The evolution of immune dysfunction in multiple myeloma.

OBJECTIVES: This review discusses the role of immune dysfunction at the different stages of multiple myeloma (MM). METHODS: Narrative review. RESULTS: MM is a complex disease and immune dysfunction has been known to play an important role in disease pathogenesis, progression, and drug resistance. MM is known to be preceded by asymptomatic precursor states and progression from the precursor states to MM is likely related to a progressive impairment of the immune system. CONCLUSIONS: An understanding of the role of the immune system in the progression of MM is important to guide the development of immunotherapeutic strategies for this disease.

Treatment horizon in multiple myeloma.

OBJECTIVES: This paper reviews current and emerging therapies for multiple myeloma (MM). METHODS: Narrative review. RESULTS: MM is a complex, heterogenous condition, and in recent years there has been an expansion in the number and range of treatments. Several new treatment approaches, including enhanced monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen-T-cell therapy are under development. CONCLUSIONS: The emergence of new treatments that aim to tackle MM-associated immune dysfunction has led to improvements in overall survival.

Immunoglobulin M Monoclonal Gammopathies of Clinical Significance.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler's syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Fibrillary Glomerulonephritis and Monoclonal Gammopathy: Potential Diagnostic Challenges.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.

Genomic characterization of functional high-risk multiple myeloma patients.

Multiple myeloma (MM) patients with suboptimal response to induction therapy or early relapse, classified as the functional high-risk (FHR) patients, have been shown to have poor outcomes. We evaluated newly-diagnosed MM patients in the CoMMpass dataset and divided them into three groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or complete loss of functional TP53 (bi-allelic deletion of TP53 or mono-allelic deletion of 17p13 (del17p13) and TP53 mutation) or 1q21 gain and International Staging System (ISS) stage 3; FHR group for patients who had no markers of GHR group but were refractory to induction therapy or had early relapse within 12 months; and standard-risk (SR) group for patients who did not fulfill any of the criteria for GHR or FHR. FHR patients had the worst survival. FHR patients are characterized by increased mutations affecting the IL-6/JAK/STAT3 pathway, and a gene expression profile associated with aberrant mitosis and DNA damage response. This is also corroborated by the association with the mutational signature associated with abnormal DNA damage response. We have also developed a machine learning based classifier that can identify most of these patients at diagnosis.

Daratumumab-based induction therapy for multiple myeloma: A systematic review and meta-analysis.

This study aims to evaluate the efficacy and safety of Daratumumab-based induction therapy (DBI) in newly diagnosed multiple myeloma (MM). We identified four eligible RCTs including 2735 patients. The primary outcomes of RCTs involving transplant eligible (TEMM) and non-transplant eligible MM (NTEMM) were stringent complete response (sCR) and progression-free survival (PFS) respectively. Meta-analysis was performed using random-effects models. DBI improved sCR rates for standard risk (SR) (OR 1.86, 95 % CI 1.41-2.46) but not HiR (high risk) (OR 0.78, 95 % CI 0.41-1.48) (interaction P = 0.01) TEMM. In NTEMM, DBI improved PFS in SR (HR 0.44, 95 % CI 0.35-0.55) but not HiR patients. (HR 0.81, 95 % CI 0.52-1.27) (interaction P = 0.02). In conclusion, while DBI is efficacious in SR patients, there is insufficient data to support a benefit in HiR-MM.

Natural History and Prognostic Factors at First Relapse in Multiple Myeloma.

