D-KRd for untreated myeloma

Journal Pre-proof

Daratumumab plus carfilzomib, lenalidomide, and dexamethasone in

patients with newly diagnosed multiple myeloma

Andrzej Jakubowiak MD, PhD , Saad Z. Usmani MD ,

Amrita Krishnan MD , Sagar Lonial MD ,
Raymond L. Comenzo MD , Jianping Wang PhD ,
Carla de Boer PhD , William Deraedt MS , Brendan M. Weiss MD ,
Jordan M. Schecter MD , Ajai Chari MD

PII: S2152-2650(21)00204-4
DOI: https://doi.org/10.1016/j.clml.2021.05.017
Reference: CLML 1858

To appear in: Clinical Lymphoma, Myeloma and Leukemia

Received date: Oct 2, 2020

Revised date: May 7, 2021
Accepted date: May 17, 2021

Please cite this article as: Andrzej Jakubowiak MD, PhD , Saad Z. Usmani MD ,
Amrita Krishnan MD , Sagar Lonial MD , Raymond L. Comenzo MD , Jianping Wang PhD ,
Carla de Boer PhD , William Deraedt MS , Brendan M. Weiss MD , Jordan M. Schecter MD ,
Ajai Chari MD , Daratumumab plus carfilzomib, lenalidomide, and dexamethasone in patients
with newly diagnosed multiple myeloma, Clinical Lymphoma, Myeloma and Leukemia (2021), doi:
https://doi.org/10.1016/j.clml.2021.05.017

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Daratumumab plus carfilzomib, lenalidomide, and dexamethasone in patients with newly

diagnosed multiple myeloma

Andrzej Jakubowiak, MD, PhDa; Saad Z. Usmani, MDb; Amrita Krishnan, MDc; Sagar Lonial,

MDd; Raymond L. Comenzo, MDe; Jianping Wang, PhDf; Carla de Boer, PhDg; William

Deraedt, MSh; Brendan M. Weiss, MDi; Jordan M. Schecter, MDj; and Ajai Chari, MDk

a
University of Chicago Medical Center, 5841 S. Maryland Ave, MC 2115, Chicago, IL 60637-

6613, USA. Email address: ajakubowiak@medicine.bsd.uchicago.edu;

b
Levine Cancer Institute/Atrium Health, 1021 Morehead Medical Dr, Charlotte, NC 28204,

USA. Email address: saad.usmani@atriumhealth.org;

c
Judy and Bernard Briskin Myeloma Center, City of Hope, 1500 E. Duarte Rd, Duarte, CA

91010, USA. Email address: akrishnan@coh.org;

d
Winship Cancer Institute, Emory University, 1365 Clifton Rd, Atlanta, GA 30322, USA. Email

address: sloni01@emory.edu;
e
John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, 800 Washington St,

Boston, MA 02111, USA. Email address: rcomenzo@tuftsmedicalcenter.org;

f
Janssen Research & Development, LLC, 920 Route 202 S, Raritan, NJ 08869, USA. Email

address: jiwang@its.jnj.com;
g
Janssen Research and Development, LLC, Einsteinweg 101, 2333 CB Leiden, The Netherlands.

Email address: cboer@its.jnj.com;

h
Janssen Research & Development, LLC, Turnhoutseweg 30, B-2340 Beerse, Belgium. Email

address: wderaedt@its.jnj.com;

1
i
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400

Civic Center Blvd, Philadelphia, PA 19104, USA.1 Email address: bweiss8@its.jnj.com;

j
Janssen Research & Development, LLC, 920 Route 202 S, Raritan, NJ 08869, USA. Email

address: jschecte@its.jnj.com;
k
Tisch Cancer Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Pl, New York, NY

10029, USA. Email address: ajai.chari@mountsinai.org.

1
Present address: Janssen Research & Development, LLC, 1400 McKean Rd, Spring House, PA

19477, USA.

