Multiple Myeloma

Multiple Myeloma (MM) is a malignancy of plasma cells that typically affects multiple sites within the bone marrow. The malignant cells secrete monoclonal antibodies (M proteins) that may thicken the blood and damage the kidneys. The disease is often symptomless for a long time and already advanced at the time of diagnosis.

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Common symptoms of advanced MM include bone pain, anemia, frequent infections, and kidney failure. In the past ten years, several novel MM drugs have appeared, which have significantly improved the survival of MM patients. Despite these recent advances, the vast majority of patients eventually relapse, and the disease remains largely incurable. Mainly affecting elderly individuals, the incidence of MM is expected to increase as a result of the aging of our population. MM is the second most common hematologic malignancy in Europe.

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Key questions

HARMONY researchers will combine data of thousands of MM patients, with the aim to predict disease course and drug response based on factors such as patient age and fitness, molecular characteristics of the malignant cells (e.g., genetic profile and immunophenotype), and disease characteristics measured with MRI or PET-CT. The ultimate goal is to improve MM treatment by allowing physicians to match patient profiles with the most promising treatment strategy. Examples of key questions that HARMONY will address for MM are:

Which factors predict therapy resistance? Why do some patients die despite of a successful initial treatment?

• The vast majority of MM patients eventually relapse. To be able to cure more patients, we need to understand the mechanisms of therapy resistance and disease course.

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What is the optimal combination of drugs for various subgroups of patients? Do less intensive treatments suffice for certain subgroups? Which subgroups benefit most from expensive drugs?

• Many novel MM drugs are extremely expensive and may cause adverse effects. HARMONY will analyze how the efficacy of various combinations of drugs relates to patient and disease characteristics, aiming to prevent over-and under-treatment and to keep healthcare affordable in the future.

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Which factors predict if and how MM progresses from a pre-malignant condition to malignant metastatic disease?

• The majority of MM patients present with advanced disease upon diagnosis, but in some patients, MM is detected in its symptomless phase (e.g., an increased M-protein level measured during a routine check-up). These individuals offer a valuable opportunity to study the mechanism of transition from early (monoclonal gammopathy of undetermined significance), to intermediate (indolent or smoldering MM), to advanced stage MM (symptomatic and ultimately resistant or refractory MM).

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What can MM tell us about the existence of putative cancer stem cells?

• Some recent scientific discoveries suggest the existence of ‘lymphoid cancer stem cells’. These may represent highly desirable targets to achieve a definitive cure. MM is a unique paradigm to study these.

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MM Features

• Type of malignant cells: plasma cells (i.e., fully differentiated B-lymphocytes that produce a single type of antibody).
• Tissue of origin: typically involves multiple sites within the bone marrow.
• Clinical symptoms: often symptomless for a long time; common symptoms of advanced MM are bone pain, frequent infections, anemia, bleeding, and weakness.
• Five-year survival in Europe: ~47%.
• Incidence in Europe: ~6 per 100,000 (38,928 new cases and 24,287 deaths per year).
• Age at diagnosis: mainly in elderly: median age at diagnosis ~65-70 years.
• Relevant outcomes: progression-free survival.

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HARMONY Leadership: MM

• Pieter Sonneveld, Erasmus MC, The Netherlands
• Jesus San Miguel, Universidad de Navarra, Spain
• Mario Boccadoro, UNITO, University of Turin, Italy

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