Pilot Study To Evaluate The Prevalence Of Actionable Oncogenic Mutations In Patients With Relapsed Refractory Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 755-755 ◽  
Author(s):  
Alexander Lesokhin ◽  
Mithat Gonen ◽  
Kaitlyn Redling ◽  
Nikoletta Lendvai ◽  
Hani Hassoun ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Pilot Study ◽  
High Risk ◽  
Plasma Cell ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Small Sample ◽  
Braf V600e ◽  
Oncogenic Mutations

Abstract Background Patients with multiple myeloma (MM) have realized improved survival with the development of multi-drug combinations using immunomodulatory drugs (IMiDs), proteasome inhibitors, and alkylating agents. Nevertheless, all MM patients eventually become refractory to available therapies, underscoring the importance of identifying additional rational therapeutic targets. Recent genomic studies using exome/copy number analysis have demonstrated that, at presentation, multiple myeloma is characterized by a dominant plasma cell clone and a heterogeneous group of subclones, with resistance emerging due to altered clonal dominance driven by therapeutic selective pressure or clonal evolution through the acquisition of additional mutational events. This suggests oncogenic mutations in dominant plasma cell clones in multiply relapsed disease may not only be involved in resistance, but should also be prioritized for further clinical development. Methods We performed a pilot study by sequencing DNA from cryopreserved whole bone marrow aspirate samples obtained pre-treatment from 28 patients with newly diagnosed myeloma (Cohort A) and 27 heavily pre-treated patients enrolled on a phase II clinical study of infusional carfilzomib (NCT01351623), a selective 2nd generation proteasome inhibitor (Cohort B). Genomic DNA and total RNA was isolated from all patient samples. Adaptor ligated sequencing libraries were captured by solution hybridization using two custom baitsets targeting 374 cancer-related genes and 24 genes frequently rearranged for DNA-seq, and 258 genes frequently rearranged for RNA-seq. All captured libraries were sequenced to high depth (Illumina HiSeq), averaging 712X for DNA and >20,000,000 total pairs for RNA, to enable the sensitive and specific detection of genomic alterations. Results Median follow-up for both cohorts was 21 months (26.3m for A; 15.6m for B). Cohort B patients were treated with a median of 5 prior therapies, with 74% refractory to the non-selective 1st generation proteasome inhibitor bortezomib, 70% refractory to IMiD therapy, and 55% refractory to both therapies. 44% had high-risk cytogenetics. Responses to initial therapy in Cohort A demonstrated that 21%, 7%, and 7%, respectively harbored bortezomib--resistant, IMiD-resistant, or double-resistant myeloma at presentation. 28% of cohort A patients had high risk cytogenetics. We obtained high coverage, high quality sequence data for 54/55 cases and examined alteration prevalence in the 35 samples with sufficient plasma cell content. We observed a high frequency of mutations in the MAPK pathway, including mutually exclusive mutations in NRAS and KRAS in 48% of cases and BRAF V600E mutation in 3%. 14% of cases had TET2 frameshift/nonsense mutations or IDH2 mutations, suggesting the DNA hydroxymethylation pathway is targeted by recurrent somatic mutations in MM. Given that MEK/RAF inhibition has demonstrated efficacy in a spectrum of human tumors and that there are emerging data that epigenetic (decitabine and 5-azacytadine) and targeted (IDH2) therapies offer significant benefit in patients with TET2/IDH mutations, these data demonstrate that mutational profiling can identify patients with actionable mutations that can lead to novel therapies, including mechanism-based clinical trials. Taken together, we identified mutations in epigenetic modifiers in 41% of the patients in our cohort, including mutations in TET2/IDH, in chromatin modifying enzymes/scaffolds (ARID1A, ASXL1), and DNA methyltransferases (DNMT3A). Moreover, we identified novel mutations in DNA repair pathways (ATM, FANCA, FANCD2) and in FAT3, suggesting there are novel disease alleles, which require functional investigation for their role in MM pathogenesis. No differences in mutation frequency were found between bortezomib sensitive vs resistant MM cases present in either cohort. We did not identify mutations, which impacted progression free and overall survival in this small sample set. Conclusions We demonstrate next generation sequencing of unsorted bone marrow samples is feasible in MM and can rapidly identify actionable mutations based on genetic profiling of limited clinical isolates. These include the identification of mutations, which can guide therapeutic trials of clinically targeting specific oncogenic pathways (ex, MAPK or TET2/IDH) on an individual patient level. Disclosures: Lesokhin: Janssen Pharmaceuticals, Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Foundation Medicine, inc: Consultancy. Brennan:Foundation Medicine, Inc: Employment. Wang:Foundation Medicine, Inc: Employment. Sanford:Foundation Medicine, Inc: Employment. Brennan:Foundation Medicine, Inc: Employment. Otto:Foundation Medicine, Inc: Employment. Nahas:Foundation Medicine, Inc: Employment. Lipson:Foundation Medicine, Inc: Employment. Stephens:Foundation Medicine, Inc: Employment. Yelensky:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine, Inc: Employment. Levine:Foundation Medicine, Inc: Consultancy. Dogan:Foundation Medicine, Inc: Consultancy.