Corresponding author:

Andrzej J. Jakubowiak, MD, PhD

Professor of Medicine

Director, Myeloma Program

Section of Hematology/Oncology

University of Chicago Medical Center

5841 S. Maryland Ave, MC 2115

Chicago, IL 60637-6613

773-702-4632 (Office)

773-834-1592 (Direct)

773-702-3002 (Fax)

ajakubowiak@medicine.bsd.uchicago.edu

2
Abstract word count: 246 words

Manuscript word count: 4,974 words

Number of figures/tables: 3 figures and 4 tables

Short running title: D-KRd for untreated myeloma

3
CONFLICT OF INTEREST

AJ served on an advisory board and consulted for AbbVie, Amgen, Bristol-Myers Squibb,

Celgene, GlaxoSmithKline, Janssen, Juno, Karyopharm, Sanofi, and Takeda. SZU served in a

consulting or advisory role for Amgen, AbbVie, Celgene, MundiPharma, Sanofi, Seattle

Genetics, Janssen, Takeda, and SkylineDx, and received grants from Bristol Myers Squibb and

Pharmacyclics. AK served as a consultant for Janssen and Celgene; was a member of a speaker’s

bureau for Janssen, Sutro, Onyx Pharmaceuticals, Takeda, and Celgene; and holds equity in

Celgene. SL received honoraria from Celgene, Janssen, Takeda, Novartis, Bristol Myers Squibb,

GlaxoSmithKline, and Amgen. RLC received research funding from Takeda, Janssen, and

Karyopharm; and is a scientific advisor for Takeda, Prothena, Caelum, and Janssen. BMW

reports research funding from Janssen during the course of the study, current employment with

Janssen Research & Development, LLC, and equity ownership in Johnson and Johnson. JW is an

employee of Janssen. CdB, WD, and JMS are employees of Janssen and have equity ownership

in Johnson & Johnson. AC received research funding from, served on an advisory board for, and

consulted for Janssen, Celgene, Novartis, and Amgen; received research funding from and

served on an advisory board for Seattle Genetics; received research funding from and consulted

for Millennium/Takeda; received research funding from Pharmacyclics; served on an advisory

board for Karyopharm, Sanofi, and Oncopeptides; and consulted for Bristol Myers Squibb and

Antegene.

4
MICROABSTRACT

Triplet regimens including lenalidomide and dexamethasone plus daratumumab or carfilzomib

are effective in multiple myeloma. This phase 1b study evaluated the safety and tolerability of

the quadruplet regimen of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd)

in patients with newly diagnosed multiple myeloma (NDMM). The regimen was well tolerated,

and encouraging efficacy results support further investigation of daratumumab-based quadruplet

therapies for NDMM.

5
ABSTRACT

Background: Combination therapy regimens containing a proteasome inhibitor, an

immunomodulatory drug, and a steroid are an established standard of care for patients with

newly diagnosed multiple myeloma (NDMM) regardless of transplant eligibility. Triplet

regimens that include lenalidomide/dexamethasone combined with daratumumab or carfilzomib

are highly active in multiple myeloma, including NDMM. The aim of this open-label, phase 1b

study was to evaluate daratumumab in combination with carfilzomib, lenalidomide, and

dexamethasone (D-KRd) in patients with NDMM.

Patients and Methods: Patients (N = 22), regardless of transplant eligibility, received treatment

with D-KRd for up to thirteen 28-day cycles or until autologous stem cell transplant (ASCT).

The first daratumumab dose was administered as a split infusion (8 mg/kg on Days 1 and 2 of

Cycle 1). The primary endpoint was safety and tolerability.

Results: A total of 10 patients discontinued treatment, most frequently due to elective ASCT (n

= 8). The most common treatment-emergent adverse events (any-grade; grade 3/4) were diarrhea

(68%; 18%), lymphopenia (64%; 59%), cough (59%; 5%), and upper respiratory tract infection

(55%; 0). Stem cell collection was successful in most patients (91%). Daratumumab infusion-

related reactions occurred in 9 (41%) patients, primarily during the first infusion, and were mild

in severity (no grade 3/4 events). The best overall response rate was 95%, including 86% with a

very good partial response or better and 67% with a complete response or better.

Conclusion: D-KRd was well tolerated, and encouraging efficacy results support further

investigation of daratumumab-based quadruplet therapies for NDMM.

