Triplet and Quadruplet Regimens in Smoldering Multiple Myeloma

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Combination regimens beyond lenalidomide/dexamethasone were shown to significantly delay—and potentially prevent altogether—progression from smoldering disease to active multiple myeloma, according to researchers who reported findings from two studies at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1,2

In a post hoc analysis of the phase II GEM-CESAR trial, 94% of patients with high-risk smoldering myeloma remained progression-free 70 months after treatment with carfilzomib, lenalidomide, dexamethasone, autologous stem cell transplantation, and maintenance.1 In the phase II ASCENT trial, the combination of daratumumab, carfilzomib, lenalidomide, and dexamethasone given for a fixed duration of 2 years was also associated with high response rates and deep responses, including high rates of measurable residual disease (MRD) negativity.2

GEM-CESAR lead investigator Maria-Victoria Mateos, MD, PhD, Associate Professor of Medicine and Director of the Myeloma Program at the University Hospital of Salamanca in Spain, commented: “We have to consider that our main objective with early treatment in high-risk smoldering disease is beyond that of achieving a response or MRD negativity. Our goal has to be to maintain patients without a myeloma-defining event. We will see whether early intervention will affect the natural history of smoldering myeloma.”

In 2013, Dr. Mateos and her team reported that lenalidomide plus dexamethasone significantly delayed progression from asymptomatic disease to frank myeloma and also offered an overall survival benefit.3 In a more recent phase III trial, Lonial et al also reported benefit for this regimen.4 But with more potent agents now part of the treatment armamentarium, their use in early intervention might yield even greater benefits, according to Shaji Kumar, MD, Chair of the Myeloma, Amyloidosis, and Dysproteinemia Group at Mayo Clinic, Rochester, Minnesota, who led the ASCENT trial.

“Obviously, the ASCENT trial was not designed to answer the question of whether we should be treating all high-risk smoldering myeloma with a quadruplet regimen. It was designed to explore whether we can actually cure some of these patients,” Dr. Kumar said. “That answer is not going to come with 3 years of follow-up. It’s going to take considerably more time. But what is important is that we have phase III trials clearly demonstrating we can alter the natural history of high-risk smoldering myeloma with early intervention, which may be just lenalidomide/dexamethasone or something more akin to myeloma therapy.”

GEM-CESAR Post Hoc Analysis

As reported by Dr. Mateos, early intervention resulted in 94% of patients remaining progression-free at 70 months, with 92% of patients still alive at the time of her analysis. The seven deaths included three related to progressive disease and one each from cardiac arrest (not treatment-related), massive ischemic stroke during induction, lung cancer, and myelodysplastic syndrome. Five patients experienced progression to symptomatic disease (for four, disease progression was asymptomatic). Dr. Mateos also reported outcomes for MRD status, biochemical disease progression, and rescue therapy.

The study enrolled 90 patients with smoldering myeloma deemed at high risk of disease progression by the Mayo and/or Spanish models (> 50% at 2 years). Within this group, 30 patients (33%) were considered at “ultra–high risk” due to the presence of one or more relevant biomarkers.

Induction therapy consisted of six 4-week cycles of carfilzomib plus lenalidomide/dexamethasone (KRd); carfilzomib was given at a dose of 36 mg/m2 twice per week, lenalidomide at 25 mg on days 1 to 21, and dexamethasone at 40 mg weekly. Melphalan at 200 mg/m2 was followed by autologous stem cell transplantation, then consolidation therapy with two KRd cycles, and finally with maintenance lenalidomide/dexamethasone for up to 2 years. Patients experiencing biological disease progression (biochemical or MRD conversion from negative to positive) after stopping maintenance could receive rescue therapy with daratumumab in combination with pomalidomide and dexamethasone (DPd).

The full treatment was completed by 70 of the 90 patients (78%). The objective response rate at the end of maintenance was 95%, with 64% being complete responses or better, Dr. Mateos reported. 

Free of Active Myeloma: 94% at 70 Months

Although 94% of the intent-to-treat population had not experienced disease progression, by risk category, 98% of patients considered to have “truly high-risk smoldering myeloma” were progression-free at 70 months, as were 86% of patients in the “ultra–high-risk” category (P = .03).

The primary endpoint was sustained MRD negativity at 4 and 5 years posttransplant. At a sensitivity of 10–5, MRD negativity 3 months posttransplant was documented in 68% of evaluable patients; at 4 years, 43% were still MRD-negative. In a landmark analysis of time to progression to active disease, according to MRD status after maintenance, 100% of MRD-­negative patients were myeloma-free at 36 months compared with 88% of MRD-positive patients (P = .01).

