Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial | Hematology | JAMA Oncology | JAMA Network
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Figure 1.  Response to Therapy, by Number of Cycles and Follow-up
Response to Therapy, by Number of Cycles and Follow-up

During the time window of the study (up to 8 cycles of weekly 56-mg/m2 dosing of the second-generation proteasome inhibitor carfilzomib with lenalidomide and dexamethasone [wKRd-D] combination therapy), minimal residual disease (MRD) status was assessed in 39 patients as they achieved at least a very good partial response (VGPR); 29 patients were found to be MRD negative (10−5 sensitivity) in the bone marrow. Thus, overall MRD negativity (complete response [CR] or VGPR) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Of the 29 patients who were MRD negative, 14 had cleared their monoclonal serum protein at the time of MRD testing, and 10 had cleared their monoclonal serum protein at a median of 3 months later (range, 1-6 months); thus, an MRD-negative CR was achieved in 24 of 41 patients (59%; 95% CI, 42%-74%). Five patients achieved a VGPR at a median follow-up of 5 months after becoming MRD negative in the bone marrow. Two patients (patients 3 and 14) only achieved a partial response (PR) during the time window of the study; after 8 cycles of wKRd-D, patient 3 was given additional 2 cycles of KRd therapy followed by an autologous stem cell transplant as standard of care and became MRD negative; after 8 cycles of wKRd-D, patient 14 was given an autologous stem cell transplant as standard of care and achieved CR or MRD positivity. Patient 3 remained MRD negative at 1-year follow-up while receiving 10 mg of lenalidomide as maintenance therapy, and patient 14 remained MRD positive at 1-year follow-up while receiving 10 mg of lenalidomide as maintenance therapy. ASCT indicates autologous stem cell transplant; BL, baseline; C, cycle; FU, follow-up; PD, progressive disease; and Pt, patient.

Figure 2.  Progression-free Survival
Progression-free Survival
Table.  Patients’ Characteristics
Patients’ Characteristics
1.
Engelhardt  M, Terpos  E, Kleber  M,  et al; European Myeloma Network.  European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma.   Haematologica. 2014;99(2):232-242. doi:10.3324/haematol.2013.099358 PubMedGoogle ScholarCrossref
2.
Mikhael  J, Ismaila  N, Cheung  MC,  et al.  Treatment of multiple myeloma: ASCO and CCO Joint Clinical Practice Guideline.   J Clin Oncol. 2019;37(14):1228-1263. doi:10.1200/JCO.18.02096 PubMedGoogle ScholarCrossref
3.
Moreau  P, San Miguel  J, Sonneveld  P,  et al; ESMO Guidelines Committee.  Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2017;28(suppl_4):iv52-iv61. doi:10.1093/annonc/mdx096 PubMedGoogle ScholarCrossref
4.
Kumar  S, Flinn  I, Richardson  PG,  et al.  Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.   Blood. 2012;119(19):4375-4382. doi:10.1182/blood-2011-11-395749 PubMedGoogle ScholarCrossref
5.
Richardson  PG, Weller  E, Lonial  S,  et al.  Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.   Blood. 2010;116(5):679-686. doi:10.1182/blood-2010-02-268862 PubMedGoogle ScholarCrossref
6.
Durie  BGM, Hoering  A, Abidi  MH,  et al.  Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.   Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X PubMedGoogle ScholarCrossref
7.
Attal  M, Lauwers-Cances  V, Hulin  C,  et al; IFM 2009 Study.  Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.   N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750 PubMedGoogle ScholarCrossref
8.
Krejcik  J, Casneuf  T, Nijhof  IS,  et al.  Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.   Blood. 2016;128(3):384-394. doi:10.1182/blood-2015-12-687749 PubMedGoogle ScholarCrossref
9.
Overdijk  MB, Jansen  JH, Nederend  M,  et al.  The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking.   J Immunol. 2016;197(3):807-813. doi:10.4049/jimmunol.1501351 PubMedGoogle ScholarCrossref
10.
Overdijk  MB, Verploegen  S, Bögels  M,  et al.  Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma.   MAbs. 2015;7(2):311-321. doi:10.1080/19420862.2015.1007813 PubMedGoogle ScholarCrossref
11.
Dimopoulos  MA, Oriol  A, Nahi  H,  et al; POLLUX Investigators.  Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.   N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751 PubMedGoogle ScholarCrossref
12.
Facon  T, Kumar  S, Plesner  T,  et al; MAIA Trial Investigators.  Daratumumab plus lenalidomide and dexamethasone for untreated myeloma.   N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249 PubMedGoogle ScholarCrossref
13.
Mateos  MV, Dimopoulos  MA, Cavo  M,  et al; ALCYONE Trial Investigators.  Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.   N Engl J Med. 2018;378(6):518-528. doi:10.1056/NEJMoa1714678 PubMedGoogle ScholarCrossref
14.
Moreau  P, Attal  M, Hulin  C,  et al.  Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.   Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1 PubMedGoogle ScholarCrossref
15.
Palumbo  A, Chanan-Khan  A, Weisel  K,  et al; CASTOR Investigators.  Daratumumab, bortezomib, and dexamethasone for multiple myeloma.   N Engl J Med. 2016;375(8):754-766. doi:10.1056/NEJMoa1606038 PubMedGoogle ScholarCrossref
16.
Voorhees  PM, Kaufman  JL, Laubach  J,  et al.  Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.   Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288 PubMedGoogle ScholarCrossref
17.
World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053
18.
Rajkumar  SV, Dimopoulos  MA, Palumbo  A,  et al.  International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.   Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5 PubMedGoogle ScholarCrossref
19.
Arcila  ME, Yu  W, Syed  M,  et al.  Establishment of immunoglobulin heavy (IGH) chain clonality testing by next-generation sequencing for routine characterization of B-cell and plasma cell neoplasms.   J Mol Diagn. 2019;21(2):330-342. doi:10.1016/j.jmoldx.2018.10.008 PubMedGoogle ScholarCrossref
20.
Roshal  M, Flores-Montero  JA, Gao  Q,  et al.  MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods.   Blood Adv. 2017;1(12):728-732. doi:10.1182/bloodadvances.2016003715 PubMedGoogle ScholarCrossref
21.
Kumar  S, Paiva  B, Anderson  KC,  et al.  International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.   Lancet Oncol. 2016;17(8):e328-e346. doi:10.1016/S1470-2045(16)30206-6 PubMedGoogle ScholarCrossref
22.
Landgren  O, Lu  SX, Hultcrantz  M.  MRD testing in multiple myeloma: the main future driver for modern tailored treatment.   Semin Hematol. 2018;55(1):44-50. doi:10.1053/j.seminhematol.2018.03.001 PubMedGoogle ScholarCrossref
23.
Korde  N, Roschewski  M, Zingone  A,  et al.  Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma.   JAMA Oncol. 2015;1(6):746-754. doi:10.1001/jamaoncol.2015.2010 PubMedGoogle ScholarCrossref
24.
Landgren  O, Devlin  S, Boulad  M, Mailankody  S.  Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis.   Bone Marrow Transplant. 2016;51(12):1565-1568. doi:10.1038/bmt.2016.222 PubMedGoogle ScholarCrossref
25.
Munshi  NC, Avet-Loiseau  H, Rawstron  AC,  et al.  Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis.   JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160 PubMedGoogle ScholarCrossref
26.
An Open-Label Randomized Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone vs Standard of Care to Determine MRD Negativity in Patients With Newly-Diagnosed Multiple Myeloma (ADVANCE). ClinicalTrials.gov identifier: NCT04268498. Updated December 21, 2020. Accessed March 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04268498
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    Original Investigation
    April 15, 2021

    Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial

    Author Affiliations
    • 1Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    • 2Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
    • 3Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    • 4Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    • 5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
    • 6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
    JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611
    Key Points

    Question  Is the addition of daratumumab to weekly dosing of the second-generation proteasome inhibitor carfilzomib with lenalidomide and dexamethasone a safe combination therapy associated with minimal residual disease negativity for patients with newly diagnosed multiple myeloma?

    Findings  In this nonrandomized clinical trial, the primary end point (minimal residual disease negativity) was achieved in 29 of 41 patients, and therefore the trial was deemed successful. Serious adverse events associated with therapy were reported in 8 patients, but there were no deaths.

    Meaning  This trial suggests that carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy may be safe and tolerable and is associated with high rates of minimal residual disease negativity in patients with newly diagnosed multiple myeloma and high rates of progression-free survival.

    Abstract

    Importance  Recently, the benefit of adding daratumumab to the proteasome inhibitor–based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor–based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone.

    Objective  To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant.

    Design, Setting, and Participants  Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months).

    Interventions  Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8]).

    Main Outcomes and Measures  The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates.

    Results  Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10−5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths.

    Conclusions and Relevance  In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.

    Introduction

    Current clinical guidelines for the frontline treatment of patients with newly diagnosed multiple myeloma include combination therapy—with or without high-dose melphalan chemotherapy and autologous hemopoietic cell transplant (HDM-AHCT)—followed by maintenance therapy.1-3 The first modern 3-drug combination therapy—bortezomib with lenalidomide and dexamethasone (VRd)—was pioneered by the Dana-Farber Cancer Institute. Since its introduction in the National Comprehensive Cancer Network (NCCN) guidelines in 2008 as category 2A evidence, VRd has gradually become the most commonly used combination regimen in the US.4,5 In 2017, the Southwest Oncology Group (SWOG) S0777 cooperative group randomized phase 3 trial reported that VRd (compared with lenalidomide and dexamethasone alone [Rd]) has superior progression-free survival (PFS) and overall survival (OS), which upgraded the evidence to category 1 in the NCCN guidelines.6 Furthermore, for patients not undergoing HDM-AHCT,6 the VRd combination has been reported to deliver a median PFS of 50 months, and when used together with HDM-AHCT, the 4-year OS rate has been reported to be 81%.7 The most common and clinically important adverse event (AE) associated with VRd combination therapy is bortezomib-induced peripheral neuropathy, which commonly results in the lifelong need for pain medications.5-7

