Genomics Revolution Taking Off in Multiple Myeloma

Risk stratification is leading to increasing numbers of new molecular targets in multiple myeloma.

Large numbers of samples from patients with multiple myeloma (MM) have been sequenced over the past 3 years, and this has led to a much clearer picture of the mutational landscape in MM, according to Aurore Perrot, MD, PhD, from the University of Lorraine, France. However, she pointed out that current studies have indicated a huge heterogeneity at the molecular level in MM patients.

Dr. Perrot contributed a chapter in the 2018 ASCO Educational Book, “Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside.” (At the 2018 American Society of Clinical Oncology [ASCO] Annual Meeting, held from June 1–5 in Chicago, chapter coauthor Hervé Avet-Loiseau, MD, PhD, from the Cancer Research Center of Toulouse, France, delivered an Education Session presentation on this topic.) Dr. Perrot said the most recent investigations in MM have been disappointing in that they failed to identify clear pathophysiologic subentities and important molecular druggable targets.

Despite this significant barrier, she emphasized the critical need to continue sequencing studies in MM patients, because this testing still has clear routine applications for risk assessment. She noted that risk evaluation is paramount at diagnosis and at the time of relapse, to enable clinicians to prescribe the most appropriate combinations of therapy.

Dr. Perrot said genetic abnormalities present in the malignant plasma cells are the most important risk factors. In addition, the most important high-risk features are del(17p), del(1p32), t(4;14), and 1q gains. She said it is mandatory that clinicians assess these markers at diagnosis and at first relapse. It has been shown that the lenalidomide-dexamethasone combination is not effective in patients with high-risk features. However, a triplicate therapy adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone has been shown to improve survival in some patients, according to Dr. Perrot.

She and her colleagues theorize that another way to improve outcomes may be to specifically target genetic abnormalities with specific inhibitors. She said the sequencing of more than 1,000 MM exomes has revealed that the most frequent mutations involve KRAS (20%) and NRAS (25%). However, an effective RAS-inhibitor therapy has yet to emerge.

Unfortunately, Dr. Perrot said the only druggable target is the BRAF V600E mutation, which is present in just 3% of MM patients. Dr. Perrot said it has been reported recently that the BCL2-inhibitor venetoclax may benefit up to 20% of MM patients with a specific mutation. She noted that today MM patients have highly variable treatment outcomes, with survival times ranging from a few weeks to more than 15 years. In some cases, cure is possible, especially in transplant-eligible patients.

The researchers theorize that novel combinations may lead to better outcomes in the near future, in both high-risk and standard-risk patients. Dr. Perrot said MM is probably the cancer for which the most prognostic parameters have been described; she noted that these can be separated into three groups (related to patients, related to disease burden, and related to the malignant clone).

In the first category, age is probably the most important prognostic factor, because it can help determine the optimal treatment strategy. She said the age cutoff is usually fixed between ages 65 to 70, depending on the patient’s fitness. Comorbidities and polypharmacy must also be considered. In the second category (tumor burden), Dr. Perrot said multiple parameters have been described, such as β2-microglobulin levels, serum lactate dehydrogenase levels, anemia, thrombocytopenia, and several other factors.