Multiple myeloma and related plasma cell dyscrasias

Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.

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Chronic Inflammation May Predispose to the Development of Plasma Cell Dyscrasias.

Blood ◽

10.1182/blood.v104.11.3650.3650 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3650-3650

Author(s):

Elizabeth M. Blanchard ◽

Elizabeth Lawler ◽

Mary Brophy ◽

Louis Fiore ◽

Nikhil C. Munshi

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Myeloma ◽

Hepatitis C ◽

Hepatitis B ◽

Plasma Cell ◽

Agent Orange ◽

Source Population ◽

Chronic Infections ◽

Inflammatory Conditions ◽

Plasma Cell Dyscrasias

Abstract Background: It has been hypothesized that chronic antigenic stimulation in response to chronic inflammation or infection may predispose to the development of plasma cell dyscrasias (PCD) including multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Using Department of Veterans Affairs (VA) administrative databases we explored associations between PCD and chronic inflammatory diseases (CID) including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), psoriasis, asthma, the chronic infections hepatitis C (HEPC) and hepatitis B (HEPB), as well as history of agent orange exposure (AO). Methods: To identify a source population of veterans who are regular users of the VA system for medical care, we gathered data on patients seen in the inpatient or outpatient setting with a diagnosis of hypertension (HTN), diabetes (DM) or coronary artery disease (CAD) between Oct 1, 1996 and Sept 30, 2003. This source population represents more than 70% of all users of the VA healthcare system. Within this population, we identified from ICD-9 codes all prevalent cases of PCD inclusive of MM and MGUS and also current diagnoses of RA, HEPB, HEPC, IBD, psoriasis and asthma. Agent Orange (AO) exposure was ascertained through administrative records. Crude and age-adjusted prevalence odds ratios for associations with PCD are reported. Results: The source population consisted of 4,050,741 veterans who visited the VA Healthcare System nationwide during this time period. Of these patients, 12,936 (0.32%) carried a diagnosis of PCD, including either multiple myeloma or MGUS or both. Odds ratios are presented in Table I. Table I: Associations of Plasma Cell Dyscrasias and Inflammatory Conditions Chronic Condition # of cases Crude OR (95% CI) Age-adjusted OR (95% CI) RA 92511 2.20 (2.03,2.39) 2.15 (1.98,2.32) Hepatitis B 22958 2.03 (1.72,2.38) 3.07 (2.60,3.61) Hepatitis C 116615 1.40 (1.28,1.53) 2.326 (2.12,2.55) IBD 2675 2.83 (1.89,4.23) 3.26 (2.18,4.87) Asthma 183753 1.19 (1.10,1.29) 1.30 (1.20,1.40) Psoriasis 76697 1.43 (1.29,1.59) 1.42 (1.28,1.58) BPH 989271 1.81 (1.75,1.88) 1.53 (1.47,1.58) Agent Orange 69710 1.62 (1.45,1.80) 2.37 (2.07,2.58) Conclusions: We have identified strong associations (OR > 2) between plasma cell dyscrasias and inflammatory conditions including rheumatoid arthritis, IBD and the chronic infections hepatitis B and C. Agent Orange exposure (already known to be associated with plasma cell dyscrasias) served as the positive control and had an age adjusted OR of 2.37. We suspect that residual confounding may be responsible for what appears to be a weak association with benign prostatic hypertrophy (BPH). Asthma and psoriasis do not appear to have a strong association with the development of plasma cell dyscrasias. A detailed ethnic and age adjusted analysis that includes other inflammatory and non-inflammatory conditions is underway in an effort to identify other associations. This study provides a basis for future research efforts focused on identifying cytokine pathways that may link these disorders and subsequently serve as targets for novel interventions to prevent the development or progression of plasma cell dyscrasias.