    Daratumumab is a human immunoglobulin G κ (IgGκ) monoclonal antibody targeting CD38.8-10 In randomized phase 3 studies—including patients with both newly diagnosed and relapsed or refractory multiple myeloma—the addition of daratumumab to established combination therapies has been found to be safe and to improve the depth of response reflected in higher minimal residual disease (MRD) negativity rates, which has translated into longer median PFS.11-15 Recently, the GRIFFIN trial demonstrated a benefit in adding daratumumab to VRd combination therapy for patients with newly diagnosed multiple myeloma who underwent HDM-AHCT.16 Specifically, in the intent-to-treat population, MRD negativity (MRD sensitivity, 10−5) was achieved in 51% of patients treated with 4 cycles of daratumumab-VRd, 1 round of HDM-AHCT, and additional 2 cycles of daratumumab-VRd (compared with 20% MRD negativity rate for patients treated with 4 cycles of VRd, 1 round of HDM-AHCT, and additional 2 cycles of VRd).16

    Here, we present results from the MANHATTAN nonrandomized clinical trial, which was designed to examine whether the addition of daratumumab to weekly 56-mg/m2 dosing of the second-generation proteasome inhibitor carfilzomib with lenalidomide and dexamethasone (wKRd-D) was associated with high rates of MRD negativity by itself (ie, in the absence of HDM-AHCT) and to establish the safety profile of this novel combination therapy. The primary end point of the study was to demonstrate a 40% or higher MRD negativity rate with wKRd-D.

    Methods
    Trial Design

    This is a single-center, investigator-initiated phase 2 nonrandomized clinical trial conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York. All patients were enrolled at MSKCC between October 1, 2018, and November 15, 2019. The clinical trial protocol and amendments were approved by the MSKCC institutional review board and an independent ethics committee, and all patients provided written informed consent (trial protocol in Supplement 1). The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the principles originating from the Declaration of Helsinki,17 and MSKCC regulations. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Patients

    Eligible patients were 18 years of age or older at study entry, had newly diagnosed multiple myeloma as defined by International Myeloma Working Group (IMWG) criteria,18 and had an Eastern Cooperative Oncology Group performance status score of 0 to 2. Other inclusion criteria included measurable disease within the past 4 weeks (defined by any one of the following: serum monoclonal protein level ≥1.0 g/dL, urine monoclonal protein level >200 mg/24 hours, involved serum immunoglobulin free light chain level >10 mg/dL, and/or an abnormal κ:λ ratio); absolute neutrophil count of 1.0 K/μL or higher, hemoglobin level of 8 g/dL or higher (to convert to g/L, multiply by 10.0), and platelet count of 75 × 103/μL or higher (to convert to ×109/L, multiply by 1.0); adequate hepatic function, with a bilirubin level of less than 1.5 mg/dL (to convert to μmol/L, multiply by 17.104) × the upper limit of normal, and aspartate aminotransferase levels and alanine aminotransferase levels less than 3.0 U/L (to convert both levels to μkat/L, multiply by 0.0167) × the upper limit of normal; creatinine clearance of 60 mL/min/1.73 m2 or higher (to convert to mL/s/m2, multiply by 0.0167); and the ability to tolerate standard thromboprophylactic therapy. All study participants had to be registered into the mandatory eREMS (electronic Risk Evaluation and Mitigation Strategies) program and be willing and able to comply with the requirements of REMS.

    Pretreatment Evaluation to Rule Out Underlying Cardiovascular Disease

    In accord with the trial protocol, and per our institution’s standard workup guidelines prior to administration of carfilzomib therapy, all patients underwent standard bloodwork as well as baseline electrocardiography prior to starting therapy. Patients with known underlying cardiac disease and/or with clinically significant cardiac abnormalities detected during pretreatment evaluation were not enrolled in this clinical trial. Cardiovascular exclusion criteria specified in the trial protocol were significant cardiovascular disease with New York Heart Association class III or IV symptoms, ejection fraction less than 40%, or hypertrophic cardiomyopathy; restrictive cardiomyopathy; myocardial infarction within 6 months prior to enrollment; unstable angina; or unstable arrhythmia as determined by history and physical examination. Also, patients with pulmonary hypertension were excluded.

    Trial Treatments

    All patients received the wKRd-D dosing schedule as follows: 8 cycles of treatment; 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); lenalidomide orally, 25 mg (days 1-21); dexamethasone, 40 mg, orally or intravenously (weekly cycles 1-4), 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7-8]). For healthier patients, stem cell collection was recommended after 4 to 6 cycles of therapy; wKRd-D therapy was resumed after collection to a total of 8 cycles of wKRd-D. After the completion of 8 cycles of wKRd combination therapy; the clinical trial therapy was completed. After cycle 8 of wKRd-D, each patient was counseled to proceed with standard-of-care therapy. For example, some patients received upfront HDM-AHCT followed by maintenance, whereas others (most of the patients who achieved MRD negativity) chose to delay HDM-AHCT and proceed directly to maintenance therapy. All treatment decisions following the completion of the clinical trial were made by the treating physician in collaboration with the individual patient.

