Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

Abstract

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

Conflict of interest statement

Conflict-of-interest disclosure: N.R. had a consulting or advisory role with Amgen, Bristol-Myers Squibb, Celgene, Janssen Oncology, Merck, Novartis, and Takeda and received research funding from AstraZeneca. R.V. received honoraria from, had a consulting or advisory role with, and received funding for travel, accommodations, and expenses from Bristol-Myers Squibb and Celgene. D.R. received honoraria from Amgen, Celgene, Janssen, and Takeda, had a consulting or advisory role with Amgen, Celgene, Janssen, Karyopharm Therapeutics, and Takeda, received research funding from Bristol-Myers Squibb, Celgene, Janssen, Merck, Otsuka, and Takeda, and provided expert testimony for Amgen and Celgene. J.B. had a consulting or advisory role with Amgen, BioClinica, Bristol-Myers Squibb, Celgene, Crispr Therapeutics, Janssen, Karyopharm Therapeutics, Kite Pharma, Legend Biotech, Prothena, Servier, and Takeda, and received research funding from AbbVie, Acetylon, Amgen, Bluebird Bio, Bristol-Myers Squibb, Celgene, Constellation, CURIS, Genentech/Roche, Glenmark, Janssen, Kesios, Eli Lilly, Novartis, Poseida Therapeutics, Sanofi, Takeda, Teva, and Vivolux. P.R. had a consulting or advisory role with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, and Takeda and received research funding from Bristol-Myers Squibb, Celgene, Oncopeptides, and Takeda. D.D. received honoraria and research funding from Amgen and Celgene. T.M.Z. received honoraria from, had a consulting or advisory role with, and served on the speakers’ bureau for Celgene and Amgen. A.J.J. received honoraria from Amgen, Bristol-Myers Squibb, Celgene, and GlaxoSmithKline, was an investigator for AbbVie-sponsored clinical trials, Janssen, Karyopharm Therapeutics, Millennium Pharmaceuticals, Sanofi, Skyline Diagnostics, and Takeda, and had a consulting or advisory role with Amgen, Bristol-Myers Squibb, Celgene, and GlaxoSmithKline. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient disposition. *AE unrelated to treatment in patient retrospectively ineligible for the trial. †Discontinued on day +104 after ASCT and before starting KRd consolidation.

Figure 2.

Response rates over the course of KRd plus ASCT treatment in ITT population (n = 76). After cycle 8 (n = 72), the per protocol population excluded 2 patients who withdrew consent, 1 patient for noncompliance, and 1 patient for AE unrelated to treatment. In the ITT population after cycle 8 (n = 76), the response rate for VGPR or better was 86%, for CR or better it was 62%, and for sCR it was 57%. nCR, near complete response; PR, partial response.

Figure 3.

Time to response in respective response categories over time on treatment in months. nCR, near complete response; PR, partial response.

Figure 4.

MRD response rates over the course of KRd plus ASCT treatment. Forty-eight patients had baseline and at least 1 postbaseline bone marrow sample available for MRD assessment by next-generation sequencing (clonoSeq). MRD rates at 8 cycles, at the end of 18 cycles of KRd, and best response in evaluable patients (patients with at least 1 MRD assessment) (A), and in mITT population (B) (as described by Perrot et al and in “Methods”).

Figure 5.

PFS and OS in the ITT population. PFS and OS in the ITT population (A-B), and by MRD status (C-D). FU, follow-up; unk, unknown.

Figure 6.

PFS and OS in the ITT population. PFS and OS in the ITT population by (A-B) high-risk (HR) vs standard-risk (SR) cytogenetics, (C-D) in patients with high-risk cytogenetics by MRD status by next-generation sequencing, and (E-F) in patients with standard-risk cytogenetics by MRD status by next-generation sequencing. NR, not reached.