Keywords (5 required; cannot be included in manuscript title): phase 1; safety; tolerability;

efficacy; quadruplet regimen

6
ABBREVIATIONS

AE, adverse event; ASCT, autologous stem cell transplant; CI, confidence interval; CR,

complete response; D-Kd, daratumumab plus carfilzomib and dexamethasone; D-KRd,

daratumumab plus carfilzomib, lenalidomide, and dexamethasone; D-Pd, daratumumab plus

pomalidomide and dexamethasone; D-VRd, daratumumab plus bortezomib, lenalidomide, and

dexamethasone; ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; IMiD,

immunomodulatory drug; IFE, immunofixation electrophoresis; IMWG, International Myeloma

Working Group; KRd, carfilzomib plus lenalidomide and dexamethasone; IRR, infusion-related

reaction; LVEF, left ventricular ejection fraction; MRD, minimal residual disease; MM, multiple

myeloma; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PFS,

progression-free survival; PI, proteasome inhibitor; RRMM, relapsed or refractory multiple

myeloma; SAE, serious adverse event; sCR, stringent complete response; TEAE, treatment-

emergent adverse event; VRd, bortezomib plus lenalidomide and dexamethasone; VGPR, very

good partial response; VTd, bortezomib plus thalidomide and dexamethasone.

7
INTRODUCTION

Despite recent advances in treatment, multiple myeloma (MM) remains largely incurable.1

Selection of frontline treatment for patients with newly diagnosed MM (NDMM) is a topic of

particular interest, as the depth and duration of response is reduced with each treatment relapse.2

Triplet regimens consisting of a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and

steroids (with or without autologous stem cell transplant [ASCT]) are now established as

standards of care for NDMM. Bortezomib, lenalidomide and dexamethasone (VRd) is an

effective regimen in NDMM based on the SWOG 0777 and IFM 2009 studies.3, 4 In Europe,

bortezomib, thalidomide, and dexamethasone (VTd) is a widely used regimen in transplant-

eligible patients.5, 6 In phase 2 studies, carfilzomib, lenalidomide, and dexamethasone (KRd) has

shown activity as a first line of treatment for patients with MM.7-10 Although this regimen is only

approved for patients with relapsed or refractory MM (RRMM),11 the deep responses, ability to

proceed to ASCT, and tolerability of the combination shown in these phase 2 studies warrant

further investigation in patients with NDMM, and suggest that KRd may provide an excellent

backbone in quadruplet therapies. Findings from the phase 3 ENDURANCE trial demonstrated

similar efficacy of KRd and VRd in patients with standard-risk NDMM patients who were not

intended for immediate ASCT or were ineligible for ASCT.12

Daratumumab is a human immunoglobulin (Ig)Gκ monoclonal antibody targeting CD38 with a

direct on-tumor13-16 and immunomodulatory mechanism of action.17-19 Daratumumab is approved

as a monotherapy, producing deep and durable responses in patients with heavily pre-treated

RRMM.20-22 In the phase 3 studies POLLUX, CASTOR, and CANDOR, daratumumab in

combination with lenalidomide and dexamethasone, bortezomib and dexamethasone, or

8
carfilzomib and dexamethasone demonstrated a significant progression-free survival (PFS)

benefit in patients with MM treated with ≥1 prior line of therapy.23-25 The combination of

daratumumab and pomalidomide and dexamethasone (D-Pd) in patients with ≥2 prior lines of

therapy resulted in an overall response rate (ORR) of 60% and median overall survival of 17.5

months at a median follow-up of 13.1 months.26 Additionally in the ALCYONE and MAIA

studies, daratumumab in combination with bortezomib, melphalan, and prednisone or

lenalidomide and dexamethasone significantly reduced the risk or disease progression or death in

patients with NDMM who were ineligible for ASCT.27-29

Given the growing evidence of the effectiveness of PI, IMiD, and steroid combination regimens,

a logical next step is to test whether the addition of daratumumab may enhance these treatments.