Biochemical disease progression occurred in 34 patients (48%), the majority after completion of treatment. This was reflected by progressive disease in 8 patients, relapse from complete response in 19 patients, and ultrasensitive MRD relapse (conversion from negative to positive) in 7 patients. Both clinical and biochemical disease progression was driven by the persistence of MRD positivity at the end of maintenance and by the lack of sustained MRD negativity at 4 years after transplantation (which was 2 years after the end of maintenance).

Of these 34 patients, 21 received rescue therapy with DPd, to which 80% responded. Responses deepened over time, and at last follow-up, two patients had experienced progression to myelom,a and one had died. “DPd rescue treatment allowed the majority of patients to continue with no myeloma-defining events,” Dr. Mateos noted.

ASCENT Results

ASCENT enrolled 87 patients with high-risk smoldering myeloma, who received three phases of treatment: induction therapy with carfilzomib at 36 mg/m2 plus lenalidomide, daratumumab, and dexamethasone (cycles 1–6); consolidation with the same drugs but less frequent dosing of daratumumab and a lower dexamethasone dose (cycles 7–12); and maintenance with lenalidomide and daratumumab (cycles 13–24). The primary endpoint of the study was the rate of stringent complete responses at the end of maintenance.

Median follow-up was 26 months; 31% of patients remained on active treatment. A total of 12 patients (14%) went off study before completing 24 cycles.

The overall response to this early intervention was 97%, of which 38% were stringent complete responses and 92% were very good partial responses or better. MRD negativity (10–5) was achieved by 84% of patients at a median of 6.6 months; of these 73 patients, 53 achieved MRD negativity at the end of induction, 16 after consolidation, and 4 at the completion of maintenance therapy, according to Dr. Kumar.

“Patients are continuing treatment or observation after completing 2 years of therapy, with the majority still in deep response,” he observed. Of the 87 patients enrolled, 4 have experienced progression to myeloma; median progression-free survival was not reached, and the rate at 3 years was 89.9%. Three disease progressions were biochemical, and one patient developed plasma cell leukemia 6 months after completing treatment.

“The quadruplet regimen is well tolerated in this high-risk smoldering myeloma patient population,” Dr. Kumar added. “Toxicities were similar to those seen with the same regimen as used in active myeloma.”

Grade ≥ 3 hematologic toxicities were noted in 18%, and non­hematologic toxicities were seen in 61%. There were four deaths, including two related to COVID-19, one due to respiratory syncytial virus, and one due to disease progression following completion of treatment. Dose reductions were required for carfilzomib in 12 patients, for lenalidomide in 12 patients, and for dexamethasone in 14 patients, he said.

Can Patients With Smoldering Myeloma Be Cured?

Patients in ASCENT and other studies in smoldering myeloma, including those with emerging therapies, must be followed for many years to reach conclusions, Dr. Kumar emphasized, adding that 10 to 15 years of follow-up may determine “whether we are able to cure some of these patients.” He said patients who remain MRD-negative 10 years posttreatment, without the need for therapy, would represent “the first step toward cure…. If these patients lived their lives without ever having to think about myeloma, by the purest definition that is a cure.” 

DISCLOSURE: Dr. Mateos has served as a consultant or advisor to and/or received honoraria from Pfizer, Sanofi, Takeda, Oncopeptides, Bristol Myers Squibb/Celgene, Janssen/Cilag, GSK, and Amgen. Dr. Kumar reported financial relationships with Oncopeptides, MedImmune/AstraZeneca, Adaptive, Takeda, Janssen, Celgene, and AbbVie.


1. Mateos MV, San-Miguel JF, Martinez-Lopez J, et al: Curative strategy (GEM-CESAR) for high-risk smoldering myeloma: Post-hoc analysis of sustained undetectable measurable residual disease. 2022 ASH Annual Meeting and Exposition. Abstract 118. Presented December 10, 2022.

2. Kumar S, Alsina M, LaPlant B, et al: Fixed duration therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone for high-risk smoldering multiple myeloma: Results of the ASCENT trial. 2022 ASH Annual Meeting and Exposition. Abstract 757. Presented December 11, 2022.

3. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.

4. Lonial S, Jacobus S, Fonseca R, et al: Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol 38:1126-1137, 2020.


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