    Intravenous Fluids During Combination Therapy

    In accord with the trial protocol and per our institution’s standard fluid management guidelines for patients receiving carfilzomib therapy; the amount of intravenous fluids was optimized to reduce the risk of volume overload, which, in turn, may cause congestive heart failure, pulmonary edema, or other clinical issues. We gave only 250 mL of saline prior to cycle 1, dose 1 of carfilzomib. Unless there was a direct medical reason, no additional intravenous fluids were administered per the trial protocol for the 8 cycles of wKRd-D combination therapy.

    Thromboprophylaxis

    The trial protocol called for standard multiple myeloma thromboprophylaxis (ie, based on the individual patient’s risk profile: low-dose aspirin, warfarin, low-molecular-weight heparin, or oral factor Xa inhibitor). Based on our clinical experience from the standard-of-care setting, low-dose aspirin is associated with an increased risk of thromboembolism when using modern and highly effective combination therapies and is also likely associated with tumor cell killing also triggering cytokine and complement activation. Therefore, per our institution’s clinical guidelines, oral factor Xa inhibitor prophylaxis (typically, rivaroxaban, 10 mg, once daily) is the recommended default for patients with multiple myeloma receiving modern combination therapies.

    End Points and Assessments

    The primary end point was the MRD negativity rate after up to 8 cycles of wKRd-D. Treatment response was assessed with parallel bone marrow–based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing)19,20; per IMWG guidelines, both MRD assays allow for the detection of 1 myeloma cell in 100 000 cells (10−5). The MRD response criteria was based on published definitions for multiple myeloma evaluation of response criteria.7,21,22 The IMWG criteria includes both MFC and next-generation sequencing in their response definition; therefore, for clinical consistency in this trial, MFC was used for our primary end point definition, and next-generation sequencing was investigated as a secondary end point. MRD testing was performed at first evidence of suspected complete response, as recommended per IMWG criteria (including patients with very good partial response or better, and suspected daratumumab interference with immunofixation), and at the end of the 8th cycle of wKRd-D for all patients. Secondary end points included determining safety and tolerability, evaluating the rates of clinical response per IMWG criteria,21 estimating PFS and OS, assessing blood-based biomarkers in relation to clinical outcomes, and defining somatic mutational characteristics at baseline and associated patterns of disease with MRD status and clinical outcomes. PFS was measured from the date of the start of the treatment to the date of progression or death, whichever occurred first. Overall survival was measured from the date of inclusion to the date of death or end of follow-up, whichever occurred first. Investigations of preplanned blood-based and bone marrow–based biomarkers and their association with clinical outcomes are ongoing and will be presented in subsequent publications. Adverse events were monitored continuously from informed consent through 30 days after last study treatment and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.

    Statistical Analysis

    The primary end point was the rate of MRD negativity at the end of planned treatment up to 8 cycles for the combination therapy using multiparametric flow cytometry for patients with newly diagnosed multiple myeloma. This study was designed to distinguish between an unpromising MRD rate of 40% (null hypothesis) and a promising rate of 60%. Using the Simon minimax 2-stage design, the first stage of the study enrolled 28 patients. If at least 12 patients had a best response of MRD negativity within 8 cycles of therapy, the study would continue to enroll remaining patients up to a total of 41 patients. If 21 of the 41 patients obtained a best response of MRD negativity within 8 cycles of therapy, the study would be deemed successful. The study was designed to have a type I error and a type II error of 0.10. The maximum sample size was determined to be 41 patients. The MRD negativity rate at the end of planned treatment was estimated as a sample proportion with a 95% CI based on an exact binomial distribution. Secondary end points, the overall response rate, and very good partial response or complete response rates were estimated as sample proportions. Progression-free survival and OS were evaluated by use of the Kaplan-Meier method. Median follow-up was calculated using the reverse Kaplan-Meier method. As an exploratory analysis, the associations of age (<60 years vs ≥60 years) and disease risk status (high-risk vs standard risk) with MRD negativity were evaluated by use of the Fisher exact test, with odds ratios and 95% CIs estimated from corresponding 2 by 2 tables. A 2-sided P < .05 was considered statistically significant.

    Results

    A total of 41 evaluable patients were enrolled. As shown in the Table, baseline characteristics include a median age of 59 years (range, 30-70 years); 25 female patients (61%) and 16 male patients (39%); 20 patients (49%) patients had a high-risk fluorescence in situ hybridization or single-nucleotide variant signature defined as 1 or more of the following abnormalities: 1q+, t(4;14), t(14;16), t(14;20), and/or 17p−. All 41 patients completed planned treatment during the trial as well as end-of-treatment evaluations defined in the trial protocol. In the present report, the median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months).