scholarly journals Novel Alkylating Agent Melflufen Displays Potent Efficacy in Plasma Cell Leukemia Samples and Other High-Risk Subtypes of Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Beau M Idler ◽  
Olivia Perez De Acha ◽  
Owen Lockerbie ◽  
Ken Flanagan ◽  
Fredrik Lehmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Plasma Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Plasma Cell Leukemia ◽  
Peptide Drug ◽  
Cell Leukemia ◽  
Plasma Cell Disorders

Introduction: Despite the progress that has been made for standard risk multiple myeloma (MM), subsets of patients with the most advanced and aggressive plasma cell dyscrasias still suffer comparatively poor outcomes. One example is plasma cell leukemia (PCL), which carries a median overall survival of under two years. For patients with PCL, response to front line therapy occurs but is often short-lived, ultimately giving way to aggressive multi-drug resistant disease and patient mortality. Thus, there is a need for the development of new strategies that improve the prognoses for these patients. Melflufen (melphalan flufenamide) is a first-in-class peptide-drug conjugate that is currently in late-phase clinical trials for multiple myeloma. This highly lipophilic agent is preferentially retained in malignant plasma cells (MPCs), where overexpressed aminopeptidases lead to trapping of the alkylator melphalan. We evaluated the anti-myeloma effects of melflufen on patient samples treated ex vivo, and found pronounced sensitivity to melflufen in most samples, with particularly potent efficacy in PCL samples. Methods: Bone marrow aspirate or peripheral blood samples were obtained from patients with plasma cell disorders after IRB approval and informed consent. Ex vivo efficacy of melflufen and melphalan were compared using our Myeloma Drug Sensitivity Testing (My-DST) platform that optimizes viability and tests the malignant cells in the context of the normal cells from their microenvironment (Walker et al, Blood Advances, 2020). In brief, mononuclear cells from patients with plasma cell dyscrasia, including MM and PCL, were isolated and cultured in triplicate wells with titrations of melphalan, melflufen or untreated controls for 48 hours. Post-treatment survival was measured by high-throughput flow cytometry with antibodies for CD138, CD38, CD45 and CD19, and a live/dead dye to discriminate viable MPCs from normal bone marrow cells. EC50 values were determined from these titrations using nonlinear regression curve fits. When the EC50 for melflufen was established in My-DST, a single dose concentration of 10 nM was used to screen patient samples and distinguish relative sensitivity or resistance. Results: Using the My-DST approach with 48 hour drug treatments, melflufen significantly decreased the viable MPC populations, whereas melphalan had little effect (Fig 1A). Concurrent titrations revealed significantly higher MPC sensitivity to melfufen (mean melphalan EC50 = not reached, mean melflufen EC50 = 22.9 nM) (Fig 1B). By comparison to another alkylator, cyclophosphamide's active metabolite has an EC50 of 3.75 µM in this assay. Response to melflufen was accentuated in 2/3 PCL samples tested (HTB-1802.1, HTB-1389.1), with the EC50 < 1nM (Fig 1B). Melflufen demonstrated toxicity in CD45 positive white blood cells, which is consistent with neutropenia observed in clinical trials (data not shown). In single dose screening studies in additional MM patient samples, 4/8 (50%) showed >20% decrease in viable MPCs after incubation with melflufen at 10 nM (Fig 1C). Overall, using those parameters for ex vivo "response" to meflufen, 3/3 patients with PCL responded, 5/6 patients with del(17p) responded, and 3/3 patients with c-MYC translocations responded (Fig 1C, italics). In addition, 3/5 samples from patients that were clinically daratumumab-refractory displayed sensitivity to melflufen. Of five samples from patients with prior exposure to alkylators, four were sensitive to melflufen. Conclusion: Overall, these data support that the peptide-drug-conjugate melflufen shows a broad efficacy across samples from patients with plasma cell disorders. Patients facing poor prognoses, including those with PCL, high-risk cytogenetics and daratumumab-refractory disease, have a great need for new treatments. Thus, the encouraging ex vivo results with melflufen in samples from these aggressive subsets support further clinical exploration. In particular, our preliminary data suggest that plasma cell leukemia patients may be exquisitely sensitive to melflufen. To follow-up these findings, we will expand the number of samples tested from PCL and other forms of high-risk MM samples. Ultimately, if the trend for accentuated sensitivity in plasma cell leukemia holds, a clinical approach for melflufen in these patients may improve outcomes for this group. Figure 1 Disclosures Lockerbie: Oncopeptides AB: Current Employment. Flanagan:Oncopeptides AB: Current Employment. Lehmann:Oncopeptides AB: Current Employment. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Mark:Takeda: Consultancy; Kayopharm: Consultancy; Bristol-Myers Squibb: Research Funding; Janssen: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Sherbenou:Oncopeptides Inc.: Research Funding.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: 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. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1907-1907
Author(s):  
Eva Sahakian ◽  
Jason B. Brayer ◽  
John Powers ◽  
Mark Meads ◽  
Allison Distler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Myeloma Cells ◽  
Peripheral Blood Plasma

