The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma

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

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The prognostic significance of CD45 expression by clonal bone marrow plasma cells in patients with newly diagnosed multiple myeloma

Leukemia Research ◽

10.1016/j.leukres.2016.03.003 ◽

2016 ◽

Vol 44 ◽

pp. 32-39 ◽

Cited By ~ 10

Author(s):

Wilson I. Gonsalves ◽

Michael M. Timm ◽

S.Vincent Rajkumar ◽

William G. Morice ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Prognostic Significance ◽

Newly Diagnosed ◽

Bone Marrow Plasma

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PS1408 PROGNOSTIC SIGNIFICANCE OF CD56 EXPRESSION ON BONE MARROW PLASMA CELLS OF NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS

HemaSphere ◽

10.1097/01.hs9.0000563908.04283.a9 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 647

Author(s):

G. Rivoli ◽

N. Bisso ◽

A. Cagnetta ◽

S. Aquino ◽

M. Bruzzone ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Prognostic Significance ◽

Newly Diagnosed ◽

Bone Marrow Plasma ◽

Cd56 Expression

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Improved cytogenetic analysis of bone marrow plasma cells after cytokine stimulation in multiple myeloma: a report on 46 patients

British Journal of Haematology ◽

10.1111/j.1365-2141.1993.tb03155.x ◽

1993 ◽

Vol 84 (4) ◽

pp. 743-745 ◽

Cited By ~ 28

Author(s):

T. Facon ◽

J. L. Lai ◽

E. Nataf ◽

C. Preudhomme ◽

M. Zandecki ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cytogenetic Analysis ◽

Plasma Cells ◽

Bone Marrow Plasma ◽

Cytokine Stimulation

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Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽

10.1182/blood.v64.2.352.bloodjournal642352 ◽

1984 ◽

Vol 64 (2) ◽

pp. 352-356

Author(s):

GJ Ruiz-Arguelles ◽

JA Katzmann ◽

PR Greipp ◽

NJ Gonchoroff ◽

JP Garton ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Peripheral Blood ◽

Plasma Cells ◽

Peripheral Blood Lymphocytes ◽

Tumor Burden ◽

B Cell Differentiation ◽

Blood Lymphocytes ◽

Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

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Abstract 4762: Deficient double strand breaks repair of bone marrow plasma cells correlates with better clinical outcome of multiple myeloma patients

10.1158/1538-7445.am2014-4762 ◽

2014 ◽

Author(s):

Maria Gkotzamanidou ◽

Masood Shammas ◽

Evangelos Terpos ◽

Sathees C. Raghavan ◽

Kenneth C. Anderson ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Clinical Outcome ◽

Plasma Cells ◽

Double Strand Breaks ◽

Strand Breaks ◽

Bone Marrow Plasma

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PD-L1 expression in bone marrow plasma cells as a biomarker to predict multiple myeloma prognosis: developing a nomogram-based prognostic model

Scientific Reports ◽

10.1038/s41598-020-69616-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Byung-Hyun Lee ◽

Yong Park ◽

Ji Hye Kim ◽

Ka-Won Kang ◽

Seung Jin Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Prognostic Model ◽

Plasma Cells ◽

Bone Marrow Plasma

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Serum Free Light Chain Ratio in Distinguishing Smoldering Multiple Myeloma From Active Multiple Myeloma,

Blood ◽

10.1182/blood.v118.21.3948.3948 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3948-3948

Author(s):

