Study of MGUS-Series: Disease Evolution, Coexistant Disorders and Other Clinical Observations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5323-5323
Author(s):  
Dimitrios Maltezas ◽  
Nikolaou Eftychia ◽  
Paraskevi Papaioannou ◽  
Aikaterini Bitsani ◽  
Tatiana Tzenou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
General Population ◽  
Plasma Cell ◽  
Research Funding ◽  
Common Finding ◽  
Benign Tumors ◽  
Disease Course ◽  
Disease Evolution ◽  
Monoclonal Protein ◽  
And Behavior

Abstract Introduction: Monoclonal Gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder occurring mainly in the elderly population. Its evolution, association with various diseases and behavior is an interesting study field in an attempt to understand its pathogenesis and disease course. Aim: To study the grade of coexistence of non-malignant and malignant diseases along with disease evolution and behavior in patients with MGUS, diagnosed in a single center. Patients and methods:We studied 138 MGUS-patients that were diagnosed in our center and then followed up to a median of 36 months (6months - 22 years). Median age was 66 years (27-92 years). 57% were of female sex. Monoclonal heavy chain was IgG in 76%, IgA in 14% and IgM in 10% of the patients while 63% presented k-chain clonality. Non-malignant and malignant preexisting diseases were documented at the time point of MGUS-Diagnosis. Patients with B-NHL expressing monoclonal Protein were not classified as MGUS since malignant B-Lymphocytes can be responsible for its production. Results: 10.9% of the patients presented solid tumors. The most common malignancy was Prostate-Cancer in 8.5% of the male patients followed by Thyroid-Cancer which was present in 2.2% of the whole patient group.Hematological malignancies were existent in 10.9% of the patients. 4.3% presented myeloproliferative neoplasms while myelodysplastic syndromes were represented in 5% of the patients.18.1% of the patients presented with diverse benign tumors, 8% had been diagnosed with Diabetes Mellitus while 32.6% presented cardiovascular disease, mainly hypertension (23.2%). Hyperlipidemia was present in 8.7%. Finally 18.1% of the patients presented non-malignant thyroid disease, mainly hypothyroidism (10.9%) which is increased compared to the general population.17 MGUS-Patients (12%) presented disease evolution. 3 Patients evolved directly to multiple myeloma while 3 more evolved initially to smoldering myeloma (SMM) before developing overt myeloma. 8 patients evolved to SMM without any further progression. 2 patients with IgM-MGUS presented Waldenström's maroglobulinemia in the follow up while one patient developed a B-NHL. We performed a statistical analysis, where only abnormal serum free light chain ratio (sFLCR) was found to have a prognostic impact on MGUS-progression (p=0.03).Within this group of evolving MGUS-patients two of them presented a very remarkable course. The first one was diagnosed with MGUS while she was in remission after Hodgkin's Lymphoma. She evolved then to SMM confirmed by bone marrow biopsy with more than 10% plasma cell infiltration by immunohistochemistry. After being stable for several months, monoclonal protein was no longer detectable and plasma cells in the bone marrow were normal without any treatment. The second patient was initially diagnosed with MGUS with a high sFLCR of 60. She then evolved to SMM with further sFLCR-increase up to 100 but remained without treatment according to the guidelines at that time. Four years later she developed anemia and the final diagnosis was B-NHL. Conclusion: In our study group MGUS was associated with numerous malignant and non-malignant disorders. Hypothyroidism was a common finding, increased compared to the general population. MGUS-evolution was also observed however disease course was unexpected in some patients showing the heterogeneity of the disease. sFLCR was confirmed as a prognostic factor. Further study is necessary to investigate any possible implication of the above findings in the disease pathogenesis and course. Disclosures Kyrtsonis: Genesis: Honoraria; Millenium: Research Funding; Lilly: Research Funding; Amgen: Research Funding.

scholarly journals Characterization of Patients with Multiple Myeloma in Long- Term Remission

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4508-4508 ◽  
Author(s):  
Raphael K. Lutz ◽  
Katharina Kriegsmann ◽  
Mohamed H.S. Awwad ◽  
Carsten Müller-Tidow ◽  
Gerlinde Egerer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Research Funding ◽  
High Dose ◽  
Disease Course ◽  
Monoclonal Protein ◽  
Single Cell Rna Sequencing ◽  
Indolent Disease

