Daratumumab (DARZALEX), developed by Johnson & Johnson, is a CD38-directed monoclonal antibody that has become a backbone of therapy across multiple myeloma treatment settings, from newly diagnosed to relapsed disease. Carfilzomib (KYPROLIS), developed by Amgen, is a second-generation proteasome inhibitor and Lenalidomide (REVLIMID), developed by Bristol Myers Squibb, remains one of the most widely used immunomodulatory agents in plasma cell disorders. Together, the Dara-KRd regimen has demonstrated deep and durable responses in newly diagnosed multiple myeloma, prompting interest in evaluating whether such an intensive approach could potentially alter the natural history of high-risk smoldering multiple myeloma (SMM).

The Phase II ASCENT trial was designed to test the hypothesis that early intervention with an intensive quadruplet regimen could induce deep responses, eradicate malignant plasma cell clones, and potentially delay or prevent progression to symptomatic multiple myeloma. Treatment consisted of induction (Cycles 1–6), consolidation (Cycles 7–12), and maintenance (Cycles 13–24) using daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), with therapy limited to 24 cycles.

A total of 87 patients were enrolled. At a median follow-up of 52.4 months, 70 patients (80%) completed all 24 cycles of therapy, providing one of the longest follow-ups reported for an intensive intervention strategy in high-risk SMM.

Safety Outcomes-

• 5 patients have died; causes include 2 from Cardiac Arrest, 1 from Covid, 1 from Plasma cell leukemia/relapsed disease, and 1 Unknown. 

• Any grade toxicity, considered possibly related to therapy, was observed in 84 patients. 

• Grade 3 or higher hematological toxicity of any relation was seen in 22% patients and non-hematological toxicity in 70%.

KOL Insights-

“The quadruplet regimen is quite effective in this high-risk smoldering myeloma population. This is a limited-duration therapy with a quadruplet without using autologous stem cell transplant, and the toxicities that we saw were quite similar to what we have seen with this regimen in patients with newly diagnosed myeloma.”– Expert Opinion

“One goal of the study is to determine whether a limited course of therapy could potentially cure a fraction of these patients, rather than simply controlling the disease indefinitely. The researchers note that this will require longer follow-up to assess, particularly now that the field has arrived at a working definition of what constitutes a cure in multiple myeloma.” – Expert Opinion

Conclusion-

Smoldering multiple myeloma (SMM) represents an intermediate precursor state between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma, accounting for approximately 10–15% of newly diagnosed myeloma-spectrum disorders. Patients with high-risk SMM face a substantially elevated risk of progression to active multiple myeloma, particularly within the first five years following diagnosis, making early intervention an area of significant clinical interest.

The Phase II ASCENT trial evaluated a fixed-duration, quadruplet Dara-KRd regimen in high-risk SMM and demonstrated high response rates, deep MRD negativity, and durable disease control with a median follow-up exceeding four years. The study supports the potential of intensive early treatment strategies to achieve prolonged remission in selected high-risk patients. While longer follow-up and randomized studies are needed to determine whether such approaches can alter the natural history of the disease, ASCENT provides important evidence supporting the role of deep-response–driven intervention in high-risk smoldering multiple myeloma.