Jeremy T Larsen ◽

Shaji Kumar ◽

S. Vincent Rajkumar

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Predictive Value ◽

Plasma Cells ◽

Organ Damage ◽

End Organ Damage ◽

Cut Point ◽

Smoldering Multiple Myeloma ◽

Bone Marrow Plasma

Abstract Abstract 3948 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor disease of multiple myeloma, and is defined by excess bone marrow plasma cells and monoclonal protein without evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions [CRAB]). The identification of SMM patients with more aggressive underlying disease remains a challenge. We hypothesize that SMM is a clinical entity comprised of both premalignant, high-risk MGUS and early multiple myeloma in transition to malignant disease, which may be differentiated with the use of the serum FLC (FLC) ratio. Methods: This was a retrospective analysis of 586 patients with newly diagnosed SMM from 1970–2010 with available stored serum samples around the time of diagnosis to be utilized for quantification of FLC ratios. SMM was defined by the International Myeloma Working Group 2003 definition; serum M-protein ≥ 3 g/dL and/or ≥ 10% bone marrow plasma cells with no evidence of CRAB features. The immunoglobulin FLC assay (Binding Site, U.K.) was used for testing. The FLC ratio was calculated as κ/λ (reference range 0.26–1.65). The involved/uninvolved FLC ratio was recorded to simplify the reporting of data. Receiver Operating Characteristics (ROC) curves were created to assess the ability of the FLC ratio to discriminate patients who progressed to symptomatic multiple myeloma (MM) in the first 2 years or at any point during follow-up versus patients without evidence of progression. Patients with less than 24 months follow-up without progression were censored. The optimal diagnostic cut-point for FLC involved/uninvolved ratio to identify patients with progressive disease from the ROC curve was >88.6 (equivalent to <0.011 or >88.6). For ease of clinical application, the optimal value for involved/uninvolved FLC ratio was rounded to >100. Time to progression (TTP) from date of the initial FLC to active MM was calculated using Kaplan-Meier analysis and compared to patients with a high (>100) and low (<100) involved/uninvolved FLC ratio at time of SMM diagnosis. TTP within 24 months of the initial FLC was also calculated. Results: During the study period, 54% of patients progressed to active MM. On ROC analysis, a cut-point of >100 corresponded to a sensitivity of 25% (95% CI, 20.5–30.4) and specificity of 99.3% (97.3–99.9), with positive likelihood (+LR) ratio of 33.9 (38.1–41.0), negative likelihood ratio (−LR) of 0.75 (0.2–3.0), positive predictive value (PPV) of 97.6 (91.5–99.7) and negative predictive value of 53.0 (48.5–57.4). Using the ROC to assess progression to MM within 24 months (Figure 1), sensitivity was 29.6% (23.5–36.4), specificity 94.5% (91.7–96.5), +LR 5.36 (4.3–6.6), -LR 0.75 (0.5–1.1), PPV 85.8 (77.7–91.8), and NPV 54.3 (49.8–58.9). Median TTP to active MM in the FLC >100 group was 15 months (9–17) versus 52 months (44–60) in the FLC <100 group (p <.0001) [Figure 2]. In the FLC ratio >100 group, progression at 1 year was 47%, 76% at 2 years, and 90% at 3 years. Only 25% of the FLC <100 patients had progressed at 2 years. The most common progression event was bone disease (42%), followed by anemia (26%), renal impairment (23%), and hypercalcemia (5%). Conclusion: Elevation of the FLC ratio >100 (or <0.01) is highly specific for the future development of active MM, with 76% of these patients developing end-organ damage requiring therapy within 2 years. Risk of transformation to MM in the FLC <100 group was similar to previously reported rates of 10% per year for the first 5 years. Development of an FLC ratio >100 is associated with increasing disease burden and in this study behaved in a malignant fashion rather than a precursor state. The FLC is a simple and useful predictor of progression to MM in SMM, and patients with FLC ratios of <0.01 or >100 within the first 2 years of SMM diagnosis should be monitored especially closely. Future studies are needed to determine optimum cutoffs for FLC ratio to where a change in definition of MM could be considered. Disclosures: No relevant conflicts of interest to declare.

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Metabolomics Identifies Potential Biomarkers of Multiple Myeloma Development and Progression

Blood ◽

10.1182/blood.v120.21.3985.3985 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3985-3985

Author(s):

Francesca Fontana ◽

Josè Manuel garcia Manteiga ◽

Magda Marcatti ◽

Francesca Lorentino ◽

Giovanni Tonon ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Conflicts Of Interest ◽

In Vitro Tests ◽

Incurable Cancer ◽

Disease Evolution ◽

Cell Counts ◽

Bone Marrow Plasma ◽

Active Disease

Abstract Abstract 3985 Multiple myeloma is a malignancy of plasma cells, which grows at multiple foci in the bone marrow, secretes monoclonal immunoglobulins, and typically induces skeletal destruction, hypercalcemia, anemia, and renal failure. Although it remains an incurable cancer, novel therapeutic regimens have improved overall survival in the last decade. Multiple myeloma originates from post germinal center, terminally differentiated B lymphocytes through a multi-step process involving early and late genetic changes. Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS), a frequent age-progressive premalignant expansion of bone marrow plasma cells that behave benignly despite the presence of most myeloma-specific genetic abnormalities. Indeed, development and progression of multiple myeloma are believed to rely on vicious interactions with the bone marrow environment, offering a paradigm to investigate the bone-cancer relationship. In particular, bone and stromal cells are known to be diverted by cancer cells through altered cytokine circuitry. The resulting enhanced osteoclastogenesis and neoangiogenesis, and reduced osteoblast differentiation and activity sustain cancer cell survival, proliferation, migration and chemoresistance. Such crucial interactions, however, have only partially been elucidated in their complexity, dynamics and exact role in disease evolution. A better knowledge of this interplay, still elusive, could help identify prognostic markers, pathomechanisms, and therapeutic targets for future validation. Aiming to achieve an unbiased, comprehensive assessment of the extracellular milieu during multiple myeloma genesis and progression, we performed a metabolomic analysis of patient-derived peripheral and bone marrow plasma by ultra high performance liquid and gas chromatography followed by mass spectrometry. By feature transformation-based multivariate analyses, metabolic profiling of both peripheral and bone marrow plasma successfully discriminated active disease from control conditions (health, MGUS or remission). Moreover, both central and peripheral metabolic scores significantly correlated with bone marrow plasma cell counts. Significant changes in the peripheral metabolome were found to be associated with abnormal renal function in the subset of myeloma patients. Noteworthy, however, renal dysfunction-associated features failed to independently predict disease load, while non-overlapping disease vs. control analyses consistently identified a number of metabolites associated with disease. Among these, increased levels of the C3f-derived peptide, HWESASLL, and loss of circulating lysophosphocholines emerged as hallmarks of active disease. In vitro tests on myeloma cell lines and primary patient-derived cells revealed a previously unsuspected direct trophic role exerted by lysophosphocholines on malignant plasma cells. Altogether, our data demonstrate that metabolomics is a powerful approach suitable for studying the complex interactions of multiple myeloma with the bone marrow environment and general metabolism. This novel strategy holds potential to identify unanticipated markers and pathways involved in development and progression of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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