Abstract INTRODUCTION: Multiple Myeloma is still considered an incurable disease despite the development of new therapy options. However, there is a small fraction of patients achieving a long- term remission (LTR) after induction therapy followed by high dose chemotherapy and autologous stem cell transplantation (ASCT). Such patients that are still in complete remission or experience an indolent disease course over many years after high dose therapy are referred to as functionally cured. To date, it is still unclear which patients experience a long term disease control. METHODS: We have screened our Myeloma register for patients that experienced a LTR over 7 years after high dose chemotherapy followed by ASCT. Characteristics of patients that fit to these criteria have been analyzed in detail. The current disease state was evaluated according to the IMWG criteria. Using the Next Generation Flow technique from Cytognos, bone marrow samples from the patients were examined for minimal residual disease (MRD, sensitivity <10-5). To further characterize the bone marrow environment of myeloma patients in LTR, we currently perform a quantitative analysis of the lymphocyte compartment in peripheral blood and bone marrow using flow cytometry. Moreover, bone marrow mononuclear cells are currently being characterized using the single cell RNA sequencing approach by 10X Genomics. RESULTS: We have identified 24 living patients with ongoing remission from 7 till 17 years after high dose therapy and autologous stem cell transplantation. Patients' characteristics are summarized in Table 1. Unexpectedly, 10 patients had a poor prognosis score at first diagnosis (6 patients with ISS score II and 4 patients with ISS score III). Furthermore, the average tumor burden, determined by plasma cell infiltration of bone marrow at initial diagnosis, was remarkably high with 49.5 %. 4 patients had high risk cytogenetics (3 patients with TP53/del17p and 1 patient with t(4;14)). Regarding the depth of response, the 24 patients were subdivided into 3 groups (Table 2). 9 of 24 patients had a detectable monoclonal protein in serum with an indolent disease course. 15 of 24 patients had no detectable monoclonal protein in serum. Of note, MRD assessment of the bone marrow by Next Generation Flow revealed MRD positivity in 4 of 15 patients. Preliminary data using flow cytometry and single cell RNA sequencing suggest a unique immunological profile of the different patient cohorts in LTR. CONCLUSION: Patients with multiple myeloma in LTR can be subdivided into 3 groups: patients with detectable monoclonal protein but indolent disease course, patients in Flow MRD negative complete remission and patients in Flow MRD positive remission. A deep analysis of patients' peripheral blood and bone marrow by flow cytometry and single cell RNA sequencing is currently being performed focusing on the immunological signature of the different patient cohorts. Preliminary results suggest a unique immunophenotype which is possibly associated to long- term disease control. Data will be presented at the meeting. Disclosures Kriegsmann: BMS: Research Funding; Celgene: Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Durie:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Goldschmidt:Takeda: Consultancy, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria.

MLN9708 Elicits Pharmacodynamic Response in the Bone Marrow Compartment and Has Strong Antitumor Activity in a Preclinical Intraosseous Model of Plasma Cell Malignancy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1834-1834 ◽  
Author(s):  
Edmund Lee ◽  
Bret Bannerman ◽  
Michael Fitzgerald ◽  
Jennifer Terkelsen ◽  
Daniel Bradley ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antitumor Activity ◽  
Plasma Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Human Multiple Myeloma ◽  
Cell Malignancy