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Military Service in Vietnam/Korea and Serum Dioxin Levels Do Not Affect the Outcomes of Patients Diagnosed with Plasma Cell Dyscrasias

Blood ◽

10.1182/blood.v118.21.5098.5098 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5098-5098

Author(s):

Prasanth Ganesan ◽

Emil Kuriakose ◽

Carla Smith ◽

Robert T Harris ◽

Jonathan E Dowell ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Military Service ◽

Conflicts Of Interest ◽

Military Veterans ◽

Cell Transplant ◽

Increased Risk ◽

Plasma Cell Dyscrasias ◽

Chlorinated Dioxins ◽

The Impact

Abstract Abstract 5098 Military Service in Vietnam/Korea and Serum Dioxin Levels Do Not Affect the Outcomes of Patients Diagnosed with Plasma Cell Dyscrasias. Background: Exposure to dioxin, a contaminant found in herbicides has been associated with increased risk of cancers including multiple myeloma and postulated to cause poorer survival in the exposed population. Military personnel, especially those who had served in Vietnam and Korea have an increased risk of dioxin (which contaminated the herbicide Agent Orange which was sprayed during these wars) exposure. We looked at the impact of dioxin exposure and blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which is the most toxic of the poly-chlorinated dioxins on the survival outcomes of military veterans diagnosed with plasma cell dyscrasias (PCD). Methods: A prospective analysis of newly diagnosed and existing myeloma patients was done. Information regarding the patient and disease characteristics, the military record, and outcomes were collected. Approximately 60 ml of heparinised peripheral blood was collected and immediately frozen at −20 degrees. These samples were shipped to Eurofins Laboratory, Hamburg, Germany for dioxin level measurement. Patients' blood lipid levels were also measured and the dioxin toxic equivalent (Teq) was calculated. Overall survival (OS) was calculated from the date of diagnosis till death (Kaplan Meier method). Cox regression and log rank analysis were used to look for prognostic variables. Results: Fifty two (52) patients of PCD were available for analysis. Majority had a diagnosis of multiple myeloma. Forty one underwent treatment including stem cell transplant in 16 (Table 1 shows the patient characteristics, laboratory results and treatment outcomes). During a median follow up of 54 months (2–348), 21 patients died (progressive myeloma: 12(23%), cardiac failure: 3 (5.7%), infections: 1 (1.9%), acute myeloid leukemia: 1 (1.9%), pulmonary embolism: 1 (1.9%) and unknown: 3 (5.7%). The median OS was 111 mos (95% CI 56–155) and the estimated survival at 5 yrs was 69.5% (+/− SE 0.067). The 5 yr OS was negatively impacted by abnormal cytogenetics (40.3 % vs. 75.5%; p=0.012), and service in the army (non-army vs. army: 83% vs. 40%; p=0.032). Patients who had served in Vietnam had outcomes similar to others; Korean War veterans had a poorer OS, but this was not statistically significant (5 yr OS 68% vs. 48%; p=0.1). There was no association between TCDD levels or the Teq with OS. Abnormal cytogenetics was the only significant factor on multivariate analysis. Conclusions: We did not find an association between military service in Korea/Vietnam or serum dioxin levels and poor survival in military veterans diagnosed with Plasma cell dyscrasias. However, a study of a larger sample of myeloma patients with similar service and exposure histories maybe warranted. Disclosures: No relevant conflicts of interest to declare.

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Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines

Leukemia ◽

10.1038/leu.2017.345 ◽

2017 ◽

Vol 32 (4) ◽

pp. 1043-1047 ◽

Cited By ~ 34

Author(s):

F Maura ◽

M Petljak ◽

M Lionetti ◽

I Cifola ◽

W Liang ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Plasma Cell ◽

Myeloma Cell ◽

Prognostic Impact ◽

Induced Mutations ◽

Multiple Myeloma Cell ◽

Plasma Cell Dyscrasias

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Amyloid neuropathy in multiple myeloma and other plasma cell dyscrasias

Journal of the Neurological Sciences ◽

10.1016/0022-510x(83)90041-2 ◽

1983 ◽

Vol 59 (2) ◽

pp. 237-246 ◽

Cited By ~ 24

Author(s):

Jacob P. Verghese ◽

Walter G. Bradley ◽

Raffaello Nemni ◽

Keith P.W.J. McAdam

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cell Dyscrasias

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Plasma Cell Dyscrasias in HIV, Epidemiology, Presentation and Treatment Characteristics and Its Strong Association with Hepatitis C- Report Form a Large HIV Cohort

Blood ◽

10.1182/blood-2018-99-119222 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5607-5607

Author(s):

Nishi Shah ◽

Sakshi Jasra ◽

Ana Acuna-Villaorduna ◽

Urvi A Shah ◽

Gurbakhash Kaur ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Plasma Cell ◽