In the CASSIOPEIA phase 3 clinical trial, the addition of daratumumab to VTd in transplant-

eligible NDMM patients improved outcomes compared with VTd, leading to its approval in

many countries across the world.30-32 Furthermore, the addition of daratumumab to weekly

carfilzomib 70 mg/m2 and dexamethasone (D-Kd) in the multi-arm phase 1b study MMY1001

was well tolerated and resulted in an ORR of 84% in patients with RRMM.33 Based on the

efficacy of KRd in phase 2 clinical trials and the efficacy of D-Rd and D-Kd, we report a phase

1b study of the quadruplet regimen of daratumumab in combination with KRd (D-KRd) in

patients with NDMM.

PATIENTS AND METHODS

Study design

9
This was an open-label, nonrandomized, multicenter, multi-arm, phase 1b study. Daratumumab

was evaluated in combination with a variety of backbone regimens (ClinicalTrials.gov Identifier:

NCT01998971). Here, we describe the D-KRd treatment arm for patients with NDMM (no prior

treatment). The study protocol was approved by an independent ethics committee or institutional

review board at each study center, and was conducted in accordance with the principles of the

Declaration of Helsinki and the International Conference on Harmonization Good Clinical

Practice guidelines. All patients provided written informed consent.

Eligibility criteria

Patients aged ≥18 years with newly diagnosed, documented measurable myeloma per

International Myeloma Working Group (IMWG) criteria34 were candidates regardless of

transplantation eligibility. For patients with IgG disease, serum M-protein level was ≥1.0 g/dL

(≥0.5 g/dL in IgA, IgD, or IgE disease) or urine M-protein ≥200 mg/24 hours per IMWG criteria.

For patients with light-chain MM, serum immunoglobulin free light chain was ≥10 mg/dL, and

an abnormal serum immunoglobulin κ:λ free light-chain ratio was required. All patients had an

Eastern Cooperative Oncology Group (ECOG) performance status of ≤2; hemoglobin ≥7.5 g/dL;

absolute neutrophil count ≥1.0 ×109/L; aspartate aminotransferase and alanine aminotransferase

≤2.5 × upper limit of normal; total bilirubin ≤1.5 mg/dL; calculated creatinine clearance >30

mL/min/1.73 m2; corrected serum calcium <14 mg/dL or free ionized calcium <6.5 mg/dL; and a

platelet count >50 ×109/L (≥70 ×109/L in patients for whom <50% of bone marrow nucleated

cells were plasma cells).

10
Patients who received previous treatment with daratumumab or other anti-CD38 therapies, had

prior or current systemic therapy (except emergency use of a short course of corticosteroids), or

stem cell transplantation were ineligible. Patients with a diagnosis of monoclonal gammopathy

of undetermined significance, smoldering MM, amyloidosis, or Waldenström disease were not

eligible for this study. Patients were not included if they had peripheral neuropathy grade ≥2;

meningeal involvement of myeloma; chronic obstructive pulmonary disease (with a forced

expiratory volume in 1 second <50% of predicted normal); moderate, severe, or uncontrolled

asthma; or a known hypersensitivity to thalidomide or lenalidomide. Significant cardiac disease

as determined by transthoracic echocardiography (left ventricular ejection fraction [LVEF]

<40%) also warranted study exclusion.

Treatment

D-KRd treatment (28-day cycles) continued for up to 13 cycles or until elective discontinuation

for ASCT. Daratumumab 16 mg/kg (intravenous) was administered weekly during Cycles 1 and

2, every 2 weeks during Cycles 3 through 6, and every 4 weeks thereafter. All patients received

the first daratumumab dose as a split dose over 2 days (8 mg/kg in 500 mL on Cycle 1 Days 1

and 2). If no grade >1 infusion-related reactions (IRRs) occurred, the second dose was 16 mg/kg

(in 500 mL) at an initial rate of 50 mL/hour (increased by 50-mL/hour increments at 60-minute

intervals to a maximum rate of 200 mL/hour); if grade >1 IRR occurred, daratumumab 16 mg/kg

was given in 1 000 mL on Cycle 1 Day 8. From Cycle 1 Day 15 and beyond, daratumumab was

administered at the standard 16 mg/kg dose.