Abstract The role of HDACs in cellular biology, initially limited to their effects upon histones, is now appreciated to encompass more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, and the stage of cellular differentiation. Recently, our group has demonstrated that the newest member of the HDAC family of enzymes, HDAC11, is an important regulator of IL-10 gene expression in myeloid cells (Villagra A Nat Immunol. 2009). The role of this specific HDAC in B-cell development and differentiation is however unknown. To answer this question, we have utilized a HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allows the monitoring of the dynamic changes in HDAC11 gene expression/promoter activity in B-cells at different maturation stages (Heinz, N Nat. Rev. Neuroscience 2001). First, common lymphoid progenitors are devoid of HDAC11 transcriptional activation as indicated by eGFP expression. In the bone marrow, expression of eGFP moderately increases in Pro-B-cells and transitions to the Pre- and Immature B-cells respectively. Expression of eGFP doubles in the B-1 stage of differentiation in the periphery. Of note, examination of both the bone marrow and peripheral blood plasma cell compartment demonstrated increased expression of eGFP/HDAC11 mRNA at the steady-state. These results were confirmed in plasma cells isolated from normal human subjects in which HDAC11 mRNA expression was demonstrated. Strikingly, analysis of primary human multiple myeloma cells demonstrated a significantly higher HDAC11 mRNA expression in malignant cells as compared to normal plasma cells. Similar results were observed in 4/5 myeloma cell lines suggesting that perhaps HDAC11 expression might provide survival advantage to malignant plasma cells. Support to this hypothesis was further provided by studies in HDAC11KO mice in which we observed a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Taken together, we have unveiled a previously unknown role for HDAC11 in plasma cell differentiation and survival. The additional demonstration that HDAC11 is overexpressed in primary human myeloma cells provide the framework for specifically targeting this HDAC in multiple myeloma. Disclosures: Alsina: Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baz:Celgene Corporation: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding.

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.

The Prognostic Significance of Polyclonal Bone Marrow Plasma Cells in Patients with Actively Relapsing Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1194-1194
Author(s):  
Toshi Ghosh ◽  
Wilson I Gonsalves ◽  
Dragan Jevremovic ◽  
S. Vincent Rajkumar ◽  
Michael M. Timm ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Research Funding ◽  
Plasma Cells ◽  
Labeling Index ◽  
Light Chains ◽  
Fish Cytogenetics ◽  
Kaplan Meier