    Effectiveness

    The primary end point (to target an MRD negativity rate [10−5 sensitivity in the bone marrow] of 40% or higher after up to 8 cycles of wKRd-D) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful (Figure 1). The median time to MRD negativity was 6 cycles (range, 1-8 cycles). Subgroup analyses for standard clinical factors were conducted for the primary effectiveness end point showing similar a benefit of wKRd-D across subgroups. Specifically, the rate of MRD negativity was not significantly different for patients with high-risk vs standard risk disease (odds ratio, 1.7; 95% CI, 0.36-8.6; P = .50), and the same was true for the association between MRD status and age (<60 years vs ≥60 years) (odds ratio, 0.48; 95% CI, 0.08-2.3; P = .32). Among 29 patients found to be MRD negative at the completion of combination therapy with wKRd-D, there was 1 patient who progressed 9 months later (Figure 1; patient 28). So far, among the 29 patients found to be MRD negative at completion of wKRd-D, 8 patients have been assessed for MRD at 1-year follow-up, and 7 of these 8 patients (88%) showed 1-year sustained MRD negativity. The patient who converted from MRD negative to MRD positive at 1-year follow-up maintained a complete response in the peripheral blood, without onset of clinical symptoms, and the patient continued to receive unchanged maintenance therapy.

    Secondary end points of overall response rate and very good partial response or complete response rates were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. As shown in the swimmer plot (Figure 1), for individual patients, the clinical response continued to deepen over time. At 11 months of median follow-up, the 1-year PFS and OS rates were 98% (95% CI, 93%-100%) (Figure 2) and 100%, respectively.

    Safety

    The most common AEs of any grade are summarized in the eTable in Supplement 2. The most common (≥2 patients) grade 3 or 4 AEs were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). One patient with a normal echocardiogram at baseline developed chest discomfort and cardiac catheterization showing evidence of coronary disease during the trial. The patient received a diagnosis of acute coronary syndrome, withdrew consent, and continued with other standard-of-care therapy. There were no patients with grade 3 or higher peripheral neuropathy. Infusion-related reactions to daratumumab occurred in 18 patients (40%) and were grade 2 in all patients. All patients with an infusion-related reaction experienced the reaction during the first infusion, with no patients experiencing reactions during the second or subsequent infusions. No infusion-related reaction led to the discontinuation of treatment. Serious AEs associated with therapy were reported in 8 patients (18%); the most common was lung infection (7% of patients).

    There were 45 dose reductions for 41 patients; the majority were for lenalidomide (n = 17) and dexamethasone (n = 22). Two patients discontinued therapy: one discontinued therapy owing to a new malignant neoplasm (lung carcinoma) and another chose to withdraw consent owing to COVID-19 (the patient wanted to stop combination therapy to limit clinic visits and instead switch to standard-of-care oral maintenance therapy).

    There were no deaths during the trial. Overall, the therapy was deemed to be well tolerated, and no added major clinical toxic effects were observed with wKRd-D compared with our institution’s standard-of-care 3-drug combination therapy: carfilzomib-lenalidomide-dexamethasone (KRd).23

    Stem Cell Collection

    In this trial, MRD status was determined prior to HDM-AHCT. Per standard guidelines, for healthy patients, stem cell collection was recommended after 4 to 6 cycles of therapy; wKRd-D therapy was resumed after collection to a total of 8 cycles of wKRd-D. After the completion of 8 cycles of wKRd combination therapy; the clinical trial therapy was completed. Our institutional standard-of-care protocol for stem cell mobilization and collection is based on granulocyte colony-stimulating factor followed by plerixafor administered to all patients. For patients who underwent stem cell collection (n = 40), the median yield was 8 million CD34 cells/kg (range, 2-10.7 million CD34 cells/kg). Based on small numbers, we noted a better yield if conducted after 4 cycles (rather than 5 or 6 cycles); however, the trial was not adequately statically powered to definitively address this topic.

    Discussion

    Our phase 2 trial was designed to examine whether the addition of daratumumab to weekly 56-mg/m2 dosing of carfilzomib with lenalidomide and dexamethasone (ie, wKRd-D combination therapy) was associated with high rates of MRD negativity by itself (ie, in the absence of HDM-AHCT) and to establish the safety profile of this novel combination therapy. Specifically, we set the primary end point at a 60% or higher MRD negativity rate. Seventy-one percent of the patients achieved MRD negativity, and therefore the trial was deemed successful. The observed MRD results are approximately 20% higher than previously reported MRD rates among patients with newly diagnosed multiple myeloma treated with KRd,23 which indicates that the addition of daratumumab to an existing backbone combination therapy was associated with a clinically meaningful benefit. This finding is further supported by the recently published phase 2 study evaluating the benefit of adding daratumumab to VRd combination therapy for patients with newly diagnosed multiple myeloma who underwent HDM-AHCT.16 In the GRIFFIN study, in the intent-to-treat population, MRD negativity was achieved in 51% of patients treated with 4 cycles of daratumumab-VRd, 1 round of HDM-AHCT, and additional 2 cycles of daratumumab-VRd (compared with 20% MRD negativity rate for patients treated with 4 cycles of VRd, 1 round of HDM-AHCT, and additional 2 cycles of VRd).16 Furthermore, the benefit of adding daratumumab has been evaluated together with older combination therapies that are used outside the US (eg, bortezomib-thalidomide-dexamethasone [VTd]), and the benefit of daratumumab has been found to be of similar magnitude.14

