomide Therapy

Abstract Introduction: Maintenance therapy with lenalidomide (LEN) is considered standard of care in the US, supported by meta analysis showing that LEN maintenance is associated with significantly longer progression free survival (PFS) and overall survival (OS). In a previously reported study of MM patients (pts) treated with extended courses of LEN, we have described a polyclonal Ig and FLC elevation exceeding the upper limit of normal (up to 3-4 X the ULN) and associated with striking polyclonal bone marrow (BM) plasmacytosis (up to 20% of plasma cells (PCs)), occurring with a relatively high frequency (20% of pts) and associated with better outcome (Zamarin, Leukemia, 2013). Importantly, we cautioned about the risk of misinterpretation of this polyclonal Ig response and plasmacytosis. Since Immuno-histochemical staining (IHS) may often be an unreliable tool to distinguish between a reactive polyclonal plasmacytosis from monoclonal disease, especially when the percentage of PCs in the BM is relatively low (5 -15%), we aimed at confirming the polyclonal nature of this often unrecognized and paradoxical response to prolonged LEN exposure, and at validating the important role of BM assessment by flow cytometry (FACS) in this setting. Methods: Pts analyzed in this study were enrolled at MSKCC on three randomized, first line therapy, clinical trials (NCT01109004, NCT01208662, and NCT00807599). All pts were kept on LEN maintenance until POD, toxicity, or major event. BM aspirate and biopsy with IHS were performed as per standard of care. Eight-fluorochrome FACS method (minimum of 1 x 106 cells) was used for 2014 samples employing a surface marker cocktail (CD117 PC5.5, CD19 BV421, CD138 APC, CD56 PC7, CD45 APC-H7, CD38 BV510) and cytoplasmic Kappa FITC/Lambda PE staining. Ten-fluorochrome (minimum of 5 x 106 WBCs) method was used in 2015 and performed employing a surface marker cocktail (CD117 PC5.5, CD19 PC7, CD138 APC, CD56 APC-R700, CD45 APC-H7, CD81 Pacific Blue, CD38 BV510, CD27 BV605) and cytoplasmic Kappa FITC/Lambda PE staining. Results: Among 147 pts enrolled in the three trials, 55 achieved serologic CR after first line therapy. Of those, 46 had a BM biopsy with FACS analysis available. Among these 46 patients, bone marrow plasmacytosis as assessed by light microscopy of BM aspirate and biopsy ranged from 2% to 15% (32 pts had PCs ≤ 5%, 14 PCs > 5%). Among the 14 pts with > 5% PCs, 2 had PCs = 15%, 9 had PCs = 10%, and 3 between 6% and 9%. By FACS, 9 of 14 pts showed no clonal or phenotypically aberrant PCs. The percentage of aberrant PCs among all PCs in the other 5 pts remained low (≤7.3%). Among the 2 pts with PC = 15%, the percentage of aberrant PCs among all PCs was 0% and 7.3%. In pts with PC = 10%, the percentage of aberrant PCs among all PCs was 0% (6 pts), or ranged from 0.17% to 5.1% (3 pts). Figure 1 depicts representative pt cases with BM plasmacytosis estimated at 15% by light microscopy. PCs were gated based on CD38 and CD138 expression as well as forward and side scatter (not shown). Blue dots represent kappa LC expression; Red lambda LC. Proportion of aberrant PCs among total PCs in the sample is quantitated and shown using high sensitivity MRD detection with 10-color panel with 6-million event acquisitions. Panel A shows a pt with 15% PC in the BM with no residual disease confirming the polyclonal nature of the plasmacytosis. Panel B shows a pt with 15% PC exhibiting a low proportion of aberrant PCs (green) among a predominant background of normal polytypic PCs. In contrast, Panel C shows a pt with early relapsed disease with 15% PCs exhibiting a high proportion of aberrant PCs (99% of all PCs). Conclusions: These results confirm the common and striking polyclonal plasmacytosis (up to 15% PCs in this cohort) associated with prolonged LEN exposure, and the importance of FACS in the assessment of BM plasmacytosis in these MM pts. In the setting of current MM response criteria established by the IMWG and NCCN guidelines, mandating a BM plasmacytosis <5% in addition to negative serum and urine immunofixation for CR determination, as well as an increase in plasmacytosis from baseline by 25% with an absolute value ≥10% for determination of disease progression, FACS analysis with assessment of clonality and percentage of aberrant PCs among total PCs, becomes an essential tool to distinguish reactive polyclonal patterns from monoclonal disease persistence or recurrence. Figure 1 Figure 1. Disclosures Hassoun: Novartis: Consultancy; Binding Site: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Research Funding. Roshal:BD Biosciences: Consultancy. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Spectrum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Korde:Medscape: Honoraria. Landgren:Merck: Honoraria; BMS: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria

Risk of Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS): Results from a Population-Based Screening Study

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin. Methods The cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström's macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates. Results During follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%. In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for <35 g/L, and HR = 3.9, 95% CI 1.1-14.2 for 35-40 g/L), high M-protein concentration (HR = 4.1, 95% CI 1.2-14.0), and isotype A (HR = 5.8, 95% CI 1.6-21.0) were significantly associated with risk of progression. In a similar model for progression to multiple myeloma only, low serum albumin, high M-protein concentration, and isotype A were also significantly associated with risk of progression, although the impact of low serum albumin was greater (HR = 33.1, 95% CI 2.4-462.2 for <35 g/L, HR = 10.97, 95% CI 1.4-88.3 for 35-40). When assigning a risk score for progression where 1 point each was assigned for isotype IgA, serum albumin 15 g/L, the HRs for individuals with 1 point was 3.9 (95% CI 1.6-9.9), and for 2 points 10.02 (95% CI 2.3-43.3). No individual had 3 points. For Kaplan-Meier estimates from risk scores, see Figure. Summary and conclusions In this large, population-based screening study, we found an annual risk of progression from MGUS to lymphoproliferative disease of 1%. Low serum albumin, high M-protein concentration, and M-protein isotype A were all independent risk factors for progression. Our results are in line with results from previous studies where a low serum albumin at MGUS diagnosis also has been associated with shorter survival and/or malignant transformation. Results from our study contradict previous studies that have pointed to skewed FLC ratio as an important risk factor for progression; in our study, a skewed FLC ratio was not significantly associated with risk of progression when adjusted for other covariates. The findings in our study suggest that serum albumin is important to take into account when assessing the risk of progression for individuals with MGUS. Figure 1 Kaplan-Meier estimates for risk of progression, by risk score. Figure 1. Kaplan-Meier estimates for risk of progression, by risk score. Disclosures Korde: Medscape: Honoraria. Landgren:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding