In a single-center phase II trial reported in JAMA Oncology, Kazandjian et al found that triplet therapy with carfilzomib, lenalidomide, and dexamethasone (KRd), followed by lenalidomide maintenance, produced high rates of measurable residual disease (MRD)-negative complete response and freedom from disease progression to symptomatic multiple myeloma in patients with high-risk smoldering myeloma. 

As stated by the investigators, “High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment-sensitive.”

Study Details

The trial enrolled 54 patients with high-risk smoldering myeloma on Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria at the National Institutes of Health Clinical Center between May 2012 and July 2020. Patients received KRd in eight 4-week cycles of carfilzomib at 36 mg/m² (first two doses at 20 mg/m²), dexamethasone twice weekly at 20 mg during cycles 1 to 4 and 10 mg during cycles 5 to 8, and lenalidomide at 25 mg on days 1 to 21. Lenalidomide maintenance consisted of 24 cycles at 10 mg on days 1 to 21 every 28 days.

The primary outcome measure was MRD-negative complete response rate.

MRD-Negative Complete Response

Median follow-up was 31.9 months (range = 6.7–102.9 months). MRD-negative complete response was achieved in 38 patients (70.4%, 95% confidence interval [CI] = 56.4%–82.0%), with a median sustained response duration of 5.5 years (95% CI = 3.7 years–not estimable). MRD-negative very good partial response or better was achieved in 77.8% of patients (95% CI = 64.4%–88.0%).

Among the patients with MRD-negative complete response, 31 (81.6%) had at least one subsequent MRD assessment at least 1 year apart, with a median MRD-negative complete response duration of 66.5 months (95% CI = 44.6 months–not estimable). The probability of sustained MRD negativity was 81.8% at 24 months, 54.5% at 60 months, and 40.9% at 90 months.

Median clinical progression-free survival (ie, freedom from development of multiple myeloma or death) was not reached. Multiple myeloma occurred in two patients, with both developing osteolytic lesions off treatment. The probability of remaining free of multiple myeloma was 100% at 24 months, 91.2% (95% CI = 67.4%–97.9%) at 60 months, and 91.2% (95% CI = 67.4%–97.9%) at 96 months. No deaths occurred.

Adverse Events

No grade 4 or 5 nonhematologic adverse events were observed. Grade 3 nonhematologic adverse events occurred in 38.9% of patients, most commonly rash (7.4%), hyperglycemia (5.6%), lung infection (5.6%), and thromboembolism (3.7%). Adverse events of interest of any grade included dyspnea (27.8%), upper respiratory tract infection (24.1%), thromboembolism (20.4%), pulmonary infection (18.5%), hypertension (16.7%), neoplasm (5.6%), heart failure (3.7%), and atrial fibrillation (1.9%). Adverse events led to discontinuation of carfilzomib in two patients, due to grade 2 heart failure in one and grade 3 heart failure in one, who discontinued all study treatments. 

The investigators concluded, “Results of this phase II nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile.”

Dickran Kazandjian, MD, of the Multiple Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the National Institutes of Health Intramural Research Program, Bristol Myers Squibb/Celgene, and Amgen. For full disclosures of the study authors, visit jamanetwork.com.