Abstract Background: Prior studies suggest that the presence of >5% polyclonal plasma cells (pPCs) among total plasma cells (PCs) within the bone marrow (BM) is associated with a longer progression-free survival, higher response rates, and lower frequency of high-risk cytogenetic abnormalities in patients with newly diagnosed multiple myeloma (MM). However, the incidence and prognostic utility of this factor in patients with relapsed and/or refractory MM has not been previously evaluated. Thus, we evaluated the prognostic value of quantifying the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM. Methods: We evaluated all MM patients with actively relapsing disease (biochemical and/or symptomatic) seen at the Mayo Clinic, Rochester, from 2012 to 2013, who had BM samples evaluated by seven-color multiparametric flow cytometry. All patients had at least 24 months of follow-up from the date of flow evaluation. Cell surface antigens were assessed by direct immunofluorescence antibodies for CD45, CD19, CD38, CD138, cytoplasmic Kappa and Lambda Ig light chains, and DAPI nuclear stain. The flow cytometry data was collected using the Becton Dickinson FACSCanto II instruments that analyzed 150,000 events (cells); this data was then analyzed by multi-parameter analysis using the BD FACS DIVA Software. PCs were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. Clonal PCs were separated from pPCs based on the differential expression of CD45, CD19, DAPI (in non-diploid cases), and immunoglobulin light chains. The percentage of pPCs was calculated in total PCs detected. Survival analysis was performed by the Kaplan-Meier method and differences were assessed using the log rank test. Results: There were 180 consecutive patients with actively relapsing MM who had BM biopsies analyzed via flow cytometry as part of their routine clinical evaluation. The median age of this group was 65 years (range: 40 - 87); 52% were male. At the time of this analysis, 104 patients had died, and the 2-year overall survival (OS) rate for the cohort was 58%. The median number of therapies received was 4 (range: 1 - 15). Of these patients, 61% received a prior ASCT, and almost all (99%) received prior regimens containing either immunomodulators or proteasome inhibitors. There were 55 (30%) patients with >5% pPCs among the total PCs in their BM. The median percentage of pPCs among total PCs in these 55 patients was 33% (range: 5 - 99). The median OS for those with >5% pPCs was not reached compared with 22 months for those with <5% pPCs (P = 0.028; Figure 1). Patients with <5% pPCs PCs had a higher likelihood of high-risk FISH cytogenetics compared with the rest of the patients. In a univariate analysis, increasing number of pPCs was associated with an improved OS, while higher labeling index, number of prior therapies, and the presence of high-risk FISH cytogenetics were associated with a worse OS. In a multivariate analysis, only the increasing number of pPCs (P = 0.006), higher labeling index (P = 0.0002) and number of prior therapies (P = 0.003) retained statistical significance. Conclusion: Quantitative estimation of the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM was determined to be a predictor of worse OS. As such, this parameter is able to identify a group of patients with MM with actively relapsing disease who have a particularly poor outcome. Further studies evaluating its biological significance are warranted. Figure 1 Kaplan-Meier curve comparing OS between patients with ≥5% pPCs and <5% pPCs among the total PCs in their BM. Figure 1. Kaplan-Meier curve comparing OS between patients with ≥5% pPCs and <5% pPCs among the total PCs in their BM. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gertz:Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Kumar:AbbVie: Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy; BMS: Consultancy.

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 Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1852-1852
Author(s):  
Noemi Puig ◽  
Teresa Contreras ◽  
Bruno Paiva ◽  
María Teresa Cedena ◽  
José J Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Advisory Committees ◽  
Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Feasibility and Benefit of Molecularly-Informed Enrollment into Personalized Therapies or Early Phase Trials for Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2001-2001
Author(s):  
Tarek Assi ◽  
Jean-Marie Michot ◽  
Toni Ibrahim ◽  
Fabien Le Bras ◽  
Karim Belhadj ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Research Funding ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Refractory Multiple Myeloma ◽  
Generation Sequencing ◽  
Tumor Genotyping

