KRd Plus Lenalidomide Maintenance Yielded Positive MRD- CRs and May Delay End-Organ Disease in High-Risk Smoldering Myeloma


Patients with high-risk smoldering myeloma who were treated with carfilzomib, lenalidomide, and dexamethasone and lenalidomide maintenance experienced an improvement in minimal residual disease–negative complete response and could have delayed end-organ disease.

A regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Decadron; KRd) with lenalidomide (Revlimid) maintenance therapy yielded a promising minimal residual disease (MRD)–negative complete response (CR) rate and may delay end-organ disease in high-risk smoldering myeloma, according to a phase 2 study (NCT01572480) published in JAMA Oncology.

Patients who received the regimen achieved an MRD-negative CR rate of 70.4% (95% CI, 56.4-82.0%), and a median sustained duration of 5.5 years (95% CI, 3.7–not estimable [NE]). Patients also experienced an 20-month probability of being free from progression to multiple myeloma of 100%, and 91.2% (95% CI, 67.4%-97.9%) at 60 months.

“In this phase 2 nonrandomized controlled trial, KRd-R triplet combination therapy for the management of high-risk smoldering myeloma appeared to be highly efficacious and tolerable. Treatment was associated with deep and sustained MRD- negative remissions and a delay in clinical progression, with an overall favorable benefit-to-risk profile,” the investigators wrote.

A total of 54 patients were enrolled in the trial between May 2012 and July 2020. Patients had a median age of 59 years, and 55.6% (n = 30) were men. In this group, all patients had an ECOG score of 0 to 1. Additionally, 37.0% (n = 20) of patients had high-risk multiple myeloma cytogenetics, 18.5% (n = 10) had myeloma-defining events, and 66.7% (n = 36) had high-risk smoldering myeloma.

Patients were given 8, 28-day cycles of KRd, which included 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16; 25 mg of oral lenalidomide on days 1 through 21; and 20 mg of oral dexamethasone during cycles 1 to 4 and 10 mg during cycles 5 to 8 either intravenously or orally twice a week. Eligible patients also underwent stem cell transplant and resumed treatment following transplantation. Following completion of KRd therapy, patients were administered 24, 28-day cycles of maintenance lenalidomide at 10 mg on days 1 through 21.

The median follow-up time was 31.9 months, with patients achieving an MRD-negative CR or very good partial response rate of 77.8% or greater (95% CI, 64.4%-88.0%). Among those who achieved an MRD CR, 81.6% (n = 31) had at least 1 subsequent MRD assessment at least 1 year apart for a median MRD-negative CR duration of 66.5 months (95% CI, 44.6-NE).

At the 24-month milestone, the sustained MRD negativity was 81.8% (95% CI, 61.4%-92.0%), 54.5% (95% CI, 28.7%-74.5%) at 60 months, and 40.9% (95% CI, 17.6%-63.1%) at 90 months. The median progression-free survival (PFS) objective was not reached because 2 patients on the study developed multiple myeloma.

The median biochemical PFS objective was also not reached, with 6 patients developing multiple myeloma. Patients had a biochemical PFS probability of 95.5% (95% CI, 83.1%-98.9%) at 24-months, 82.5% (95% CI, 60.6%-92.9%) at 60 months, and 77.0% (95% CI, 53.5%-89.7%) at 96-months. The overall response rate was 100% (95% CI, 93.4%-100%). Patients also experienced a median duration of response rate of 77.4% (95% CI, 54.0%-89.9%) at 96-months.

The best overall responses included a very good partial response rate of 94.4% (95% CI, 84.6%-98.8%) or better and in addition a CR or better rate of 75.9% (95% CI, 62.4-86.5). Patients had OS rate of 100% at 96 months.

No patients experienced grade 4/5 nonhematologic adverse effects (AE). A total of 38.9% (n = 21) of patients experienced grade 3 nonhematologic AEs, with the most common being thromboembolism (3.7%), rash (7.4%), hyperglycemia (5.6%), and lung infection (5.6%). Some AEs of interest included dyspnea (27.8%), upper respiratory tract infection (24.1%), thromboembolism (20.4%).

Regarding discontinuations, 3.7% (n = 2) stopped carfilzomib because of AEs. Additionally, 3.7% (n = 2) discontinued the lenalidomide maintenance due to grade 3 diarrhea and grade 3 alanine aminotransferase elevation. No patients prematurely discontinued due to progression. A total of 5.6% (n = 3) of patients had dose reductions of lenalidomide due to arthralgia, diarrhea, and fatigue. Patients also had common AEs such as rash, diarrhea, and constipation.

“Future randomized clinical trials should be conducted of triplet medication regimens to confirm this conclusion and elucidate the balance between potency and safety that derives the most clinical benefit for patients. Therefore, in light of these findings, we recommend that patients with smoldering myeloma be encouraged to enroll in clinical trials but not receive this triplet medication treatment as part of standard of care,” investigators concluded.


Kazandjian D, Hill E, Dew A, et al. Carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance for prevention of symptomatic multiple myeloma in patients with high-risk smoldering myeloma: a phase 2 nonrandomized controlled trial. JAMA Oncol. Published Online September 16, 2021. doi:10.1001/jamaoncol.2021.3971

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