How to Think About Risk in Myeloma

Abstract

An integral part of myeloma therapy is risk stratification of newly diagnosed patients. This method involves a combination of staging and genetic risk assessment. Although survival has dramatically improved for patients with genetically defined, standard-risk myeloma, those with high-risk disease remain a therapeutic challenge. Current treatment approaches might include the use of combination therapy for induction and maintenance. Future approaches are expected to involve drugs that are “risk agnostic,” such as monoclonal antibodies and immunotherapy.

Introduction

When assessing risk, perception is sometimes as important as reality. For instance, a “double black” advanced ski run would be perceived as risky to an average skier but not to a confident champion. The steep slope is a reality for both people, yet the risk is mitigated with the better skier. Similarly, in myeloma we might perceive risk in a patient who looks weak and frail, with a high tumor burden. Other times, cytogenetics and organ function are our own black diamond. The truth is, risk is different for everyone.

Median survival for myeloma has improved and is likely to continue to improve as a consequence of new agents.¹ However, there are subgroups of patients who are destined for early relapse despite these treatments. In general, such patients are considered to be high-risk. Genetically defined high-risk myeloma comprises 15% to 20% of patients with myeloma,2, 3 and advanced stage of disease as defined according to the International Staging System (ISS) at the time of presentation also confers a poor prognosis. In addition, I would also add that high risk might be determined on the basis of patient characteristics. With respect to significant comorbidities or frailty, therapeutic options might be limited, thus rendering treatments less effective and leading to a higher risk of relapse.

Consider 2 scenarios.

A 65-year-old man who presents with back pain, nausea, and constipation. Blood work reveals hypercalcemia, elevated creatinine level at 2.5 mg/dL, hemoglobin 9.0 mg/dL, and β₂ microglobulin at 6.5 mg/mL. Skeletal x-rays show an L4 compression fracture and generalized osteopenia. A bone marrow biopsy shows 70% plasmacytosis with 17p deletion on 50% of cells using targeted fluorescence in situ hybridization (FISH) analysis, as well as trisomy 9.

A 75-year-old man with diabetes, hypertension, and coronary artery disease with a previous myocardial infarction 3 years ago. The patient lives alone, and he requires some assistance for regular errands. He is able to dress himself; however, his activity outside the house is limited as he describes himself as unsteady on his feet. He develops increasing dyspnea on exertion. Cardiac work-up was negative. Blood work revealed a hemoglobin of 7.5 mg/dL, creatinine 3.0 mg/dL, and albumin 3.0 mg/mL. A bone marrow biopsy shows 70% plasmacytosis with normal karyotyping in FISH studies. Skeletal x-rays show scattered lucencies in the long bones.