11
Carfilzomib was administered weekly on Days 1, 8, and 15 of each 28-day cycle. Patients

received an initial dose of 20 mg/m2 on Cycle 1 Day 1 (30-minute infusion), escalated to 70

mg/m2 at Cycle 1 Day 8+ (30-minute infusion) if deemed tolerable. Lenalidomide 25 mg was

given on Days 1 through 21 of each cycle. Dexamethasone was administered at a dose of 40

mg/week in patients aged ≤75 years (20 mg/week, age >75 years). As this study was designed to

evaluate the safety and tolerability of up to 13 cycles of D-KRd administration only, patients did

not receive lenalidomide maintenance during the study. However, patients could receive

additional therapy off study thereafter.

To reduce the risk of IRRs, all patients received diphenhydramine 25 mg to 50 mg,

acetaminophen 650 mg to 1 000 mg, and montelukast 10 mg prior to infusion (montelukast was

optional after first dose). Post-infusion medications included methylprednisolone 20 mg if

dexamethasone was reduced to 20 mg/week and given as a pre-infusion medication. All patients

received antithrombotic prophylaxis (daily subcutaneous low molecular weight heparin or oral

aspirin [100 mg]). Growth factors were permitted for patients experiencing neutropenia.

Prophylaxis (acyclovir, famciclovir, or valacyclovir) for herpes zoster reactivation was

recommended during the treatment phase. Pneumocystis carinii pneumonia prophylaxis was

considered per institutional guidelines. Information on stem cell collection (including

mobilization agents used and number of CD34+ cells harvested) was recorded.

Study endpoints and analyses

The primary endpoint was safety and tolerability. Safety was evaluated in all patients who

received ≥1 administration of study treatment and included adverse event (AE) monitoring,

12
physical examinations, electrocardiogram monitoring (echocardiogram required every 3 months

and within 72 hours of cardiac failure), clinical laboratory tests, vital sign measurements, and

ECOG performance status. Toxicities were graded using the National Cancer Institute Common

Terminology Criteria for Adverse Events Version 4.35

Secondary endpoints included pharmacokinetics and efficacy (ie, ORR, rate of complete

response [CR]). Response to treatment and disease progression were evaluated according to

IMWG response criteria at the end of each cycle.34, 36 Patients were censored at the time of

discontinuation and responses were not assessed following ASCT. Paraproteins were assessed by

a central laboratory. The response analysis cohort included patients who received ≥1

administration of study treatment and had ≥1 post-baseline disease assessment. Disease

progression was confirmed by ≥1 repeated test performed 1 to 3 weeks after the initial test

showing progression. Serum and urine immunofixation electrophoresis (IFE) were performed at

screening and when CR was suspected. A daratumumab-specific IFE assay was used to confirm

CR for patient samples in which daratumumab interference with IFE was suspected.37 Minimal

residual disease (MRD) was evaluated in bone marrow aspirate samples from patients who

achieved a ≥CR. Samples were prepared with Ficoll using the ClonoSEQ™ assay (v2.0;

Adaptive Biotechnologies, Seattle, WA, USA).

Treatment-emergent AEs (TEAEs) were summarized using descriptive statistics, including AEs

of clinical interest. Efficacy assessment was performed and responses were categorized per

IMWG criteria. For each response category, an exact 2-sided 95% confidence interval (CI) was

calculated; ORR was analyzed for response-evaluable patients and defined as the proportion of

13
response-evaluable patients who achieved a stringent CR (sCR), CR, very good partial response

(VGPR), or partial response. Duration of response and PFS were estimated using the Kaplan-

Meier method for descriptive summaries.

The MMY1001 study was designed to generate preliminary data for the use of daratumumab in

combination with various backbone treatment regimens; therefore, the sample size was not

determined based on formal hypothesis testing.

RESULTS

Patients

Twenty-two patients were enrolled in the study between December 31, 2015 and July 12, 2016.