Abstract Background: Treatments of patients with relapsed or refractory multiple myeloma (r/r MM) remains a challenge and there is no molecular-informed personalized therapies available in this context. Cytogenetics and next-generation sequencing (NGS) panels can rapidly identify recurrent molecular abnormalities, thus helping to orient patients (pts) in appropriate targeted therapies or clinical trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with a better outcome. Methods: From 2013 to 2018, all pts with r/r MM screened for molecular and/or cytogenetics before enrollment in early clinical trials (eaCTs) were included. Molecular screening methods included bone marrow cytogenetics, sanger assays for BRAF screening or next-generation sequencing on sorted CD138 positive bone-marrow cells. The actionable targets and therapies related were BRAF V600E mutation with BRAF inhibitor and t(11;14) with BCL2 inhibitor. The objective were to evaluate the feasibility and potential benefit of using tumor genotyping to orient patients with molecularly-informed multiple myeloma in personalized therapies or eaCTs. The tumor responses rates, median duration of treatments and overall survival (OS) were assessed in molecularly oriented (MO) and non-molecularly oriented (non-MO) pts. Efficacy was evaluated using International Myeloma Working Group Uniform Response Criteria. Results: Forty-six pts with r/r MM were enrolled, mean age was 66 y (range 52-81), median of previous lines of therapies was 3 (range 1-8). Prior systemic therapies included immunomodulatory agents (n=46, 100%), alkylating agents (n=43, 94%) or proteasome inhibitors (n=44, 95%), and 28 (62%) pts had previously received auto stem-cell transplant. Identification of potentially actionable targets was found in 13 (28%) pts, including 8 (17%) pts with t(11;14) and 5 (11%) pts with BRAF V600E mutations. Eight (17%) out of the 46 pts were treated in molecularly oriented (MO) personalized therapies or eaCTs, and 38 (83%) pts were treated in non-MO therapies or eaCTs. The MO pts received BRAF inhibitor alone or in combination with MEK inhibitor (n=5), or BCL2 inhibitor given in combination with bortezomib and dexamethasone (n=3). The overall response rate was 75% (4 VGPR, 1 PR and 1 CR) in MO pts versus 11% (4 PR) in non-MO pts (p<0.0001). The median decrease of serum monoclonal component was -94% (range: -99; -55) in MO pts versus -4% (range: -72; +967) in the non-MO pts (p<0.0001). The median durations of treatment were 7.3 [CI95: 0.5-29.0] months and 2.3 [CI95: 1.7-8.0] months in MO and non-MO pts, respectively (p=0.009). The median OS were not reached in MO pts and 43 months in non-MO pts (p=0.76; HR=0.8 [CI95: 0.2-3.4]). Conclusions: Molecular-oriented treatments of relapse or recurrent multiple myeloma can be associated with higher responses rates and prolonged durations on therapy. Accelerating the use of prospective genomics tumor molecular portraits may increase the chances of precision medicine for patients with relapse or recurrent multiple myeloma. Disclosures Le Bras: Amgen: Consultancy. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Soria:Medimmune: Employment. Ribrag:Amgen: Research Funding; Gilead: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Incyte Corporation: Consultancy; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; argenX: Research Funding; MSD: Honoraria; pharmamar: Other: travel; Servier: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel.

scholarly journals The Mutational Landscape of Primary Plasma Cell Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 114-114 ◽  
Author(s):  
Carolina D. Schinke ◽  
Cody Ashby ◽  
Yan Wang ◽  
Ruslana G. Tytarenko ◽  
Eileen Boyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Kras Mutations ◽  
Aggressive Disease ◽  
Primary Plasma Cell Leukemia

Abstract Introduction: Primary Plasma Cell Leukemia (pPCL) is a rare form of multiple myeloma (MM) that is characterized by an aggressive disease course with >20% peripherally circulating plasma cells (PCs) and poor clinical outcome. Despite the advances of modern anti-MM therapy, pPCL patients continue to experience low median overall survival (OS) suggesting a distinct biological background. Due to its low incidence of 1-2% of all MM patients, studies on physiopathology remain challenging and are limited. The aim of this study was to elucidate the differences in biology and outcome between non-pPCL MM and pPCL, to determine the genetic landscape of pPCL and to identify distinct signatures and pathways that potentially could be used as therapeutic targets. Methods: We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. Results: GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36-77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. MYC breakpoints (8q24) were identified in 25% with Ig partner loci including IGH (5%), IGK (10%), and IGL (10%). The remaining samples had partner loci including FAM46C (5%), MYNN (5%), SPARC (5%), QRSL1 (5%), RNF126 (5%), PLXNA4 (5%) and CDH7 (5%). The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. Biallelic inactivation of TP53 - a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. Conclusion: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored. Disclosures Davies: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; TRM Oncology: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria. Barlogie:Multiple Myeloma Research Foundation: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Millenium: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding.

scholarly journals Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3295-3295 ◽  
Author(s):  
Eirini Katodritou ◽  
Efstathios Kastritis ◽  
Moshe E. Gatt ◽  
Yael C Cohen ◽  
Irit Avivi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Steering Committee ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Lytic Lesions ◽  
Travel Grant