The prognosis of multiple myeloma has considerably improved due to the introduction of novel agents in the upfront setting. However, the great majority of patients ultimately relapse, and choosing a salvage treatment at first relapse remains challenging. The natural history of first relapsed disease in the current era is also not well described. We retrospectively studied 300 patients with first relapsed myeloma seen between 2004 and 2019 from two institutes in Singapore. The median duration from diagnosis to first relapse was 22.7 months (1.1-97.0 months). Most patients received novel agent-based induction therapy, and 41.3% underwent autologous stem cell transplant. A very good partial response (VGPR) or better was achieved in 48.6%. Regarding first relapse, 50.5% were symptomatic and 19.0% received newer agent-containing regimens. Nearly a third of patients (31.7%) had a VGPR or better response. The median progression free and overall survival from first relapse was 12.0 and 44.8 months, respectively. Based on a randomized sample splitting, we first identified non-hyperdiploid karyotype at diagnosis, clinical relapse, and treatment sequence as impacting survival independently from a testing cohort, and we then further demonstrated their significance in a validation cohort. This study provides a real-world picture of first relapsed myeloma and highlights the prognostic importance of the treatment sequence.

Immunoglobulin M Paraproteinaemias.

Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15-20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of "monoclonal gammopathy of clinical significance" entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.

Immunotherapy in Multiple Myeloma.

Multiple myeloma is a complex disease and immune dysfunction has been known to play an important role in the disease pathogenesis, progression, and drug resistance. Recent efforts in drug development have been focused on immunotherapies to modify the MM disease process. Here, we summarize the emerging immunotherapies in the MM treatment landscape.

Bacterial Infection Among Patients With Multiple Myeloma Treated With Bortezomib-based Induction Therapy: Real-World Experience in an Asian Cancer Center.

BACKGROUND: The treatment landscape for multiple myeloma (MM) has progressed significantly, and over the past decade, bortezomib-based induction therapy has been a standard of care. However, the practice of antibacterial prophylaxis during induction therapy has been diverse. The aim of our study is to evaluate the proportion of patients with febrile episodes and bacteremia among patients with MM, during the first 12 weeks of bortezomib-based induction therapy, without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), in a region with high fluoroquinolone resistance rate. Of note, these patients have direct access to health care facilities and timely supportive care. PATIENTS AND METHODS: We evaluated newly diagnosed MM patients from 2014 to 2018 receiving bortezomib-based induction therapy for the proportion of patients who had febrile episodes and bacteremia in the first 12 weeks of bortezomib-based induction therapy. We also evaluated if there were factors associated with increased febrile episodes including age, absolute neutrophil count, creatinine clearance, M-band level at diagnosis, nadir platelet count, International Staging System, and Revised International Staging System. RESULTS: Of the 108 evaluable patients, there were a total of 25 (23.1%) patients who had febrile episodes, and 1 (0.9%) patient who had bacteremia during the first 12 weeks of bortezomib-based induction therapy. All patients recovered well. No deaths were seen. Febrile episodes were associated with lower absolute neutrophil count (P = .036), renal impairment (P = .013), and ISS stage (P = .026). CONCLUSION: The proportion of patients with significant bacterial infection during the first 12 weeks of bortezomib-based induction therapy without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), is low in a population with adequate access to health care facilities and timely supportive care.

Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network.

Pomalidomide is a third generation immunomodulatory drug which in combination with dexamethasone, has been shown to be active in relapsed/refractory multiple myeloma. However, the data in Asian patients remain limited. We conducted a prospective phase two clinical trial in major cancer centers in Singapore, South Korea, Taiwan, Japan and Hong Kong to assess the efficacy and safety of pomalidomide and dexamethasone combination (PomDex) +/- cyclophosphamide in Asian patients with relapsed/refractory multiple myeloma who failed lenalidomide and bortezomib. Patients were treated with pomalidomide (4 mg daily for 21 days every 4 weeks) and dexamethasone (40 mg weekly). If there is less than a minimal response after three cycles of PomDex, cyclophosphamide 300 mg/m2 can be added (PomCyDex). A total of 136 patients were enrolled. The median PFS was 9 and 10.8 months for the PomDex and PomCyDex group, respectively. The median OS was 16.3 months. This regimen appears to be active across age groups and prior lines of treatment. This combination was overall well tolerated with grade 3 and 4 adverse events of mainly cytopenias. PomDex is highly active and well-tolerated in Asian patients. The addition of cyclophosphamide can improve the response and outcomes further in patients with suboptimal response to PomDex.