Abstract Abstract 1834 Poster Board I-860 Introduction The clinical success of VELCADE® (bortezomib) for Injection has validated the proteasome as a therapeutic target for the treatment of human cancer. The novel proteasome inhibitor MLN9708 is a potent, reversible, and specific inhibitor of the b5 site of the 20S proteasome identified in preclinical studies. MLN9708 is currently in human clinical development for both hematological and non-hematological malignancies. Here we describe the pharmacodynamic (PD) response of MLN9708 in the murine bone marrow compartment and its strong antitumor activity in an intraosseous xenograft model of plasma cell malignancy. Materials MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies described below. Methods It has been previously shown that double transgenic iMycCa/Bcl-XL mice develop de novo plasma cell malignancies (J. Clin. Invest. 113:1763-1773, 2004) in which neoplastic plasma cell development is driven by the targeted expression of the transgene Myc (c-myc; myelocytomatosis oncogene) and Bcl-x (Bcl2l1; encodes the oncoprotein Bcl-XL). DP54 is a plasma cell tumor cell line derived from the bone marrow of a syngeneic mouse previously inoculated with an iMycCa/Bcl-XL tumor (Cancer Res. 67:4069-4078, 2007). In vitro, DP54 cells express both the Myc and Bcl-XL transgenes, various plasma cell and B-cell markers including CD38, CD138 and B220, and has gene expression profile very similar to human multiple myeloma. To establish a preclinical intraosseous model of plasma cell malignancy for efficacy studies, freshly dissociated DP54-Luc cells (constitutively expressing firefly luciferase under a mouse Ig-k promoter) were aseptically injected into the bone marrow space of the upper shaft of the right tibia of NOD-SCID mice. Once tumor growth has been established, mice were randomized into treatment groups and then treated intravenously (IV) with vehicle, bortezomib (at 0.8 mg/kg twice weekly [BIW]) or MLN2238 (at 11 mg/kg BIW) for 3 consecutive weeks. Tumor burden was measured by bioluminescent imaging. Results MLN2238 strongly inhibited proteasome activity in the blood and bone marrow compartments of mice (maximum b5 inhibition of 84% and 83%, respectively). In vivo, when DP54 cells were aseptically injected into the bone marrow space of the mouse tibia, signs of bone erosion in the tibia, femur and cranial sagittal sultures (as determined by ex-vivo mCT imaging) were observed which resembled osteolytic lesions frequently seen in human multiple myeloma. Dissemination of DP54-Luc cells after intratibia inoculations were detected by in vivo bioluminescent and confirmed by ex vivo imaging where luminescent tumor nodules were detected in the spleen, kidneys, intestine, lymph nodes and bones including right tibia, spine and cranium. To assess the antitumor activity of MLN2238 in the bone marrow compartment, an efficacy study was performed using the DP54-Luc intraosseous xenograft model of plasma cell malignancy. Tumor burden (bioluminescence), osteolytic lesions (mCT) and overall survival after treatment with bortezomib and MLN2238 will be presented. Conclusion The novel proteasome inhibitor MLN9708 demonstrates strong activity in the bone marrow compartment in vivo. MLN9708 is currently in human clinical development for both hematological and solid tumor indications. Disclosures Lee: Milllennium: Employment, Equity Ownership. Bannerman:Milllennium: Employment. Terkelsen:Milllennium: Employment. Bradley:Milllennium: Employment, Equity Ownership, Research Funding. Li:Milllennium: Employment. Li:Milllennium: Employment. Janz:Milllennium: Research Funding. Van Ness:Milllennium: Research Funding. Manfredi:Milllennium: Employment. Kupperman:Milllennium: Employment.

Preliminary Results of a Phase I Study of the Pan-PI3 Kinase Inhibitor SF1126 in Patients with Relapsed and Refractory Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3879-3879
Author(s):  
Sagar Lonial ◽  
R. Donald Harvey ◽  
Dixil Francis ◽  
Engin Gul ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Solid Tumor ◽  
Stable Disease ◽  
Research Funding ◽  
Median Number ◽  
Pi3k Inhibitor ◽  
Post Infusion

