Combination Therapy with Lenalidomide, Bortezomib, Liposomal Doxorubicin and Dexamethasone (LBlipDD) May Overcome Resistance to Prior Treatment with Doxorubicin, Lenalidomide, and Bortezomib in High-Risk Multiple Myeloma (MM).

Abstract Introduction: Lenalidomide (Revlimid®) plus dexamethasone therapy and single-agent bortezomib therapy are approved for the treatment of relapsed/refractory multiple myeloma (MM) patients. A recent phase II trial has shown activity of lenalidomide/bortezomib/dexamethasone in patients with relapsed/refractory MM (Richardson, IMW 2007). Here, we present a case report on the efficacy of combination therapy with lenalidomide, bortezomib, liposomal doxorubicin, and dexamethasone in a patient who was refractory to prior treatments with bortezomib, lenalidomide, and doxorubicin. Methods and Results: A male patient (58 years) presented with IgG-lambda MM in June 2006. Laboratory tests at diagnosis showed total protein of 123g/L (normal value, 66–87 g/L) and a serum IgG of 87.3g/l (normal value, 7–16 g/L). The patient had t(11;14)(q13;q32) translocation and a del13q14, and bone marrow aspirate showed >90% plasma cells. From July 2006 to March 2007, the patient received 3 different chemotherapy treatment regimens (VAD: vincristine, Adriamycin® [doxorubicin], dexamethasone; VDD: Velcade® [bortezomib], doxorubicin, dexamethasone; and LD: lenalidomide, dexamethasone). He showed primary resistance to VAD treatment and developed resistance after 3 and 5 cycles of VDD and LD, respectively. At that point, the patient’s free light chain (fLCh) concentration was 2,320 mg/L (normal value, 5.7–26.3 mg/L). We changed the patient’s treatment regimen to the 4-fold combination of lenalidomide plus bortezomib plus liposomal doxorubicin (lipD) plus dexamethasone (LBlipDD), (lenalidomide 25 mg day 1–21, bortezomib 1mg/m2 day 1+4+8+11, lipD 50 mg/m2 day 4, dexamethasone 40 mg day 1+2+4+5+8+9+11+12; q28 days). The patient received 3 cycles of LBlipDD from May 2007 to July 2007. This treatment combination was well tolerated with no WHO grade 3 or 4 adverse events. The patient was reassessed after 3 treatment cycles. FISH showed a complete eradication of the former cytogenetic abnormalities, bone marrow aspirate showed <5% plasma cells and serum analysis demonstrated a normalized serum IgG value, and a decrease in the fLCh from 2,320 to 173 mg/L. The patient is for the first time transfusion independent and in very good clinical condition. High-dose melphalan with autologous stem cell support is currently planned. Conclusion: Treatment with LBlipDD leads to a good remission in a VAD-, VDD- and LD-resistant patient. The present observation suggests that the use of 4-fold combination of lenalidomide, bortezomib, liposomal doxorubicin, and dexamethasone can be effective in high-risk MM patients and warrants further investigation.

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Role of immune-related conditions in smoldering myeloma and MGUS.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8104 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8104-8104 ◽

Cited By ~ 2

Author(s):

Mary Kwok ◽

Neha Korde ◽

Elisabet E. Manasanch ◽

Manisha Bhutani ◽

Irina Maric ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Mayo Clinic ◽

Plasma Cells ◽

Risk Model ◽

Expression Patterns ◽

Autoimmune Disorder ◽

Epidemiological Studies ◽

Smoldering Myeloma

8104 Background: Recent guidelines emphasize tailored follow-up and the need for clinical trials for high-risk smoldering myeloma (SMM). Emerging evidence from epidemiological studies suggests that immune-related conditions play a role in the causation of myeloma precursor disease (SMM and monoclonal gammopathy of undetermined significance; MGUS) and are of clinical importance for the risk of developing multiple myeloma. The aim of our study is to assess whether there is an altered biology in SMM/MGUS patients with preceding immune-related conditions. Methods: From our ongoing prospective SMM/MGUS natural history study, we evaluated 56 SMM and 60 MGUS patients. Information on autoimmunity was identified at baseline. All patients underwent extensive clinical and molecular characterization. At baseline, all patients underwent bone marrow biopsy evaluation using immunohistochemistry and multi-color flow cytometry of plasma cells. We assessed expression patterns of adverse plasma cell markers (CD56 and CD117), and applied risk models based on serum immune markers and bone marrow findings. Results: Among enrolled SMM and MGUS patients, 7 (12%) and 9 (15%) had a preceding autoimmune disorder. We found SMM patients with (vs. without) a preceding autoimmune disorder to have a substantially lower rate of CD56 (28% vs. 61%) and CD117 (28% vs. 61%) expressing plasma cells. When we compared the same markers in MGUS patients, CD56 and CD117 expression patterns were similar among patients with vs. without preceding autoimmunity (10% vs. 17%, and 50% vs. 48%). Using the Mayo Clinic risk model, none of the SMM patients with a preceding autoimmune disorder had high-risk features; in contrast, 3/41 (7%) of those without a preceding autoimmune disorder were high-risk SMM. Using the Mayo Clinic risk model, none of the MGUS patients were high-risk independent of autoimmune status. Conclusions: Our prospective clinical study found SMM patients with preceding immune-related conditions to have less adverse biology, supportive of epidemiological studies suggesting the risk of developing multiple myeloma is substantially lower in these patients.