Median (range) age was 59.5 (34-74) years, 95% of patients had an ECOG performance status

≤1, and 81.8% of patients had IgG disease (Table 1). Although not specified in the protocol, all

patients were determined to be ASCT eligible (based on inclusion criteria that included an

ECOG performance status ≤2 and LVEF >40%). A total of 12 (55%) patients completed

treatment (13 cycles), with no patients continuing to receive therapy. Ten (46%) patients

discontinued D-KRd treatment prior to completing 13 cycles, including 8 due to elective ASCT,

1 due to progressive disease (last treatment Study Day 219), and 1 because of a TEAE

(pulmonary embolism, unrelated to daratumumab or carfilzomib; last treatment Study Day 23).

Treatment exposure

The median (range) duration of follow-up was 23.3 (6.9-27.7) months. Patients received a

median (range) of 13.0 (1-13) treatment cycles. The median (range) time for the first split-dose

14
daratumumab infusion was 4.15 (4.0-6.0) hours on Cycle 1 Day 1 and 4.15 (3.9-6.0) hours on

Cycle 1 Day 2. The second daratumumab infusion had a median (range) of 4.19 (4.0-7.1) hours

and all subsequent infusions had a median duration of 3.38 (1.4-6.1) hours.

Nineteen (86%) patients escalated to the full carfilzomib dose (70 mg/m2) by Cycle 2 Day 1. Of

the remaining 3 patients, 1 patient discontinued treatment by Cycle 2 Day 1 (due to pulmonary

embolism), 1 patient experienced dose reduction to 56 mg/m2 at Cycle 2 Day 1 (due to left

ventricular failure), and 1 patient was escalated to carfilzomib 70 mg/m2 at Cycle 3 Day 8.

Among treated patients, 5 of 22 (23%), 5 of 21 (24%), and 1 of 16 (6%) patients experienced

dose modifications (skipped or delayed) of daratumumab during Cycles 1-2, 3-6, and ≥7,

respectively. Skipped daratumumab doses occurred in 4 (18%), 5 (24%), and 1 (6%) patients

during Cycles 1-2, 3-6, and ≥7, respectively. Two (9%) patients had delayed daratumumab doses

during Cycles 1-2. Dose modifications (skipped, reduced, or delayed) of carfilzomib occurred in

4 of 22 (18%), 10 of 21 (48%), and 11 of 16 (69%) treated patients during Cycles 1-2, 3-6, and

≥7, respectively. Skipped carfilzomib doses occurred in 4 (18%), 7 (33%), and 10 (63%) patients

during Cycles 1-2, 3-6, and ≥7, respectively. Carfilzomib dose reductions occurred in 1 (5%), 3

(14%), and 1 (6%) patients during Cycles 1-2, 3-6, and ≥7, respectively, and 1 (6%) patient had a

delayed carfilzomib dose during Cycles ≥7. Lenalidomide dose modifications (skipped or

reduced) occurred in 11 of 22 (50%), 13 of 21 (62%), and 12 of 16 (75%) treated patients during

Cycles 1-2, 3-6, and ≥7, respectively. Skipped lenalidomide doses occurred in 10 (46%), 12

(57%), and 10 (63%) patients during Cycles 1-2, 3-6, and ≥7, respectively. Lenalidomide dose

reductions occurred in 2 (9%), 5 (24%), and 4 (25%) patients during Cycles 1-2, 3-6, and ≥7,

respectively. Dose modifications (delayed or reduced) of dexamethasone occurred in 7 of 22

15
(32%), 6 of 21 (29%), and 9 of 16 (56%) treated patients during Cycles 1-2, 3-6, and ≥7,

respectively. Dexamethasone dose reductions occurred in 2 (9%), 3 (14%), and 4 (25%) patients

during Cycles 1-2, 3 through 6, and ≥7, respectively.

Safety

The most common any-grade TEAEs (≥50%) included diarrhea (68%), lymphopenia (64%),

cough (59%), upper respiratory infection (55%), insomnia (50%), fatigue (50%), and

constipation (50%; Table 2). The most common (≥10%) grade 3/4 TEAEs were lymphopenia

(59%), diarrhea (18%), neutropenia (18%), and lymphocyte count decrease (18%). Any-grade

superficial thrombosis and deep vein thrombosis occurred in 1 (5%) patient and 3 (14%) patients,

respectively; 1 (5%) patient experienced grade 3/4 deep vein thrombosis. Rates of grade 3/4

infection were low, including 2 (9%) patients each with influenza and pneumonia and 1 (5%)

patient each with atypical pneumonia and gastroenteritis. Eight (36%) patients total received

acyclovir for herpes zoster antiviral prophylaxis; no patients received intravenous

immunoglobulins or prophylaxis for Pneumocystis carinii.

