04 April 2013

On the first day of the 14th International Myeloma Workshop in Kyoto, Japan, the conference got off to a great start, with an overview of current understanding in the pathology of multiple myeloma (MM) in terms of both the genetics and cell biology, as well as a review of the latest imaging techniques used to predict clinical outcomes.

 

The pathology of MM updated

The elucidate of the mechanisms behind MM not only enables a better understanding of the disease process but how this can be influenced by current and novel therapeutics to enhance the care of patients with MM.

Around 7-10 distinct biological subtypes of MM have been identified, the majority linked to specific immunoglobulin translocations. Next generation sequencing has identified both known and novel mutations and has further expanded out knowledge of the genetic events that occur in each individual tumour. This knowledge, when translated into current clinical practice in the management of MM, will progress the development of additional novel targeted therapeutics.

Malignant plasma B cells characteristic of MM rely on their interactions with a number of other cells, including bone marrow stromal cells (BMSCs), to thrive. This interaction can affect tumour cell signalling, survival, proliferation and drug sensitivity. There has been particular interest in how BMSCs confer resistance of MM cells to different classes of therapeutics, depending on the specific microenvironmental context. Research is ongoing to better understand the mechanisms behind these microenvironmental interactions, which will ultimately influence the evaluation and selection of candidate agents for the treatment of MM.

Myeloma bone disease

Myeloma bone disease (MBD) results from increased osteoclast and decreased osteoblast activity induced by MM cells, leading to the appearance of lytic bone lesions, and occurs in around 80% of MM patients. This is mediated through an increase in RANKL (receptor activator of NFκB ligand). A feature of MBD is the lack of bone repair at the site of these lytic lesions, even in patients with prolonged remission. A number of targets, including the inhibitor of osteoblast activity, DKK1, have been identified. These targets could provide potential strategies to treat MBD and may indirectly impact on the tumour itself. Interestingly, in addition to anti-myeloma properties, carfilzomib and oprozomib have been shown to effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.

Imaging techniques as prognostic indicators in MM

Magnetic resonance imaging (MRI) and positron emission tomography (PET) integrated with computed tomography (CT), are being investigated in MM. Imaging not only plays an important role in the diagnosis and management of MM, but also in the prediction of clinical outcomes. MRI has been particularly useful in the assessment of risk of early progression from asymptomatic or smouldering MM to symptomatic disease. Both PET/CT and MRI can help to predict outcomes at diagnosis in symptomatic disease, as well as during the early phases of treatment and at the end of treatment. PET/CT can also predict risk of progression in patients achieving conventionally defined complete responses. 18F-fluorodeoxyglucose (18F-FDG) is commonly used in PET/CT. However, it is not a cancer-specific agent. This has led to the development of the amino acid based radiolabelled tracer, 11C-labelled methionine (MET). Preliminary data suggest that MET-PET can identify more viable lesions in patients with plasma cell malignancies (which include MM) than 18F-FDG. With further study, this imaging technique may enable improvements in future therapeutic decision making in the management of MM.