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Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818242116 ◽

2019 ◽

Vol 116 (15) ◽

pp. 7425-7430 ◽

Cited By ~ 10

Author(s):

Christian Männe ◽

Akiko Takaya ◽

Yuzuru Yamasaki ◽

Mathias Mursell ◽

Shintaro Hojyo ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Autoimmune Diseases ◽

Plasma Cell ◽

Plasma Cells ◽

Therapeutic Option ◽

Immune Memory ◽

Humoral Immune ◽

Serum Igg ◽

Specific Igg

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella. A SiiE-derived peptide with homology to laminin β1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin β1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.

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Intra-Tumoral Heterogeneity In Multiple Myeloma Gleaned From Gene Expression Profiling Analysis Of Plasma Cells and Bone Marrow Biopsies: Comparison Of Random Bone Marrow Samples and CT-Guided Fine Needle Aspirations Of MRI-Defined Focal Lesions

Blood ◽

10.1182/blood.v122.21.3123.3123 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3123-3123

Author(s):

Bart Barlogie ◽

Emily Hansen ◽

Sarah Waheed ◽

Jameel Muzaffar ◽

Monica Grazziutti ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Plasma Cells ◽

P Value ◽

Focal Lesions ◽

Molecular Subgroup

Abstract Intra-tumoral heterogeneity (ITH) is increasingly viewed as the Achilles heel of treatment failure in malignant disease including multiple myeloma (MM). Most MM patients harbor focal lesions (FL) that are recognized on MRI long before bone destruction is detectable by conventional X-ray examination. Serial MRI examinations show that eventually 60% of patients will achieve resolution of FL (MRI-CR). However, this will lag behind the onset of a clinical CR by 18 to 24 months, thus attesting to the biological differences between FL and diffuse MM growth patterns. Consequently, we performed concurrent gene expression profiling (GEP) analyses of plasma cells (PC) from both random bone marrow (RBM) via iliac crest and FL. Our primary aims were to first compare the molecular profiles of FL vs. RBM, second to determine if ITH existed (as defined molecular subgroup and risk), and finally to investigate if the bone marrow micro-environment (ME) contained a biologically interesting signature. A total of 176 patients were available for this study with a breakdown of: TT3 (n=23), TT4 for low-risk (n=131) and TT5 for high-risk MM (n=22). Regarding the molecular analyses of PCs, GEP-based risk (GEP-70, GEP-5) and molecular subgroup correspondence were examined for commonalties and differences between RBM and FL. A “filtering” approach for ME genes was also developed and bone marrow biopsy (BMBx) GEP data derived from this method is under analysis. PC risk correspondence between FL and RBM was 86% for GEP70 and 88% for the GEP5 model. Additionally, 82% had a molecular subgroup concordance, however, they did differ among subgroups (p=0.020) by Fisher's Exact Test. A lower concordance was noted in the CD2, LB, and PR subgroups (67%, 69%, 73%, respectively). GEP70 and GEP5 risk concordance between RBM and FL samples by molecular subgroup was also examined. The overall correlation coefficients were 0.619 (GEP70) and 0.597 (GEP5). The best correspondence was noted for CD1, MF and PR subgroups especially for the GEP5 model. HY, LB and MS showed intermediate correlations, while CD2 fared worst with values of only 0.322 for GEP70 and 0.267 for GEP5 model. Figure 1 portrays these data in more detail for the GEP70 and GEP5 models. Good correlations were noted between RBM and FL based risk scores in case of molecular subgroup concordance (left panels) in both GEP5 and GEP70 risk models, whereas considerable scatter existed in case of subgroup discordance (right panels). The clinical implications in TT4 regarding RBM and FL derived risk and molecular subgroup information, viewed in the context of standard prognostic baseline variables are portrayed in Table 1. High B2M levels at both cut-points imparted inferior OS and PFS as did low hemoglobin. Although present in 42% of patients, cytogenetic abnormalities (CA) did not affect outcomes. FL-based GEP5-defined high-risk designation conferred poor OS and PFS. B2M>5.5mg/L and FL-derived GEP5 high-risk MM, pertaining to 29% and 11% of patients, survived the multivariate model for both OS and PFS. Next, in examining PC-GEP differences among RBM and FL sites, 199 gene probes were identified with a false discovery rate (FDR) of 1x10-6. Additionally, 55 of the 199 belong to four molecular networks of inter related genes associated with: lipid metabolism, cellular movement, growth and proliferation, and cell-to-cell interactions. Multivariate analysis identified the GEP5 high risk designation of focal lesion PCs to be significantly prognostic with a HR=3.73 (p=0.023).Table 1Cox regression analysis of variables linked to overall and progression-free survival in TT4.Overall SurvivalProgression-Free SurvivalVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueMultivariateB2M > 5.5 mg/L38/130 (29%)3.71 (1.49, 9.22)0.0053.84 (1.58, 9.31)0.003FL GEP5 High Risk14/130 (11%)3.68 (1.19, 11.41)0.0243.73 (1.20, 11.62)0.023HR- Hazard Ratio, 95% CI- 95% Confidence Interval, P-value from Wald Chi-Square Test in Cox RegressionNS2- Multivariate results not statistically significant at 0.05 level. All univariate p-values reported regardless of significance.Multivariate model uses stepwise selection with entry level 0.1 and variable remains if meets the 0.05 level.A multivariate p-value greater than 0.05 indicates variable forced into model with significant variables chosen using stepwise selection. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v126.23.2991.2991 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2991-2991

