Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma

Abstract

Importance: Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival.

Objective: To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM).

Design, setting, and participants: Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM).

Interventions: Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing.

Main outcomes and measures: Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed.

Results: Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively.

Conclusions and relevance: Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Trial registration: ClinicalTrials.gov NCT01402284 NCT01572480.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Korde has acted as consultant for Medscape. Ms Kong and Dr Faham are employees of Adaptive Biotech. Dr Weng is a former employee of Sequenta, Inc. Dr Landgren has acted as a consultant for BMJ Publishing, Celgene, Millennium, Medscape, and Onyx. No other disclosures are reported.

Figures

Figure 1.. Measuring Minimal Residual Disease (MRD) Status by Multiparametric Flow Cytometry (MFC) and Next-Generation Sequencing (NGS)

Comparison of MRD status among newly diagnosed multiple myeloma (NDMM) and smoldering multiple myeloma (SMM) patients who underwent testing by both MFC and NGS methodologies. CR indicates complete response; nCR, near complete response; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

Figure 2.. Individual Sequential Minimal Residual Disease Status by Multiparametric Flow Cytometry (MFC), Next-Generation Sequencing (NGS), and Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography (FDG-PET/CT)

Individual sequential MRD status among newly diagnosed multiple myeloma (NDMM) and smoldering multiple myeloma (SMM) patients who underwent testing by MFC, NGS, and FDG-PET/CT methodologies.

Figure 3.. Progression-Free Survival (PFS) by Status for Newly Diagnosed Multiple Myeloma (NDMM) Using Multiparametric Flow Cytometry (MFC), Next-Generation Sequencing (NGS), and Positron-Emission Tomography/Computed Tomography (PET/CT)

A, Overall. B, By MRD status using MFC. C, By MRD status using NGS. D, By PET/CT status. The PET-negative group includes patients with PET-negative results and patients with decreased PET standardized uptake values. The PET-positive group includes patients with PET-positive results and patients with partial positive PET results (see eMethods in the Supplement).