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JAMA Oncol. 2015 Sep;1(6):746-54. doi: 10.1001/jamaoncol.2015.2010.

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

Author information

1
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
3
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York3Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston.
4
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York4Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland5Department of Hemato.
5
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York4Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
6
Hematology Service, Department of Laboratory Medicine, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
7
Department of Pharmacokinetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
8
Lab of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
9
Sequenta Inc, San Francisco, California.
10
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
11
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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.

PMID:
26181891
DOI:
10.1001/jamaoncol.2015.2010
[Indexed for MEDLINE]

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