Role of Conventional Karyotyping in Multiple Myeloma in the Era of Modern Treatment and FISH Analysis.

BACKGROUND: The Revised International Staging System (R-ISS) has been widely adopted to prognosticate multiple myeloma. As a result, the continued utility of conventional metaphase karyotyping has been called into question. PATIENTS AND METHODS: A multi-center study for newly diagnosed patients with multiple myeloma who received novel agent(s) at induction was conducted. Conventional metaphase karyotype information was categorized based on ploidy. We evaluated the impact of ploidy on overall survival (OS) including multivariate analysis, taking into account the R-ISS stages, transplant status, age, and novel agent(s) used at induction. We also evaluated if it is possible to identify high-risk (HR) patients with conventional karyotyping when a fluorescence in situ hybridization analysis is not available. Results were validated in an independent cohort. RESULTS: There were 308 patients evaluable. Ploidy significantly affected the OS of patients with R-ISS stage II, with non-hyperdiploid patients doing the worst. In the multivariate analysis, ploidy was significantly associated with OS. R-ISS stage II patients with or without non-hyperdiploid karyotype had significantly different survival. We replaced HR fluorescence in situ hybridization abnormalities with HR metaphase karyotypic abnormalities (non-hyperdiploid karyotype). When compared with R-ISS, there was a high level of concordance in HR patients identified using HR karyotypic abnormalities. These results were validated with an independent cohort of 375 patients. CONCLUSION: Conventional metaphase karyotyping is an independent prognostic factor even in the setting of R-ISS.

Potential Clinical Application of Genomics in Multiple Myeloma.

Multiple myeloma is a heterogeneous disease with different characteristics, and genetic aberrations play important roles in this heterogeneity. Studies have shown that these genetic aberrations are crucial in prognostication and response assessment; recent efforts have focused on their possible therapeutic implications. Despite many emerging studies being published, the best way to incorporate these results into clinical practice remains unclear. In this review paper we describe the different genomic techniques available, including the latest advancements, and discuss the potential clinical application of genomics in multiple myeloma.

Epicardial and visceral adipose tissue in relation to subclinical atherosclerosis in a Chinese population.

BACKGROUND: Body fatness is associated with risk of coronary heart disease and it has been postulated that epicardial adipose tissue (EAT) may have a particularly detrimental effect because of its localized toxic effects. We therefore aimed to examine the association between EAT and coronary artery calcification and compared this with associations for visceral adipose tissue (VAT) and other regional fat depots. METHODS: We conducted a cross-sectional study of 487 Chinese participants aged 50 years old and above, living in Singapore. Participants, free from known diabetes mellitus and coronary heart diseases, completed interviews, a health screening to evaluate obesity and cardiovascular disease risk factors, and computed tomography scans of the abdomen and coronary arteries. Associations between regional fat depots and subclinical atherosclerosis defined as CAC> = 100 were determined by multiple logistic regression analysis. RESULTS: Epicardial adipose tissue (EAT) was highly correlated with visceral adipose tissue (VAT) (Pearson r = 0.72) and trunk fat mass (r = 0.66). The age and sex-adjusted odd ratio (OR) (in 1-SD increase) of subclinical atherosclerosis was 1.28 (1.01-1.61) for EAT and 1.40 (1.04-1.88) for VAT. These associations were weaker and non-significant after adjusting for markers of dyslipidemia and hyperglycemia. Total body fat, subcutaneous abdominal fat, and leg, arm and trunk fat mass were not significantly associated with atherosclerosis. CONCLUSION: VAT and EAT showed similar associations with coronary artery calcification and the associations could be mediated by traditional risk factors in this ethnic Chinese population.