    When added to all the aforementioned combinations (KRd, VRd, and VTd), daratumumab has consistently been found to be safe and tolerable.14,16 In this nonrandomized clinical trial, we found no additional grade 3 or higher toxic effects with regard to wKRd-D compared with standard-of-care biweekly KRd.23 As expected, no patients developed grade 3 or higher peripheral neuropathy when treated with wKRd-D. We observed a total of 45 dose reductions in 41 patients, and most of these reductions were for lenalidomide and dexamethasone. Using baseline cardiovascular assessments, optimized intravenous fluid management to reduce the risk of volume overload (ie, 250 mL of saline prior to cycle 1, dose 1 of carfilzomib only), and modern thromboprophylaxis (ie, oral factor Xa), we found no evidence of increased risk of cardiovascular toxic effect. Overall, we found wKRd-D therapy to be safe and well tolerated.

    Two recent meta-analyses show that MRD negativity is associated with longer PFS and OS among patients with newly diagnosed multiple myeloma.24,25 Our nonrandomized clinical trial has an unprecedented rate of MRD negativity in this setting. When we stratified our results by age (<65 years vs ≥ 65 years) and cytogenetic risk group (high-risk vs standard risk), we found no statistical difference in the rate of MRD negativity after wKRd-D. Among 29 patients found to be MRD negative at the completion of combination therapy with wKRd-D, so far, 7 of 8 evaluated patients show 1-year sustained MRD negativity. It will be important to capture additional information on sustained MRD negativity as well as PFS and OS after longer follow-up, and we intend to conduct future reports based on this trial.

    Limitations

    The limitations of this clinical trial include the singe-center, nonrandomized phase 2 design. As a next step, a larger randomized, multicenter clinical trial (An Open-Label Randomized Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone vs Standard of Care to Determine MRD Negativity in Patients With Newly-Diagnosed Multiple Myeloma [ADVANCE]) is already ongoing,26 with the aim of confirming and expanding the results.

    Conclusions

    In this nonrandomized clinical trial of patients with newly diagnosed multiple myeloma, wKRd-D cominbation therapy was associated with unprecedented high rates of MRD negativity by itself (ie, in the absence of HDM-AHCT). Indeed, we found that 71% of the patients achieved MRD negativity (primary end point of the trial), and therefore the trial is deemed successful. Building on these promising results, we have developed a large randomized multicenter clinical trial (ADVANCE) comparing wKRd-D with current standard of care for patients with newly diagnosed multiple myeloma, and the trial has already opened for enrollment.26

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    Article Information

    Accepted for Publication: February 19, 2021.

    Published Online: April 15, 2021. doi:10.1001/jamaoncol.2021.0611

    Corresponding Author: Ola Landgren, MD, PhD, Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, 1120 NW 14th St, Clinical Research Bldg, Room 650D, Miami, FL 33136 (col15@miami.edu).

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

    Concept and design: Landgren, Landau, Arcila, Giralt, Korde.

    Acquisition, analysis, or interpretation of data: Landgren, Hultcrantz, Diamond, Lesokhin, Mailankody, Hassoun, Tan, U. A. Shah, Lu, Salcedo, Werner, Rispoli, Caple, Sams, Verducci, Jones, Concepcion, Ciardiello, Chansakul, Schlossman, Tavitian, Shekarkhand, Harrison, Piacentini, Rustad, Yellapantula, Maclachlan, Maura, Landau, Scordo, Chung, G. Shah, Lahoud, Thoren, Murata, Ramanathan, Arcila, Ho, Roshal, Dogan, Derkach, Giralt.

    Drafting of the manuscript: Landgren, Salcedo, Verducci, Chansakul, Harrison, Derkach, Giralt.

    Critical revision of the manuscript for important intellectual content: Landgren, Hultcrantz, Diamond, Lesokhin, Mailankody, Hassoun, Tan, U. A. Shah, Lu, Werner, Rispoli, Caple, Sams, Jones, Concepcion, Ciardiello, Schlossman, Tavitian, Shekarkhand, Piacentini, Rustad, Yellapantula, Maclachlan, Maura, Landau, Scordo, Chung, G. Shah, Lahoud, Thoren, Murata, Ramanathan, Arcila, Ho, Roshal, Dogan, Giralt, Korde.

    Statistical analysis: Landgren, Yellapantula, Landau, Derkach.

    Obtained funding: Landgren, Landau.

    Administrative, technical, or material support: Landgren, Hultcrantz, Diamond, Hassoun, Tan, U. A. Shah, Salcedo, Rispoli, Caple, Sams, Jones, Ciardiello, Chansakul, Schlossman, Tavitian, Harrison, Piacentini, Yellapantula, G. Shah, Lahoud, Murata, Ramanathan, Ho, Roshal, Dogan, Korde.