Author(s):

Peter A. Forsberg ◽

Tomer M Mark ◽

Sujitha Yadlapati ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Overall Survival ◽

High Risk ◽

Plasma Cell ◽

Plasma Cells ◽

Initial Therapy ◽

First Line ◽

High Risk Disease

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

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

Blood ◽

10.1182/blood.v128.22.1194.1194 ◽

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.

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

Blood ◽

10.1182/blood-2021-148617 ◽

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>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>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.

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Non-Invasive Liquid Biopsy to Quantify and Molecularly Characterize Circulating Multiple Myeloma Cells in the Assessment of Precursor Disease Pathology

Blood ◽

10.1182/blood-2021-150622 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 78-78

Author(s):

Ankit K. Dutta ◽

Elizabeth D. Lightbody ◽

Ziao Lin ◽

Jean-Baptiste Alberge ◽

Romanos Sklavenitis-Pistofidis ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Molecular Characterization ◽

Peripheral Blood ◽

Plasma Cells ◽

Whole Genome ◽

Myeloma Cells ◽

Molecular Analyses ◽

Non Invasive

Abstract Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective new therapies, most MM patients inevitably relapse and require further treatment, highlighting the need for better early detection methods for precursor patients and targeted interventions to prevent early disease from progressing. The initial diagnosis of MGUS/SMM remains an incidental process following the identification of increased clonal immunoglobulin in the blood. BM biopsy is the gold standard for diagnosis and monitoring of MM progression, but is intrusive, painful, and comes with possible secondary complications for patients. Consequently, repeated assessment is not a feasible option for MGUS and SMM patients who are asymptomatic. Here we tested the utility of circulating multiple myeloma cells (CMMCs) from non-invasive blood biopsy to accompany BM as a method to monitor disease development, by enumerating CMMCs from MGUS/SMM patients. Methods: Peripheral blood from 185 precursor patients (75 MGUS and 110 SMM) from the Dana-Farber Cancer Institute observational PCROWD study (IRB #14-174) was collected in CellRescue TM Preservative Tubes and processed on the CellSearch CellTracks Autoprep system using the CMMC assay kit using 4mL of blood. This assay employs the enrichment of CMMCs through the immunophenotype of CD138 +CD45 -19 -, and leukocyte exclusion based on CD45 +CD19 +. Nucleated cells were identified using DAPI staining. The CellTracks Analyzer II fluorescence microscope system was subsequently used to scan captured CMMC cartridges, with software allowing the automated scoring and enumeration of CMMCs. Additional molecular analyses were carried out on SMM patients. Briefly, minipools of CMMCs were sorted by DEPArray and underwent whole genome amplification using Ampli1 kit, PCR-free library construction, quantification and low pass whole genome sequencing (~0.5x) on the Illumina HiSeq2500. To assess whether molecular analyses can be performed to detect hyperdiploidy as a genomic biomarker of MM disease, ichorCNA analyses was performed to determine copy number variant (CNV) events and infer tumour fraction. Results: CMMCs were detected in 27% of MGUS patients collected, with a median count of 2 CMMCs (range 0 to 1328). Comparably, CMMCs were detected in 57% of SMM patients, with a median enumeration of 13 CMMCs (range 0 to 43836). Enumeration of CMMCs illustrated a correlation with clinical measure of disease including the International Myeloma Working Group 2/20/20 risk stratification model. A higher CMMC count was associated with increasing risk group based on the 3-risk factor model, with a median of 5, 29 and 59 CMMCs detected at low, intermediate, and high-risk SMM groups, respectively. CMMC counts were significantly increased at intermediate (P = 5.0 x 10 -4) and high-risk stages (P = 3.7 x 10 -3) compared to low-risk. While enumeration provides a correlative measure of CMMCs that may be of tumor origin, downstream molecular characterization can confirm MM-associated genetic alterations. At the precursor stages, a low tumour burden is evident clinically, thus both normal and malignant plasma cells are present. Therefore, to determine the concordance between bone marrow and peripheral blood CMMCs, we performed genomic analyses to identify arm level gain or loss events. Molecular analyses