Abstract Abstract 3879 Poster Board III-815 Introduction Preclinical and clinical studies have demonstrated the central importance of the PI3K/AKT axis in malignant cell survival and proliferation, yet few therapeutic options have been available. SF1126 is a conjugate comprised of the well-characterized PI3K inhibitor SF1101 (LY294002) attached to a vascular-targeting tetra-peptide (SF1174) designed to bind to RGD-recognizing integrin receptors expressed on endothelial and tumor cells resulting in angiogenesis inhibition and direct antitumor effect. SF1126 has recently demonstrated reversal of resistance mediated through the PI3K/PTEN pathway in trastuzumab-resistant HER2-over-expressing breast cancer cell lines. From the parallel solid tumor study (ASCO 2009), SF1126 was well tolerated, inhibited the PI3K pathway selectively in tumor tissue, and resulted in stable disease in a heavily pretreated population. The rationale for using SF1126 in myeloma is based upon a body of work from Durden et al. (ASH 2007) and David et al. (ASH 2008) demonstrating in vivo and in vitro activity in human myeloma cell lines and xenograft models. These studies demonstrated SF1126 has activity at 5-10uM and combines safely and with enhanced efficacy with dexamethasone, melphalan, and bortezomib. Methods Patients were eligible if they had relapsed or refractory myeloma with at least 2 prior lines of therapy. Dose escalation using Bayesian methodology [Escalation With Overdose Control (EWOC)] incorporated information from the solid tumor trial along with information from this trial. In addition to standard measures of efficacy, a novel assay assessing in vivo PI3K inhibition was evaluated. Briefly, we have developed a protocol for multiparameter flow cytometry analysis of intracellular phosphoepitopes for monitoring pharmacodynamic (PD) molecular targets of SF1126 in study subject's myeloma cells. The aims are to determine: 1) constitutive activation of AKT (by comparing to ex vivo LY294002 treatment) 2) AKT activation in response to IGF-1 (a microenvironment stimulus) 3) inhibition of basal activation and/or inhibition of IGF-1 potentiated response following SF1126 treatment and 4) correlation of this analysis to SF1126 dose and patient response. Subjects undergo serial bone marrow (BM) sampling on day 0 and day 1 (4 hrs after dosing) of cycles 1 and 2. Results To date, a total of 7 patients have been treated with escalating doses ranging from 90 to 1110 mg/m2. Most patients were male (6), median age was 63 (50-69) and median number of prior treatments was 8 (3-10). All had documented refractory disease with bone marrow aspirates showing plasma cell percentages of 30-90%. No grade 4 drug-related toxicities have been noted to date. Approximately one-third of patients experienced grade 2 nausea/vomiting. Constitutional symptoms included fatigue and loss of appetite. Although preclinical studies demonstrated a rise in blood glucose one hour post infusion, this was not seen in any patients receiving drug. The dose limiting toxicity is still undefined. Median number of cycles is 1 (0.4-2.5), with one patient achieving stable disease (urinary protein stabilized following rapid rise prior to study initiation). All patients were taken off study due to progression. In vivo inhibitory effects of SF1126 on the pathway were demonstrated in bone marrow samples. PK data demonstrates similar PK to what has been seen in the solid tumor trial: a) SF1126 is rapidly cleared post-infusion; b) PK of active hydrolysis product (LY294002/SF1101) shows t1/2 ∼1.1-1.5 hrs; c) dose proportional Cmax and AUC(0-t); d) AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. Conclusion The PI3K inhibitor SF1126 resulted in similar PK to that seen in solid tumor patients and in vivo studies demonstrated that PI3K activity in the plasma cell compartment of the bone marrow had suppression of this key pathway following SF1126. Completion of the study at the current dose (1110mg/m2) and planning for a future trial combining SF1126 with other active agents in myeloma is currently ongoing. Additional PK/PD and clinical data from this trial will be available. Disclosures: Lonial: Millennium: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Garlich:Semafore Pharmaceuticals: Employment, Equity Ownership, Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria.

scholarly journals Significance of Bone Marrow Plasma Cell Percentage in Patients with Monoclonal Gammopathy of Unknown Significance Developing Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5688-5688
Author(s):  
Mona L Vekaria ◽  
Bharat Rao ◽  
Philip Kuriakose
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Time To Progression ◽  
Bone Marrow Biopsies ◽  
Monoclonal Protein ◽  
Cell Percentage