    Supervision: Landgren, Maura, Landau, Korde.

    Conflict of Interest Disclosures: Dr Landgren reported receiving grants from LLS, the Rising Tide Foundation, Paula and Rodger Riney Foundation, IMF, the National Institutes of Health, Glenmark, Seattle Genetics, Memorial Sloan Kettering, Amgen, and Janssen; personal fees from Amgen, Celgene, and Janssen for invited scientific talks; other fees from Takeda and Janssen for randomized clinical trials, personal fees from Karyopharm, Adaptive Biotech, The Binding Site, Bristol Myers Squibb, Cellectis, Oncopeptides, and Pfizer for invited scientific talks; grants from the Multiple Myeloma Research Foundation for genomic studies and minimal residual disease (MRD) studies in myeloma, from the Perelman Family Foundation for studies on myeloma precursor disease, from the National Cancer Institute for MRD studies in myeloma, and from the US Food and Drug Administration for racial disparities in myeloma; other fees from Theadex for randomized clinical trials and other from Merck outside the submitted work. Dr Hultcrantz reported receiving grants from the Swedish Research Council and the Karolinska Institute Foundations; and other fees from GSK, Daiichi Sankyo, the Multiple Myeloma Research Foundation, and the Memorial Sloan Kettering Cancer Center outside the submitted work. Dr Lesokhin reported receiving grants and personal fees from Janssen and Pfizer, and grants from Genentech, Bristol Myers Squibb, and Trillium Therapeutics outside the submitted work. Dr Mailankody reported receiving other fees from Takeda, Janssen, Bristol Myers Squibb, Allogene Therapeutics, PleXus Education, and Physician Education Resource outside the submitted work. Dr Hassoun reported receving grants from Janssen and Celgene and other fees from Novartis. Dr U. A. Shah reported receiving grants from the Parker Institute for Cancer Immunotherapy and research funding and a research award from Celgene/Bristol Myers Squibb, other from Janssen Research funding paid to institution for investigator initiated clinical trial, and honoraria from Physicians Education Resources Honoraria outside the submitted work. Dr Scordo reported receiving personal fees from Angiocrine Bioscience Inc, Omeros Corporation, McKinsey & Company, Kite Pharma, and i3Health outside the submitted work. Dr G. Shah reported receiving reseach funding from Janssen and Amgen outside the submitted work. Dr Lahoud reported receiving personal fees from MorphoSys for serving on an advisory board outside the submitted work. Dr Thoren reported receiving nonfinancial support from The Binding Site and personal fees and grants from Sebia Inc outside the submitted work. Dr Arcila reported receiving consulting fees from Invivoscribe, Biocartis, and AztraZeneca outside the submitted work. Dr Ho reported receiving honorarium from Invivoscribe outside the submitted work. Dr Dogan reported receiving grants from Roche and Takeda, nonfinancial support from AbbVie, and personal fees from Roche, Takeda, EUSA Pharma, PeerView, PER, and Seattle Genetics outside the submitted work. Dr Giralt reported receving grants from Amgen, Celgene/Bristol Myers Squibb, Actinuum, Miltenyi, and Sanofi during the conduct of the study; personal fees from Amgen, Sanofi, Celgene/Bristol Myers Squibb, and Novartis outside the submitted work; research support/funding from Amgen, Janssen, Celgene, Pfizer, Behring, Sanofi, Jazz Pharmaceuticals, Kite Pharma, and Actinuum; and honraria for consulting from Amgen, Celgene/Bristol Myers Squibb, Actinuum, and Sanofi during the conduct of the study. Dr Korde reported receiving funding from Amgen and Janssen during the conduct of the study and personal fees from Medimmune outside the submitted work. No other disclosures were reported.

    Funding/Support: We were supported by Memorial Sloan Kettering Core Grant (P30 CA008748) for this work. We also thank Janssen and Amgen Pharmaceuticals for support of this investigator-initiated trial.

    Role of the Funder/Sponsor: The funders 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.

    Data Sharing Statement: See Supplement 3.

