Remission and Progression-Free Survival in Patients With Newly Diagnosed Multiple Myeloma Treated With Carfilzomib, Lenalidomide, and Dexamethasone: Five-Year Follow-up of a Phase 2 Clinical Trial

State-of-the art treatment of multiple myeloma (MM) involves induction with triplet-based regimens using combinations of immunomodulatory drugs and proteasome inhibitors, which have shown improved progression-free survival and overall survival compared with doublet regimens in the newly diagnosed (ND) and relapsed and refractory (RR) setting.^1-3 Carfilzomib is a selective proteasome inhibitor approved by the US Food and Drug Administration for use in the carfilzomib, lenalidomide, and dexamethasone (KRd) regimen for the treatment of RRMM.^3,4 We previously reported early data on this phase 2 study of 45 patients with NDMM.⁵ Herein, we expand on our initial results and present the long-term durability of minimal residual disease–negative complete remissions (MRD-negative CRs) and time to progression, the last characterized by depth of response, age, and cytogenetic risk profile.

This study of KRd with lenalidomide maintenance (KRd-r) enrolled patients with treatment-naive NDMM regardless of eligibility for autologous stem cell transplant (NCT01402284).⁵ Patients received eight 28-day cycles of carfilzomib, 20/36 mg/m², with dexamethasone, 20/10 mg (days 1, 2, 8, 9, 15, 16), and lenalidomide, 25 mg (days 1-21), followed by 2 years of maintenance therapy with lenalidomide, 10 mg (days 1-21). Transplant-eligible patients underwent harvest after 4 cycles of therapy. Minimal residual disease–negative complete remission was assessed by multicolor flow cytometry (bone marrow aspirate; 10⁻⁵ sensitivity) after induction, at 1 and 2 years of lenalidomide maintenance therapy, and annually thereafter. The National Cancer Institute institutional review board approved the study, and participants provided written informed consent.

Forty-five patients who met eligibility criteria were enrolled; among these, 27 (60%) were men and mean (SD) age was 61 (12) years⁵; median (95% CI) follow-up was 5.2 (4.7-5.6) years. Treatment with KRd-r led to rapid, deep, and durable overall response rate and sustained MRD-negative CRs. All but 1 patient (overall response rate, 98%; 95% CI, 88%-100%) experienced a partial response or better as the best objective response, with a mean (SD) of 4.4 (1.1) weeks to partial response or better. The median duration of response was 65.7 months (95% CI, 55.6 months to not estimable). Twenty-eight of the 45 patients (62%; 95% CI, 47%-76%) experienced MRD-negative CR. To date, durability of MRD-negative CR has been observed at up to 70 months, with a median duration of more than 4 years (52.4 months; 95% CI, 35.3-61.6). Patients who experienced MRD negativity by the end of cycle 8 had a 78% decrease in risk of progression (Figure 1). Moreover, treatment with KRd-r was associated with unprecedented progression-free duration and overall survival, with a median time to progression of more than 5.5 years (67.3 months; 95% CI, 51.0 months to not estimable). Median overall survival was not reached because, as of this writing,40 of the 45 patients are still alive. However, at a 6-year milestone, the probability of survival was 84%. Deep responses of MRD-negative CR and long progression-free durations occurred irrespective of age or adverse cytogenetic risk factors (Figure 2). In general, KRd-r was well tolerated, with manageable low-grade toxic effects and no grade 3 or greater peripheral neuropathy, the primary end point.⁵

First-line treatment of NDMM with the modern and highly efficacious KRd regimen incorporating a “by default delayed” autologous stem cell transplant strategy led to high rates of MRD-negative CR, which were sustained with a median duration of more than 4 years. We confirm that attaining MRD negativity with at least 10⁻⁵ sensitivity is crucial for deriving long-term benefit, as shown previously.⁶ In the present study, MRD-negative CR was strongly associated with a delay in progression and with an estimated greater than 80% reduction in the risk of disease progression. Furthermore, and of clinical importance, our findings indicate that these deep responses and long progression-free durations are attainable regardless of patient age or cytogenetic risk category. Taken together, these findings stress the importance of using highly efficacious triplet-based regimens for these subcategories of NDMM and avoiding de-escalation of triplet regimen and dosage based on patient age or other factors.

Our results compare favorably with autologous stem cell transplant–based regimens. The major limitation is the single-arm nature of the study design, and cross-trial comparisons are limited. Given the impressive activity of KRd-r in NDMM, we subsequently designed a trial using KRd-r for patients with high-risk smoldering MM, which is currently enrolling participants (NCT01572480).

Accepted for Publication: September 11, 2018.

Corresponding Authors: Dickran Kazandjian, MD, Myeloma Program, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr, Bethesda, MD 20854 (kazandjiandg@mail.nih.gov); Ola Landgren, MD, PhD, Myeloma Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (landgrec@mskcc.org).

Published Online: November 21, 2018. doi:10.1001/jamaoncol.2018.5457

Author Contributions: Drs Kazandjian and Landgren had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kazandjian, Korde, Mailankody, Figg, Roschewski, Landgren.

Acquisition, analysis, or interpretation of data: Kazandjian, Mailankody, Hill, Figg, Landgren.

Drafting of the manuscript: Kazandjian, Landgren.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Landgren.

Obtained funding: Landgren.

Administrative, technical, or material support: Kazandjian, Korde, Landgren.

Supervision: Kazandjian, Figg, Landgren.

Conflict of Interest Disclosures: Dr Korde reported receiving research funding support from Amgen. Dr Mailankody reported serving as an investigator on clinical trials supported by Juno Therapeutics, Janssen, and Takeda Oncology and receiving honoraria for continuing medical education from Physician Education Resource. Dr Landgren reported receiving research funding and consultancy fees from Janssen, Amgen, Celgene, Takeda, Novartis, US Food and Drug Administration, Multiple Myeloma Research Foundation, International Myeloma Foundation, Leukemia and Lymphoma Society, Perelman Family Foundation, Rising Tides Foundation, Glenmark, Seattle Genetics; receiving consultancy fees from Pfizer, Karyopharm Adaptive Biotechnologies, The Binding Site, BMS, Cellectis, and Juno; receiving honoraria from Medscape; and serving on an advisory committee for Merck. No other disclosures were reported.

Funding/Support: This work was supported by Memorial Sloan Kettering Core Grant P30CA008748 from the National Institutes of Health, National Cancer Institute (Drs Korde, Mailankody, and Landgren).

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Trial Registration: ClinicalTrials.gov identifier: NCT01402284

Additional Contributions: Yong Zhang, PhD, Jennifer Hsu Albert, RN, Candis Morrison, PhD, Pallavi Galera, MD, Sneha Divakarla, Alina Dulau-Florea, MD, Dalia Salem, MD, Esther Gonzalez, MD, Liza Lindenberg, MD, Irina Maric, MD, Katherine R. Calvo, MD, Raul Braylan, MD, Constance Yuan, MD, PhD, Wyndham Wilson, MD, PhD, Peter Choyke, MD, Maryalice Stetler-Stevenson, MD, PhD, and Seth M. Steinberg, PhD (National Institutes of Health); Mary Kwok, MD (Walter Reed Medical Center); Elisabet E. Manasanch, MD (MD Anderson); Manisha Bhutani, MD (Carolinas Health Care System); Nishant Tageja, MD (Wheeling Hospital); Malin Hultcrantz, MD, PhD, Evan H Rustad, MD, and Venkata Yellapantula, PhD (Memorial Sloan Kettering Cancer Center) assisted with patient follow-up, patient diagnostic and response evaluation, or statistical analysis. None of these contributors were paid for their work on this study.