New Developments in Diagnosis, Prognosis, and Assessment of Response in Multiple Myeloma

Abstract

The past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to monitor treatment response. In 2014, the updated IMWG diagnostic criteria changed the definition of multiple myeloma; from being a disease defined by symptoms to a disease defined by biomarkers. Today, modern combination therapies have reported up to 60-80% of patients reaching a complete response. As a logical and necessary step forward, investigators have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. Recent meta-analysis data show that MRD negativity is associated with longer progression-free survival and overall survival. In 2016, the updated IMWG response criteria include MRD as the deepest level of treatment response in multiple myeloma. Simultaneously, we are still quite behind in our understanding of the heterogeneous biology of multiple myeloma and its implications to therapy. Emerging DNA sequencing data show that newly diagnosed multiple myeloma patients have a broad range of mutations which are distributed unevenly in multiple parallel sub-clones present already at diagnosis. To move beyond the ill-defined category “high-risk multiple myeloma” which confers to ∼25% of all newly diagnosed patients, prospective studies are needed to dissect tumor biology and define multiple myeloma subtypes, and, based on biology, seek to define rational therapies for individual subtypes. This paper discusses novel insights and gives perspectives on diagnosis and MRD monitoring and future directions for prognosis and clinical management of multiple myeloma.

Nonsecretory Multiple Myeloma Presenting as Recurrent Vertebral Compression Fractures in an Older Male Patient

“…4,5) The definition of MM from the 2014 International Myeloma Working Group includes 10% or more clonal plasma cells in the bone marrow or biopsy-proven bony or extramedullary plasmacytoma and one or more of the seven listed criteria (hypercalcemia, renal insufficiency, anemia, bone lesions, clonal bone marrow plasma cells ≥60%, involved/uninvolved SFLC ratio ≥100 and involved SFLC concentration ≥10 mg/dL, and 2 or more focal lesions based on MRI studies of the skeleton). 6) The International Myeloma Working Group still defines NSMM as MM lacking monoclonal protein on serum or urine electrophoresis. 7) However, this definition is probably not sufficient since an Ig component is actively secreted in MM.…”

“…7) However, this definition is probably not sufficient since an Ig component is actively secreted in MM. 7) Thus, NSMM patients can more accurately be divided into at least 4 groups with separate molecular mechanisms 6,7) : (1) Oligo secretors/FLC-restricted MMs: this tumor is a subset with impaired secretion among tumors with defects in Ig production, which can produce small amounts of light chains. Their protein secretion may not be as high as that seen in typical myeloma, but it can be measured by the SFLC assay.…”

GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial

“…Progression was defined as per International Myeloma Working Group (IMWG) to include an increase in the paraprotein by ≥25% and at least 5g/L, or >25% increase in difference between involved and uninvolved light chain level, with an absolute increase of >0.1g/L. Response was defined as at least an IMWG minimal response, including a reduction in the paraprotein by ≥25% . In the case of light chain only myeloma, a modified criteria of a 25% decrease in the difference between the involved and uninvolved light chains and an absolute reduction of at least 100 mg/L was chosen as a minimal response criteria is not available for light chain only myeloma.…”

Progress and Paradigms in Multiple Myeloma

“…As detailed by Landgren and Rajkumar (5), the definition of multiple myeloma (MM) has traditionally included excess monoclonal bone marrow (BM) plasma cells in the setting of monoclonal protein in blood and/or urine, and treatment was initiated only in the setting of disease-related manifestations including hypercalcemia, renal dysfunction, anemia or bone disease (CRAB). Individuals at earlier stages in the spectrum of plasma cell dyscrasias, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) with lower amounts of monoclonal protein and BM plasma cells, were followed without therapy.…”