Heavy Chain ◽

Autologous Transplantation ◽

Bone Lesions ◽

Cell Transplant ◽

Hiv Diagnosis ◽

Plasma Cell Dyscrasias ◽

Successful Outcomes

Abstract Introduction: As people with HIV live longer, the epidemiology of plasma cell disorders (PCD) including MGUS, smoldering myeloma and Multiple myeloma (MM) becomes relevant and remains unknown. Moreover, patients with HIV have a higher incidence of monoclonal proteins which may not be related to an underlying lymphoproliferative disorder[1, 2] . There are mostly anecdotal reports and very few studies in HIV myeloma[3]. A retrospective study of 10 patients with HIV+ve symptomatic MM reported possible therapeutic benefit of ART and reported better overall survival of HIV+ve MM on ART as compared to HIV -ve MM. There is a paucity of data in PCD in this population whose incidence can be expected to increase globally. We conducted a single-institution retrospective study to look at the incidence of PCD. Methodology:We reviewed an electronic database of patients with HIV related PCD treated at Montefiore Medical Center between 2001 and 2018. All patients with a new diagnosis of PCD between January 1 2001 to July 15 2018 were identified. Data on patient demographics, HIV status, clinical outcomes (including mortality) and therapy was collected. Results: Between 2001 and 2018, 14438 patients were identified with HIV and 1986 patients had a monoclonal band in SPEP (13.8%). Based on our previous study, patients who had a definitive monoclonal band or suspected MM underwent a BM biopsy. 34 patients were diagnosed with PCD --MGUS 16 (47.05%), Smoldering MM 1 (2.94%), MM 16 (47.05%) and Primary plasma cell leukemia (PCL) 1 (2.94%). The majority of the patients were AA consistent with demographics of the Bronx. Interestingly HCV co-infection was identified in 50% (n=17) of patients and HBV co-infection was present in 15% (n=5) patients. The median CD4 count was 381 (12-1080), median viral load 237 (0-501534) and 53% patients were on ART at the time of diagnosis. The median time from HIV diagnosis was 13.9 (-2.8 to 29) years. In patients with MGUS the predominant heavy chain involvement was IgG, the median protein on SPEP was 1.1 g (0.7-1.9 g) and percentage of BM involvement was 5% (2-10%). In patients with MM IgG was the predominant heavy chain involved. On presentation, ISS Stage was Stage I in 2 patients (15.4%), 4 (30.7%) had at least Stage 2, 7 patients (53.9%) had stage 3. On presentation, 10 (58.8%) patients presented with anemia, 10 (58.8%) presented with renal impairment (Cr>=1.3), 16 (94.1%) presented with bone lesions, 6 (37.5%) presented with hypercalcemia. 5 patients (34.6%) had extramedullary presentation including 1 patient (2.9%) with PCL, 2 (5.8%) with anaplastic plasmacytoma. All patients were treated with an imid or bortezomib based regimen and there were no unusual side effects in these patients. 5 patients (29.4%) underwent autologous stem cell transplant with successful outcomes. Discussion: The prevalence of a positive SPEP is 13.8% in patients with HIV and the prevalence of plasma cell dyscrasias (PCD) in our population is 0.02%. A previous study from this cohort[2] showed that approximately 6.4% of patients with a positive SPEP developed hematological malignancy and all patients with a faint monoclonal band had lymphoma (70.5%) and those with a definite monoclonal band had myeloma (29.5%). Even though prevalence is less than the general population rate of 3%, as patients with HIV live longer this number may increase. In our study there was a high rate of co-infection with HCV in patients who had a PCD and this needs further investigation to determine causality. PCD developed at a median of 13.9 years after HIV diagnosis. The ISS staging distribution in patients presenting with myeloma is consistent with non HIV myeloma. People with HIV tolerate standard imid or proteasome inhibitor based triple drug therapy and have successful outcomes with autologous transplantation. This is the largest cohort and report describing PCD in HIV population. References:Jou, E., et al., Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies. Ann Hematol, 2016. 95(4): p. 575-80.Jou, E., et al., Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients. Hematol Oncol, 2017. 35(1): p. 64-68.Li, G., et al., A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: A potential therapeutic effect of HAART in multiple myeloma. Leukemia Research, 2014. 38(9): p. 1079-1084. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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