Abstract Introduction: Monoclonal gammopathies are characterized by the detection of a monoclonal immunoglobulin in the serum or urine and underlying proliferation of a plasma cell/B lymphoid clone. (1) Patients with monoclonal gammopathy of undetermined significance (MGUS) have a clonal plasma cell population in the marrow (<10%) and secrete a monoclonal protein in the serum (<3g/dL) and/or urine. However, they lack clinical features of overt Multiple Myeloma (MM) (lytic bone lesions, anemia, renal impairment and hypercalcemia). In a study from the Mayo Clinic, 59 of 241 patients with MGUS (24%) developed MM over a period of 22 years. (2) The interval from recognition of monoclonal protein to diagnosis of MM ranged from 2-29 years, indicating that patients with MGUS need to be followed indefinitely. Many risk factors have been looked at to identify those with MGUS who are at the highest risk to progress into MM. We hypothesize that a higher number of plasma cells would correlate with a greater risk of progression to MM and sought to find out if this could be documented by arbitrarily dividing patients between < or ≥5% plasma cells seen on initial bone marrow biopsy. Methods: We retrospectively reviewed patients diagnosed with MGUS at Henry Ford Hospital between 1999-2013 who underwent a bone marrow biopsy for documenting plasma cell percentage. In addition to this, we also recorded serum hemoglobin, calcium, creatinine, monoclonal protein type and amount, serum free light chains, beta-2 microglobulin and urine for monoclonal protein at the time of diagnosis of MGUS as well as last completed values. For patients that had skeletal surveys we noted if lytic lesions were present at diagnosis, as well as cytogenetics and karyotype evaluations on bone marrow biopsy samples, if completed. Results: 120 patients with bone marrow biopsies were reviewed. Out of this 17 patients were noted from initial bone marrow biopsy to have ≥10% plasma cells. The remaining 103 patients were categorized as having MGUS. While we were not able to complete full statistical analyses, we did note that 14 of these 103 (13.6%) patients went on to develop overt MM. Further evaluation of these patients revealed that 8 of 14 (57%) had bone marrow biopsies showing ≥5% plasma cells. Interestingly the average time to progression into MM in this subgroup was 1,879 days whereas in the 6 of 14 (43%) with bone marrow biopsy showing <5% plasma cells had average time to progression into MM of 1,965 days. Abnormal cytogenetics and karyotypes of the bone marrow biopsy were also seen in 37.5% of the subgroup of patients with ≥5% plasma cells whereas it was only seen in 16.7% of the subgroup of patients with <5% plasma cells. With statistical data analyses we hope to prove significance in the above collected data as well as make further correlations in regards to risk factors in patients with MGUS. Conclusion: While we have not been able to complete full statistical analyses of the collected data yet, basic review of the above patients with MGUS and ≥5% plasma cells in the bone marrow biopsy showed a trend to develop MM faster by an average of 86 days than those that had <5% plasma cells. These same patients also were more likely to have abnormal cytogenetics and karyotypes of their bone marrow biopsies. There is a need for further investigations to be done in patients with MGUS and higher risk features. It is important that hematologists be able to recognize a high risk MGUS patient as this would lead to closer monitoring and consideration for earlier aggressive treatment to potentially delay progression into overt MM. Disclosures No relevant conflicts of interest to declare.

The role of bone marrow biopsy in patients with plasma cell disorders; should all patients with a monoclonal protein be biopsied?

2019 ◽  
Vol 19 (10) ◽  
pp. e333
Author(s):  
M Hasib Sidiqi ◽  
Mohammed Aljama ◽  
Shaji Kumar ◽  
Dragan Jevremovic ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Plasma Cell ◽  
Monoclonal Protein ◽  
Plasma Cell Disorders

A Phase III Randomized Trial of Thalidomide (THAL) Plus Zoledronic Acid (ZLD) Versus Zoledronic Acid Alone In Patients with Early Stage Multiple Myeloma (MC0289)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3053-3053 ◽  
Author(s):  
Thomas E. Witzig ◽  
Sumithra Mandrekar ◽  
Kristen Detweiler-Short ◽  
Martha Q Lacy ◽  
Kristina Laumann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Zoledronic Acid ◽  
Research Funding ◽  
Response Rate ◽  
Phase Iii ◽  
P Value ◽  
Monoclonal Protein ◽  
Duration Of Response ◽  
One Year

