Smoldering myeloma is an asymptomatic plasma cell disorder with a heterogeneous clinical behavior. Two trials presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition investigated early intervention for smoldering multiple myeloma, aiming for a “curative strategy” for patients deemed at high risk of disease progression.

Commenting on their findings for The ASCO Post was Robert Rifkin, MD, Medical Director of Biosimilars for McKesson, Associate Chair of Hematology Research and Myeloma Disease Lead for The US Oncology Network, and a hematologist with Rocky Mountain Cancer Centers in Denver.

Robert Rifkin, MD

GEM-CESAR and ASCENT Details

The Spanish GEM-CESAR study recruited patients with high-risk smoldering myeloma, 31 of whom had “high-risk” disease, “which many clinicians would regard as early myeloma requiring treatment,” Dr. Rifkin said. The regimen involved aggressive induction, followed by autologous stem cell transplantation, followed by consolidation and then maintenance therapy for up to 2 years. In the updated analysis, 23% of the patients with high-risk smoldering myeloma who were treated with this strategy achieved measurable residual disease (MRD) negativity 4 years after transplantation and 2 years after finalizing the treatment protocol. “While these are very encouraging results, there can certainly be toxicity associated with this approach,” he noted.

In contrast, in the United States–based ASCENT study, high-risk patients received a fixed duration of therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone for high-risk smoldering myeloma. Treatment consisted of three phases: induction for six cycles, consolidation for six cycles, and additional maintenance cycles, for a period totaling 2 years. This combination given for a fixed duration of 2 years was associated with high response rates, mostly deep responses, and a high rate of MRD negativity.

As Dr. Rifkin pointed out, the definitions for smoldering myeloma have been refined now to include high-risk and ultra–high-risk patient populations. Based on their significant risk of disease progression within a very short time frame, “I think it is important to intervene early but only in the high-risk smoldering population. The results of the trials presented at the ASH meeting clearly support this hypothesis,” he added. “In short, for young patients with smoldering multiple myeloma that is high-risk or ultra–high risk, the therapeutic approach should be one of ‘putting the pedal to the metal.’ The results described here validate this approach.”

Because there can be significant toxicities associated with any myeloma treatment, Dr. Rifkin further advised treatment for individuals with few comorbidities. This approach is likely to reduce the risk of adverse events and deaths, especially in older patients, he said.

GEM-CESAR evaluated a triplet with autologous stem cell transplant, and ASCENT evaluated quadruplet therapy. Dr. Rifkin maintained that the cumulative data on the topic “clearly show” that doublets, such as lenalidomide plus dexamethasone, in the majority of cases do not provide adequate therapy. “Overall, the field is moving toward triplets, if not, in fact, quadruplets, with the introduction of monoclonal antibodies. In addition, we now have many new therapies in our armamentarium including CAR [chimeric antigen receptor] T cells, bispecific antibodies, antibody-drug conjugates, and histone deacetylase inhibitors, as well as a variety of other agents in development. At this time, triplet therapies are clearly preferred, even in transplant-ineligible patients,” Dr. Rifkin said.

More Data Needed

“There is a wealth of information in a variety of recently published phase III clinical trials suggesting that more aggressive approaches and multiple drug combinations lead to improvements in overall survival,” he continued. “As always, we would like to see more mature data. In the two trials discussed here, one can see excellent results at time points now approaching 5 or more years. We would hope these data hold up over time,” he said. “As we design new approaches, we definitely need to consider issues such as quality of life and convenience, and we should be thoroughly educating our patients regarding the goals of therapy so appropriate regimens can be selected.”

Dr. Rifkin concluded: “In the unfortunate event that a patient develops high-risk smoldering myeloma, or even early symptomatic multiple myeloma, the message should be to carefully outline the goals of care and to treat aggressively enough to achieve a goal of at least a complete response. We are fortunate in this area to have so many choices for drug therapy, and as always, enrollment on clinical trials will help us advance the field further.” 

DISCLOSURE: Dr. Rifkin reported no conflicts of interest.