of CMMCs was carried out in patients who had matched BM and clinical fluorescent in situ hybridization (FISH) results. We showed that CMMCs can capture 100% of clinically annotated BM FISH CNV events. Furthermore, CMMC samples identified additional yield, with further CNVs identified that were not observed by FISH. In cases that did not have BM biopsy results, sequencing of CMMCs revealed the existence of genetic aberrations. Conclusion: Our results demonstrate clinical correlation and molecular characterization of CMMCs from MGUS/SMM patients. This study provides a foundation for non-invasive detection, enumeration and genomic interrogation of rare CMMCs from the peripheral blood of MGUS/SMM, illustrating the clinical potential of using liquid biopsies for monitoring and managing disease in the precursor setting of MM. Disclosures Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. 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.

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Neoplastic Plasma Cells Are Demonstrable at Bone Marrow Sites Distant to Solitary Plasmacytoma of Bone and Predict for Progression to Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3512.3512 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3512-3512 ◽

Cited By ~ 1

Author(s):

Quentin A. Hill ◽

Ruth M. de Tute ◽

J. Anthony Child ◽

Andy C. Rawstron ◽

Roger G. Owen

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Plasma Cells ◽

Autologous Transplantation ◽

Solitary Plasmacytoma ◽

Aberrant Expression ◽

Risk Of Progression ◽

Bone Marrow Plasma ◽

Chi Square Analysis

Abstract Solitary plasmacytoma of bone (SPB) typically present as single destructive lesions within the spinal column or long bones. Local radiotherapy is the treatment of choice but approximately 50% of patients progress to myeloma. Many patients have a monoclonal protein detectable in their serum and/or urine at diagnosis and persistence of this for greater than 1 year after radiotherapy predicts for progression to myeloma. Identification of high risk patients at the time of diagnosis is clearly desirable as it would enable risk stratification and more careful monitoring of patients. Although prophylactic adjunctive chemotherapy has not definitively been shown to benefit unselected patients with SPB, future therapeutic advances might be targeted on patients with a high risk of progression. Interestingly it has recently been shown that patients positive for serum free light chains are at greater risk of progression to myeloma. We and others have previously demonstrated that neoplastic bone marrow plasma cells are distinguishable from their normal counterparts by virtue of their lack of CD19 expression and/or their aberrant expression of CD56. We have developed a multiparameter flow cytometry assay which predicts outcome following autologous transplantation in myeloma patients and risk of progression in patients with MGUS. In this study we have applied this assay to assess the staging bone marrow specimens from patients with biopsy proven SPB for the presence of occult disease at sites distant to the primary lesion. 52 patients were included in this analysis (31 male, 21 female; median age 65) and in each case the staging bone marrow aspirate and trephine biopsy (obtained from a site distant from the SPB, typically the right iliac crest) was not indicative of myeloma (<10% plasma cells). Plasma cells comprised a median of 0.6% (0.05–6.2%) of bone marrow leucocytes while distinct populations with a neoplastic immunophenotype (>30% CD19− and/or CD56+ as per convention) were demonstrable in 35/52 (67%). Neoplastic plasma cells when present comprised a median of 70% (35–100%) of bone marrow plasma cells. 21 patients (40%) developed myeloma with a median time to progression of 476 days (range 18–1632). Progression occurred in 18 of the 35 (51%) patients with neoplastic plasma cells in their staging marrows and in 3/17 (18%) patients with a normal phenotypic profile. The difference was significant using Chi-square analysis with Yates’ correction for continuity (p=0.04). The overall risk of progression was similar in patients with a “myeloma pattern” in which >90% of bone marrow plasma cells had a neoplastic phenotype (5/12, 42%) and those with an MGUS or mixed pattern in which distinct populations of both normal and neoplastic cells are demonstrable (13/23, 57%). We would conclude that neoplastic plasma cells are frequently found at bone marrow sites distant to SPB and that their presence predicts for progression to multiple myeloma. Trials of adjuvant systemic therapy are warranted in this group.