Abstract Macrofocal Multiple Myeloma (MFMM) has been described as a distinct entity of Multiple Myeloma (MM) characterized by young age, lytic lesions and limited bone marrow infiltration by clonal plasma cells (BMPCs), in the absence of other features of symptomatic MM (i.e. anemia, renal insufficiency and hypercalcemia). Few case studies have indicated a possible favorable prognosis of MFMM patients compared to patients with typical symptomatic MM. Our aim was to investigate the incidence, characteristics and outcome of patients with MFMM, under the light of modern therapeutic approach of MM. MFMM definition required: clonal BMPCs <20%, multiple lytic lesions, absence of anemia, renal insufficiency and hypercalcemia and among 4650 MM patients (3%) registered in the MM databases of Greek and Israeli centers during 2001-2017, we identified 140 patients with MFMM (M/F: 93/47, median age: 61, range: 26-89, IgG: 86, IgA: 12, light chain: 21, IgD: 4, non-secretory: 16, IgM: 1). Most of patients with MFMM (60%) were <65 years; 68% had performance status 0-2 according to Eastern Cooperative group (ECOG) scale; 70% had advanced bone disease (>3 lytic lesions). In 20/140 (14%) patients bone plasmacytomas preceded MM diagnosis. In 95/140 (68%) patients bone, soft tissue or mixed plasmacytomas in multiple locations, were present at diagnosis or during MFMM course and this was significantly more frequent compared with standard MM. Median BMPCs infiltration was 14% (range 0-19%); immunoparesis was less common in MFMM (55% vs. 90% in standard MM). Elevated lactate dehydrogenase (LDH) and β2 microglobulin (β2Μ) ≥ 3.5mg/L were found in 9% and 20% of patients, respectively. Cytogenetics by fluorescence in situ hybridization (FISH) were available in 60% of patients and high-risk features were found in 11%; overall, adverse prognostic parameters (i.e. high LDH, advanced age, high β2Μ, high risk cytogenetics) were less common in patients with MFMM compared with others (p<0.05). According to the International staging system (ISS) patients were stratified as follows: ISS1:71%, ISS2: 25% and ISS3: 4%. Per Revised ISS the distribution was R-ISS1: 54%, RISS2: 46%, no R-ISS3). Induction therapy included novel agents in 90% of patients (bortezomib-based: 61%, thalidomide-based: 14%, bortezomib-lenalidomide-dexamethasone: 4%, lenalidomide-based: 11%); 47% underwent autologous transplantation (ASCT) upfront and 13% at 1st relapse. An objective response (ORR) was achieved in 90%: 70% had at least very good partial response (vgPR), 21% partial response, 6% stable disease and 3% had progressive disease; ORR and achievement of ≥vgPR were significantly higher compared with typical MM (p<0.05). After a median follow up of 52 months (95% CI: 40-64), 33 patients have died (MM progression: 19, lung infection: 8, other causes: 6). Early deaths (<12 months) observed in 5% of patients; 53 patients received 2nd line therapy (proteasome inhibitor-based or lenalidomide-dexamethasone: 79%) and 5 patients received only radiotherapy for plasmacytomas; early relapse (<12 months) was less common in MFMM compared with standard MM (p<0.05). Progression-free survival (PFS) and overall survival (OS) were 46 months (95% CI: 40-52) and 129 months (95% CI: 79-178) respectively, both significantly longer compared with typical MM treated during the same period (p<0.001). In the univariate analysis age <65, early stage disease (ISS1, R-ISS1), 1st line treatment with proteasome inhibitor (PI)-based regimens, ASCT, and standard risk cytogenetics predicted positively for OS in MFMM patients; treatment with PI-based therapies was the only independent predictor for OS in the multivariate analysis (HR: 3.9; p<0.001). In conclusion, MFMM is a rare entity of MM characterized by limited bone marrow infiltration, extended bone lesions and frequent presence of plasmacytomas, prior or during the diagnosis or the course of the disease. MFMM patients are younger have less often adverse prognostic features compared with standard MM and achieve high quality responses when treated with novel therapies. Treatment with PI-based regimens was the strongest predictor for OS in MFMM indicating that it is probably the best therapeutic option for these patients. Disclosures Kastritis: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

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