Recent developement, treatment, smoldering myeloma

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy that develops over years from the asymptomatic precursors, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma. Recent evidence shows that by initiating treatment at an asymptomatic stage, outcomes in MM can be significantly improved. However, a vast majority of MM patients are diagnosed after the development of symptomatic end-organ damage and cannot reap the benefits of early treatment. The precursors of MM are easily detected by serum protein electrophoresis and free light chain assay of the serum, raising the question of whether population-based screening could detect MM at an asymptomatic stage and significantly expand the availability of early treatment in MM...

BACKGROUND: Multiple myeloma is the second most common hematologic malignancy, which to date remains incurable despite advances in treatment strategies including the use of novel substances such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. SUMMARY: The bone marrow-based disease is preceded by the 2 sequential premalignant conditions: monoclonal gammo-pathy of undetermined significance and smoldering myeloma. Plasma cell leukemia and extramedullary disease occur, when malignant clones lose their dependency on the bone marrow...

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma...

Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment...

Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course...

PURPOSE OF REVIEW: Smoldering multiple myeloma (SMM) is defined as an asymptomatic clonal proliferation of pre-malignant plasma cells and an increased risk of progression to multiple myeloma (MM) relative to monoclonal gammopathy of undetermined significance. Whether patients with SMM should be treated prior to development of symptomatic disease is fiercely debated and is a highly active area of research. RECENT FINDINGS: The ECOG E3A06 study demonstrated that early treatment with lenalidomide significantly reduced the risk of progression to MM compared to observation in patients with high risk SMM...

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma...

There is remarkable progress in the treatment of multiple myeloma (MM) with significant improvement in survival in the past 10 years. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) can evolve into symptomatic multiple myeloma (sy-MM) with organ involvement. SMM has associated with a much higher progression to MM compared to MGUS. In 2014, International Myeloma Working Group (IMWG) reclassified ultra-high-risk smoldering myeloma patients with bone marrow plasma cells > 60% or serum-free light chain ratio (FLCr) > 100 or > 1 focal bone lesion on the magnetic resonance imaging as MM...

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients' serum and urine...

RATIONALE: Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common...

Currently the standard of care for smoldering multiple myeloma (SMM) is "watch and wait." However, in recent years the treatment for multiple myeloma (MM) has shifted from cytotoxic chemotherapy with poor efficacy to less toxic, more effective treatments. Therefore, the standard for SMM is coming into question, especially for patients at the highest risk of developing MM. There are currently multiple active clinical trials investigating earlier intervention in patients with SMM. This article will review the history of SMM and how the current standard of care came to be...

The interest of 18Fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging in the management of patients with multiple myeloma (MM) for the workup at diagnosis and for therapeutic evaluation has recently been demonstrated. FDG-PET is a powerful imaging tool for bone lesions detection at initial diagnosis with high sensitivity and specificity values. The independent pejorative prognostic value on progression-free survival (PFS) and overall survival (OS) of baseline PET-derived parameters (presence of extra-medullary disease (EMD), number of focal bone lesions (FLs), and maximum standardized uptake values [SUVmax ]) has been reported in several large independent prospective studies...

Smoldering multiple myeloma (SMM) is an asymptomatic, intermediate stage positioned between the plasma cell disorders of monoclonal gammopathy of undermined significance and overt multiple myeloma (MM). Although the patients with SMM have a higher risk of progression to MM in comparison to their counterparts with monoclonal gammopathy of undermined significance, their clinical course can be highly variable. The standard of care for SMM, irrespective of the risk status, continues to be observation due to paucity of high-level evidence demonstrating survival or quality-of-life benefit with early intervention...

the high expression of a number of surface antigens on malignant plasma cells, the bone marrow micro-environment and immune effector T cells, makes these appealing targets for immune therapy with monoclonal antibodies (mAbs). Areas covered: Two mAbs, anti-CD38 daratumumab (Dara) and anti-SLAMF7 elotuzumab (Elo), have achieved recent regulatory approval for relapsed or refractory MM (RRMM) and are currently being explored as possible treatment options in novel combinations and different settings. This review discusses the current landscape and possible development of anti-CD38 and anti-SLAMF7 mAbs...

One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal proliferation of malignant plasma cells mainly in the bone marrow (BM)...

PURPOSE: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy...

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use...

Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naïve patient...

Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype-switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra-high-risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super-enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3)...

Smoldering multiple myeloma (SMM) is a plasma cell disorder first described in 1980 when 6 patients were observed to meet the diagnostic criteria of multiple myeloma, defined as bone marrow plasmacytosis of 10% or greater or M protein level of 3 g/dL or greater, but did not have end-organ damage. Subsequent studies showed that the cumulative risk of SMM progression to symptomatic myeloma in 15 years was 73%. Since this time, advances have been made in understanding the biology of progression; namely, the contribution of branching evolution and microenvironment models to clonal heterogeneity...