    References
    1.
    Engelhardt  M, Terpos  E, Kleber  M,  et al; European Myeloma Network.  European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma.   Haematologica. 2014;99(2):232-242. doi:10.3324/haematol.2013.099358 PubMedGoogle ScholarCrossref
    2.
    Mikhael  J, Ismaila  N, Cheung  MC,  et al.  Treatment of multiple myeloma: ASCO and CCO Joint Clinical Practice Guideline.   J Clin Oncol. 2019;37(14):1228-1263. doi:10.1200/JCO.18.02096 PubMedGoogle ScholarCrossref
    3.
    Moreau  P, San Miguel  J, Sonneveld  P,  et al; ESMO Guidelines Committee.  Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2017;28(suppl_4):iv52-iv61. doi:10.1093/annonc/mdx096 PubMedGoogle ScholarCrossref
    4.
    Kumar  S, Flinn  I, Richardson  PG,  et al.  Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.   Blood. 2012;119(19):4375-4382. doi:10.1182/blood-2011-11-395749 PubMedGoogle ScholarCrossref
    5.
    Richardson  PG, Weller  E, Lonial  S,  et al.  Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.   Blood. 2010;116(5):679-686. doi:10.1182/blood-2010-02-268862 PubMedGoogle ScholarCrossref
    6.
    Durie  BGM, Hoering  A, Abidi  MH,  et al.  Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.   Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X PubMedGoogle ScholarCrossref
    7.
    Attal  M, Lauwers-Cances  V, Hulin  C,  et al; IFM 2009 Study.  Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.   N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750 PubMedGoogle ScholarCrossref
    8.
    Krejcik  J, Casneuf  T, Nijhof  IS,  et al.  Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.   Blood. 2016;128(3):384-394. doi:10.1182/blood-2015-12-687749 PubMedGoogle ScholarCrossref
    9.
    Overdijk  MB, Jansen  JH, Nederend  M,  et al.  The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking.   J Immunol. 2016;197(3):807-813. doi:10.4049/jimmunol.1501351 PubMedGoogle ScholarCrossref
    10.
    Overdijk  MB, Verploegen  S, Bögels  M,  et al.  Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma.   MAbs. 2015;7(2):311-321. doi:10.1080/19420862.2015.1007813 PubMedGoogle ScholarCrossref
    11.
    Dimopoulos  MA, Oriol  A, Nahi  H,  et al; POLLUX Investigators.  Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.   N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751 PubMedGoogle ScholarCrossref
    12.
    Facon  T, Kumar  S, Plesner  T,  et al; MAIA Trial Investigators.  Daratumumab plus lenalidomide and dexamethasone for untreated myeloma.   N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249 PubMedGoogle ScholarCrossref
    13.
    Mateos  MV, Dimopoulos  MA, Cavo  M,  et al; ALCYONE Trial Investigators.  Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.   N Engl J Med. 2018;378(6):518-528. doi:10.1056/NEJMoa1714678 PubMedGoogle ScholarCrossref
    14.
    Moreau  P, Attal  M, Hulin  C,  et al.  Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.   Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1 PubMedGoogle ScholarCrossref
    15.
    Palumbo  A, Chanan-Khan  A, Weisel  K,  et al; CASTOR Investigators.  Daratumumab, bortezomib, and dexamethasone for multiple myeloma.   N Engl J Med. 2016;375(8):754-766. doi:10.1056/NEJMoa1606038 PubMedGoogle ScholarCrossref
    16.
    Voorhees  PM, Kaufman  JL, Laubach  J,  et al.  Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.   Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288 PubMedGoogle ScholarCrossref
    17.
    World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053
    18.
    Rajkumar  SV, Dimopoulos  MA, Palumbo  A,  et al.  International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.   Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5 PubMedGoogle ScholarCrossref
    19.
    Arcila  ME, Yu  W, Syed  M,  et al.  Establishment of immunoglobulin heavy (IGH) chain clonality testing by next-generation sequencing for routine characterization of B-cell and plasma cell neoplasms.   J Mol Diagn. 2019;21(2):330-342. doi:10.1016/j.jmoldx.2018.10.008 PubMedGoogle ScholarCrossref
    20.
    Roshal  M, Flores-Montero  JA, Gao  Q,  et al.  MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods.   Blood Adv. 2017;1(12):728-732. doi:10.1182/bloodadvances.2016003715 PubMedGoogle ScholarCrossref
    21.
    Kumar  S, Paiva  B, Anderson  KC,  et al.  International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.   Lancet Oncol. 2016;17(8):e328-e346. doi:10.1016/S1470-2045(16)30206-6 PubMedGoogle ScholarCrossref
    22.
    Landgren  O, Lu  SX, Hultcrantz  M.  MRD testing in multiple myeloma: the main future driver for modern tailored treatment.   Semin Hematol. 2018;55(1):44-50. doi:10.1053/j.seminhematol.2018.03.001 PubMedGoogle ScholarCrossref
    23.
    Korde  N, Roschewski  M, Zingone  A,  et al.  Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma.   JAMA Oncol. 2015;1(6):746-754. doi:10.1001/jamaoncol.2015.2010 PubMedGoogle ScholarCrossref
    24.
    Landgren  O, Devlin  S, Boulad  M, Mailankody  S.  Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis.   Bone Marrow Transplant. 2016;51(12):1565-1568. doi:10.1038/bmt.2016.222 PubMedGoogle ScholarCrossref
    25.
    Munshi  NC, Avet-Loiseau  H, Rawstron  AC,  et al.  Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis.   JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160 PubMedGoogle ScholarCrossref
    26.
    An Open-Label Randomized Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone vs Standard of Care to Determine MRD Negativity in Patients With Newly-Diagnosed Multiple Myeloma (ADVANCE). ClinicalTrials.gov identifier: NCT04268498. Updated December 21, 2020. Accessed March 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04268498
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