Abstract Abstract 3053 Background: Patients with smoldering multiple myeloma (SMM) have a higher chance of progression to active MM than patients with monoclonal gammopathy of undetermined significance (MGUS). Since active MM remains incurable and since patients with SMM can have a long time to requiring treatment, observation remains an option for these patients. Bisphosphonates can prevent the bone complications of myeloma. The immunomodulatory (IMiD) drugs are well-tolerated and have documented anti-tumor activity in active MM. We hypothesized that treatment with the IMiD THAL and a bisphosphonate (ZLD) would prolong the time to progression (TTP) over the control arm of ZLD alone. This is the first report of this phase III trial of THAL/ZLD vs ZLD alone for patients with untreated SMM. Goals: The primary goal of this trial was to compare the TTP between patients treated with THAL/ZLD versus ZLD alone in asymptomatic MM. Secondary goals were progression rate at one year, response rate, duration of response, time to next therapy, and toxicity. Methods: Patients were required to have measurable disease as defined by either a serum monoclonal protein >1.0 g by protein electrophoresis or nephelometry or >200 mg of monoclonal protein in the urine on 24 hour electrophoresis or a measurable soft tissue plasmacytoma; >10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index; absolute neutrophil count >1500/μL; platelet count >100,000/μL; creatinine <2.0 mg/dL, and a performance status of 0, 1, or 2. Patients could not have symptomatic MM that required chemotherapy. The statistical plan was to accrue 120 eligible patients (60 per arm) over 4 years and after a minimum follow-up of 12 months the study would provide >90% power at a type I error rate of 0.05 to detect an increase in the median TTP from 12 months (ZLD) to 24 months (THAL/ZLD), and >80% power to detect an increase in median TTP from 12 to 21 months). Results: The study was activated in July 2003 and closed March 2009 due to slow accrual. Sixty-eight patients (35 Thal/ZLD; 33 ZLD) with a median age 63 years (range, 47–84) were randomized. The median TTP for Thal/ZLD versus ZLD was 2.4 years versus 1.2 years, respectively, P=0.02 one-sided log-rank. After adjusting for pre-specified stratification factors, the hazard ratio for TTP was 2.2 (one-sided p value = 0.01, univariate stratified Cox PH model) for ZLD compared to Thal/ZLD. 89% of patients on the Thal/ZLD arm were progression-free survival (PFS) at one year compared to 55% on ZLD alone (one-sided p<0.001, chi-square). Similar results were obtained (Table and Figures) when the CRAB (calcium, renal, anemia, bone) criteria were applied. Confirmed response was evaluated using the first 12 months of treatment. In the Thal/ZLD arm the response rate was 31% with a median duration of response of 5.1 years (95% CI: 1.9 - NA). There were no confirmed responses in the ZLD alone arm. The median overall survival has not been reached for either arm. In regards to toxicity, no grade 5 adverse events (AEs) have been reported. Thirty patients have reported grade 3+ AEs (17 Thal/ZLD; 13 ZLD, Fisher's exact p-value 0.47). Eight patients have reported grade 4 adverse events (5 Thal/ZLD; 3 ZLD, Fisher's exact p-value 0.71). Overall, only one grade 4 event was felt to be at least possibly related to study treatment – grade 4 neutropenia in Thal/ZLD. Conclusions: While the trial did not meet its planned accrual goals, there was a significant improvement in improved in outcomes in the Thal/ZLD arm compared to control (ZLD). Thal/ZLD produces anti-tumor responses that are quite durable with the median response duration of over 5 years. ZLD alone did not produce any anti-tumor responses. This study indicates that a non-chemotherapy approach can be effective in SMM and may be a useful strategy to test in future studies. Disclosures: Off Label Use: Thalidomide for smoldering myeloma. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria.

AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4044-4044
Author(s):  
Wesley Witteles ◽  
Ronald Witteles ◽  
Michaela Liedtke ◽  
Sally Arai ◽  
Richard Lafayette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Renal Involvement ◽  
World Health ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Bone Marrow Biopsies

Abstract Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with <10% plasma cells (p=NS). Discussion: As defined by bone marrow plasma cell involvement, a strikingly high percentage (84%) of AL amyloidosis patients would be considered to have concurrent myeloma. This figure is much higher than has been traditionally quoted in the literature, likely due to the utilization of newer methods of counting plasma cells. There was a low prevalence of myeloma-associated end-organ effects (hypercalcemia, anemia, renal insufficiency, lytic bone lesions), and a myeloma diagnosis had no impact on survival. Conclusion: In this cohort of AL amyloid patients, concomitant myeloma was present in the vast majority of patients using modern diagnostic techniques. The significance of this diagnosis appears to be minimal – calling into question whether the diagnostic criteria for myeloma should be redefined in this population. Disclosures: Witteles: Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding.

Bone Marrow Biopsy May Be Required During the Initial Evaluation of Individuals with Asymptomatic Monoclonal Gammopathy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5067-5067
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Evangelos Terpos ◽  
Maria Gkotzamanidou ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Magdalini Migkou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Plasma Cell ◽  
Light Chain ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Incidental Finding ◽  
M Protein ◽  
Monoclonal Protein