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

Blood ◽

10.1182/blood-2021-149797 ◽

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 <10% bone marrow plasma cells and <3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of <0.26 or >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 <0.125 or >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.

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A Phase II Trial of Gleevec™ in Patients with Refractory/Relapsed Myeloma.

Blood ◽

10.1182/blood.v104.11.2420.2420 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2420-2420

Author(s):

Angela Dispenzieri ◽

Thomas E. Witzig ◽

Martha Q. Lacy ◽

Susan M. Geyer ◽

Teresa Kimlinger ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Stem Cell ◽

High Risk ◽

Cell Lines ◽

Stem Cell Factor ◽

Plasma Cells ◽

Myeloma Cell ◽

Grade 3

Abstract Background: Though STI-571 (Gleevec™) was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases at physiologically attainable concentrations, including c-kit (steel factor receptor, stem cell factor receptor, SCF-R or CD 117). Studies have shown that about one-third of patients with multiple myeloma or monoclonal gammopathy of undetermined significance have plasma cells that display reactivity for c-kit. Others have shown that several myeloma cell lines and fresh myeloma bone marrow cells proliferate in response to stem cell factor. mRNA transcripts for c-kit ligand and, more commonly, its receptor have been detected in myeloma cell lines RPMI 8226, JJN3, U266 B1, NCI-H929, ARH77 and HS-Sultan by RT-PCR. Methods: Patients were eligible for study if they presented with relapsed or refractory myeloma, an ECOG performance score < 3, ability to sign informed consent, serum creatinine <3.5 mg/dL, direct bilirubin <2 mg/dL, alkaline phosphatase <750 U/L, absolute neutrophil count > .5 x 10(9)/L and platelet count > 50 x 10(9)/L. Patients were treated with Gleevec™ 400 mg po qd. The purpose of the study was to assess the response rate of the drug Gleevec™ in patients with relapsed multiple myeloma. Secondary objectives included assessment of the tolerability of the regimen in this cohort of patients and to correlation between disease response and c-kit positivity (CD117) by flow cytometry. Results: Overall, 23 patients were enrolled between 12/01 and 11/02, of which 16 were male and 12 had a prior PBSCT. Median age was 63 years (range: 49 – 82), and the baseline performance scores were 0 (8 patients), 1 (10), and 2 (4). Median time from MM diagnosis to enrollment was 57 months (range: 11 – 133). Patients were high risk with a median PCLI of 1.3 (range: 0 – 23%) and a median beta-2 microglobulin of 4.6 (range: 1.4 – 10.1). Eleven of 21 tested patients had positive CD117 (≥20%) staining of their bone marrow plasma cells by flow cytometry. None were PDGF positive. The treatment was well tolerated. After treatment with Gleevec™, there were only 3 non-hematologic grade 3 or 4 toxicities, and they occurred in 1 patient: he developed a capillary leak type syndrome, ascites, and dyspnea as part of his terminal phase of myeloma which included evolution into plasma cell leukemia. Grade 3 myelosuppression was observed in a minority of patients: thrombocytopenia (3), neutropenia (1), and anemia (3). There were no responses, and no patients are currently receiving treatment. Patients ended treatment due to progressive disease (18 patients), death on study (3), adverse reactions (1), and other reasons (1). The median duration of treatment was 48 days (range: 12 to 349). Of the 7 patients who remained on study for more than 60 days, CD117 status was as follows: positive (4); negative (3); not ascertained (1). As of August 2004, 12 patients have died. Conclusions: Though forty-eight percent of the enrolled myeloma patients were CD117 positive, providing a putative target for the Gleevec™, no responses were seen in this high risk population of relapsed patients. Further study will be necessary to determine the significance of the observed stabilization of disease in 36% of the CD117 positive patients.

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