The overall survival of patients with multiple myeloma has improved, particularly in the past decade. Current first-line therapies often keep the disease under control for 4 to 6 years. However, approximately 20% of patients relapse sooner than we anticipate, often less than 18 months after treatment initiation. We consider these patients to have functional high-risk multiple myeloma. There is work to be done to better identify high-risk patients at diagnosis. A risk stratification system will hopefully be published later this year that is based primarily on genomic alterations. For now, we rely on measuring the patient’s duration of response to identify high-risk disease.

Factors that are related to high-risk multiple myeloma can be grouped into 3 categories. The first is patient-related factors, including older age, comorbidities, frailty, and social or logistical challenges such as transportation limitations or financial difficulty. The second category is tumor-related factors, which are the biggest drivers of outcomes and includes tumor proliferation rate and burden, as well as genetic abnormalities such as hyperdiploidy, chromosomal monosomy, chromosomal translocation, and deletion or amplification of certain chromosomal regions. The third category is a mixture of tumor- and patient-related factors and includes renal insufficiency and immunosuppression.

Patients with high-risk disease have poorer responses to therapy and a higher risk of mortality. We know that their multiple myeloma mutates very quickly over the course of the disease and becomes treatment refractory sooner. The question is: How can we deepen and maintain patient responses? Intensifying initial and maintenance therapies may allow more patients to achieve a deeper, longer-lasting response, although it comes with greater toxicity.

To maximally eradicate the multiple myeloma clone, it is important to combine drugs with different mechanisms of action. At my center, we tend to give high-risk patients a quadruplet regimen that includes an anti-CD38 monoclonal antibody (daratumumab), a proteasome inhibitor (typically bortezomib), an IMiD (lenalidomide), and the corticosteroid dexamethasone. This combination is probably the best option that we have for initial treatment. In patients who are older than 65 years, we start with less intense therapy and gradually escalate. We may put them on a triplet induction regimen, but we continue that treatment for a longer period to slowly achieve a greater treatment effect.

Multiple phase 3 trials have shown that autologous hematopoietic stem cell transplant (ASCT) significantly improves outcomes, including progression-free survival (PFS), when used as part of the initial treatment. The DETERMINATION trial randomized patients to lenalidomide, bortezomib, and dexamethasone (the RVd regimen) with or without ASCT. The study showed that patients with high-risk multiple myeloma benefited more from RVd with ASCT than from RVd alone as initial therapy, extending PFS by more than 30 months. ASCT also improves the rate of measurable residual disease negativity. Many studies have shown that high-risk patients who achieve measurable residual disease negativity for 1 to 2 years have outcomes that are closer to those of standard-risk patients.

For patients who do not respond to their initial treatment, novel therapies are an area of active research. We do not know how well immunotherapies such as CAR T cells and bispecific antibodies work in high-risk patients in early stages of disease. In the future, we might use CAR T-cell therapy to get deeper responses in high-risk patients followed by conventional maintenance or bispecific antibodies to maintain the responses.