Study of genomic changes in multiple myeloma may lead to new approaches to treating early, smoldering myeloma

• Smoldering myeloma is often genomically indistinguishable from symptomatic myeloma, researchers find, suggesting need to redefine smoldering disease.
• Researchers identify two patterns of myeloma progression. Timing of treatment may be geared to the type each patient has.

For many people diagnosed with smoldering multiple myeloma – a condition that is often a precursor to myeloma – the shock of the diagnosis can be compounded by the distress of learning they won't receive treatment until physical symptoms of myeloma develop.

Now, Dana-Farber Cancer Institute scientists and an international team of researchers have tracked the genomic changes that occur as smoldering multiple myeloma (SMM) advances to myeloma. Their findings lay the groundwork for tests that can identify patients whose SMM is likely to progress rapidly to myeloma, and who could benefit from prompt treatment. Patients with SMM that has a longer lead time to myeloma could be candidates for preventive treatments.

The research, published online today by Nature Communications, found that SMM can progress by two distinct patterns: one in which the genetic makeup of SMM tissue doesn't change much in becoming myeloma; and one in which the transition to myeloma is marked by the appearance of new, genetically distinct groups of myeloma cells. The first type, dubbed the static progression model, tends to progress fairly quickly to myeloma. The second, called the spontaneous evolution model, usually takes longer.

The findings have implications not only for how patients with SMM are treated but for how multiple myeloma is defined, says the senior author of the study, Nikhil Munshi, MD, of Dana-Farber. "Traditionally, a diagnosis of myeloma requires not only the presence of myeloma cells but also the development of symptoms such as anemia, bone disease, too much calcium in the blood, and kidney malfunction. Treatment generally doesn't begin until symptoms appear," Munshi says. "Our study shows, however, when the disease follows the static progression model, SMM is, from a genomic standpoint, myeloma. The advance of the disease is solely a matter of an accumulation of diseased tissue. For such patients, it may make sense to begin treatment soon.

"In the spontaneous evolution model, by contrast, SMM is genomically distinct from myeloma," Munshi continues. "It advances toward myeloma only when genetic mutations create new subsets of SMM cells that develop into myeloma. Treatment for such patients might involve agents that prevent such subsets from arising."

Currently, there is no way of determining whether a patient's SMM is likely to follow the static progression or spontaneous evolution model, Munshi notes, but he and his associates are conducting research in that area.   Making such distinctions would be crucial to selecting the appropriate treatment for individual patients.

Before and after analysis

The study began with blood samples from 11 patients with SMM, all of whom went on to develop multiple myeloma over the next three-plus years. Researchers took one set of samples when patients had SMM and a second set when they were diagnosed with myeloma, and analyzed the complete genome of the myeloma cells, looking for differences between those in the myeloma set and those in the SMM set.

They found that the genomic composition of cells at the smoldering stage is very similar to that of myeloma cells, and that the course of the disease follows either the static progression or spontaneous evolution model.

The investigators also uncovered some of the processes that foul the genome of myeloma cells at key points in the development of the disease. Myeloma originates in plasma cells, which are white blood cells responsible for producing disease-fighting antibodies. As genetic mutations and other molecular derangements accumulate in the cells, they begin to grow out of control and crowd out normal, healthy cells, eventually producing the symptoms associated with myeloma.

Munshi and his colleagues found that an enzyme called activation-induced cytidine deaminase (AID), which plays a role in the development of plasma cells, is overactive early in the myeloma process, producing some of the first mutations plasma cells experience. The researchers also found that enzymes known as APOBEC cytidine deaminases become overactive at a later stage – triggering genetic changes as the disease progresses to myeloma.

"Our findings have provided important insights into the patterns of myeloma progression and into some of the mechanisms responsible for the genomic changes that occur as the disease advances," Munshi remarks. "These results suggest that multiple myeloma needs to be redefined to include some patients with smoldering myeloma, and points the way to new treatment approaches geared to the course of disease development in each patient."

The lead authors of the paper are Niccolò Bolli, MD, PhD, of the University of Milan, Milan, Italy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, and the Wellcome Trust Sanger Institute; and Francesco Maura, MD, of the University of Milan and the Wellcome Trust Sanger Institute. Co-authors are Raphael Szalat, MD, Mehmet Kemal Samur, PhD, Mariateresa Fulciniti, Masood A. Shammas, Yu Tzu Tai, PhD, and Kenneth Anderson, MD, of the Jerome Lipper Multiple Myeloma Center at Dana–Farber; Stephane Minvielle, PhD, Florence Magrangeas, PhD, and Philippe Moreau, MD, of Université de Nantes, Université d'Angers, Nantes, France; Dominik Gloznik, PhD, Anthony Fullam, PhD, Inigo Martincorena, PhD, Kevin J. Dawson, PhD, Jorge Zamora, Patrick Tarpey, PhD, and Helen Davies, of the Wellcome Trust Sanger Institute; Paolo Corradini, MD, of the University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori; Ludmil Alexandrov, PhD, of the University of California, San Diego, La Jolla; David C. Wedge, PhD, of the University of Oxford; Herve Avet-Loiseau, MD, PhD, of L'Institut Universitaire du Cancer Oncopole, Toulouse, France; and Peter Campbell of the University of Milan.

Funding for the study was provided by: the Department of Veterans Affairs (grant I01BX001584-01), the National Institutes of Health (grants P01-155258 and 5P50 CA100707-13), the Leukemia and Lymphoma Society, Associazione Italiana per la Ricerca sul Cancro, Associazione Italiana Contro le Leucemie-Linfomi e Mieloma, and Società Italiana di Ematologia Sperimentale.