Abstract Abstract 5067 The incidental finding of a monoclonal gammopathy during workup for various conditions or in the context of a routine check-up is increasingly common. Several “patients” are then referred for diagnostic evaluation of their monoclonal gammopathy and additional workup is needed. It has been proposed that a bone marrow (BM) aspirate and biopsy is indicated when the monoclonal protein (M-protein) is ≥1.5 g/dL, when abnormalities are noted in the complete blood cell count, serum creatinine level, serum calcium level, or radiographic bone survey, in individuals with non-IgG monoclonal gammopathy and in those with an abnormal serum free light chain (FLC) ratio. The aim of this study was to identify factors that could aid in the evaluation of individuals presenting with asymptomatic monoclonal gammopathy and in whom invasive diagnostic testing with a bone marrow biopsy is considered. Thus, we analyzed our database and identified patients who were referred to the Department of Clinical Therapeutics of the University of Athens, Greece, for evaluation of asymptomatic monoclonal gammopathy and in whom a BM trephine biopsy, a serum and urine protein electrophoresis (SPEP) with immunofixation and quantitative immunoglobulins were performed. SPEPs were scanned and M-protein was measured using imaging analysis software. Patients with a monoclonal M-protein ≥ 3 g/dl (30 g/L), i.e. those diagnosed with asymptomatic/smoldering myeloma (SMM) or Waldenstrom's macorglobulinemia based on the standard criteria, were not included in the analysis. Clonality of BM plasma cells or lymphoplasmacytes was assessed by immunohistochemistry. Patients who eventually were diagnosed with plasma cell related conditions (i.e. amyloidosis, peripheral neuropathy, dermatoses, etc.) were also excluded from the analysis. Our analysis included 161 patients: 53% were females, median age was 64 year (range 33–89 years), 53% had a monoclonal IgG protein, 15.5% had a monoclonal IgA protein, 24% a monoclonal IgM protein and 2.5% had only a monoclonal light chain, while 4% had a biclonal protein. In 64% of patients the monoclonal light chain was kappa and in 37% was lambda. The median serum M-protein was 0.948 g/dl (range 0.1–2.99 g/dl); 52% of patients had an M-protein of <1 g/dl and 79% of <2 g/dl. Immunoparesis of at least one of the uninvolved immunoglobulins was present in 38% of cases and of both of the uninvolved immunoglobulins in 6%. Median BM infiltration by monoclonal plasma cells or lymphoplasmacytes was 15%. In 66.5% of individuals there was a BM infiltration of ≥10% by monoclonal plasma cells or lymphoplasmacytes, while in 10% of the studied cases the BM infiltration was ≥50%. A significant correlation of the size of M-protein and of the infiltration of the BM was found (R=0.592, p<0.001). However, 27% of patients with M-protein <0.5 g/dl had ≥10% clonal plasma cells or lymphoplasmacytes in their BM biopsies. The respective rates were 46% for those with M-protein <1 g/dl, 54% for those with M-protein 1.5 g/dl and 58% for those with M-protein <2 g/dl. Ninety per cent of those who had immunoparesis of at least one of the uninvolved immunoglobulins had ≥10% clonal plasma cells or lymphoplasmacytes. A BM infiltration of ≥10% was more frequent in individuals with a monoclonal IgG or IgA protein (72% and 80%, respectively) vs. 45% of those with a monoclonal IgM protein (p=0.015). Light chain isotype, age and gender were not predictive of the degree of BM plasma cell infiltration. In multivariate analysis, immunoparesis of at least one of the uninvolved immunoglobulins (OR: 6.45, 95% CI: 2.32–18, p<0.001), an IgG or IgA monoclonal protein (OR: 2.67, 95% CI: 1.1–6.4, p=0.028) and an M-protein of ≥1 g/dl (OR: 5.4, 95% CI: 2.23–13) were independently associated with the presence of ≥10% of clonal infiltration in BM biopsy. By combining the above risk factors we found that in those who had all three, 97% had ≥10% clonal cells in the BM biopsy, while in those with 0–1 of the above factors the probability to find ≥10% clonal cells was 43%. These findings indicate that even patients with low risk for BM infiltration by clonal plasma cells, may be diagnosed as SMM when a BM biopsy is performed. In conclusion, our data on a large number of individuals with asymptomatic monoclonal gammopathy who underwent a BM biopsy may indicate that the latter exam may provide useful information and could be included in the standard initial workup of these individuals. Disclosures: No relevant conflicts of interest to declare.

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.

Natural History of Amyloidosis Isolated to Fat and Bone Marrow Aspirate

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5303-5303
Author(s):  
Rajshekhar Chakraborty ◽  
Morie A. Gertz ◽  
Angela Dispenzieri ◽  
Wilson I. Gonsalves ◽  
Ronald S. Go ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Natural History ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Systemic Amyloidosis ◽  
Plasma Cell Disorder ◽  
Cell Disorder

Abstract Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

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