Serious AEs (SAEs) were reported in 10 (46%) patients. The most common SAE was pulmonary

embolism (3 [14%] patients); 1 of these 3 patients also experienced bilateral deep vein

thrombosis (none had a medical history of thrombosis). Two (9%) patients experienced SAEs of

influenza, and 1 (5%) patient each experienced SAEs of pneumonia, atypical pneumonia, or

gastroenteritis infections. Among 7 (32%) patients with SAEs reasonably related to treatment, 1

patient experienced SAEs of influenza and pneumonia that were considered related to all four

study treatments; 1 patient experienced an SAE of pyrexia that was considered related to

16
daratumumab, carfilzomib, and lenalidomide; and 1 patient experienced an SAE of left

ventricular failure related to daratumumab and carfilzomib. One patient experienced an SAE of

atypical pneumonia related to carfilzomib and lenalidomide; that same patient also had an SAE

of dyspnea related to carfilzomib alone and an SAE of pulmonary embolism related to

lenalidomide alone. One additional patient experienced an SAE of pulmonary embolism related

to lenalidomide alone. One patient each had an SAE of chest pain related to carfilzomib alone

and an SAE of pulmonary embolism related to lenalidomide and dexamethasone.

No notable change from baseline over time was observed in median LVEF with study treatment

(per protocol definition, median change from baseline was <2% at Cycles 3, 6, 9, and 12). Three

(14%) patients had a history of or ongoing coronary artery disease; 1 (5%) of these patients also

had ongoing heart palpitations and coronary arteriospasm. Two of the patients with a medical

history of coronary artery disease experienced low-grade (grade 1/2) cardiac TEAEs. Transient

grade 3 cardiac failure was reported in 1 (5%) additional patient, who resumed treatment on

Cycle 2 Day 1 with a reduced carfilzomib dose (56 mg/m2). The patient elected to undergo

ASCT on Day 113 (Cycle 5), ended treatment with a VGPR, and did not experience further

cardiotoxicity.

IRRs occurred in 9 (41%) patients, primarily during the first infusion (8 [36%] patients). IRRs

only occurred in 2 (9%) patients during the second infusion and 1 (5%) patient in subsequent

infusions. Overall, IRRs were mild, with no grade 3/4 events. No IRR was predominant, with

each occurring in ≤2 patients (Table 3).

17
Efficacy

The response-evaluable analysis set included 21 patients (1 patient was not included due to

treatment discontinuation [due to pulmonary embolism] before post-baseline disease

assessment). Best overall response and response rates after 4, 8, and 13 treatment cycles in the

response-evaluable population are shown in Figure 1 (note that patients who discontinued to

proceed to transplant were not assessed for response post-transplant). Responses deepened with

time, including an increased rate of ≥CR from after 4 cycles to after 8 and 13 cycles. Best overall

response rates in all-treated patients (patients who received ≥1 dose of study drug [N =22]) were

similar to best overall response rates in the response-evaluable population (Supplementary

Table 1). For the 8 patients who achieved a ≥CR and underwent MRD testing, the MRD-

negativity rate at the time of suspected CR/sCR was 100% at a 10–4 sensitivity threshold and

75% at a 10–5 sensitivity threshold; all were indeterminate at a 10–6 sensitivity threshold (Figure

2).

At a median follow-up of 23.3 months, 1 (5%) patient experienced disease progression and

median PFS had not been reached (Figure 3). The estimated 12-month PFS rate was 95% (95%

CI 70.7%-99.3%). All patients remain alive, and follow-up is ongoing.

All patients (N = 22) underwent stem cell harvest. Information regarding the number of stem cell

harvest attempts and number of days per collection attempt is not available. Patients received a

median (range) of 5 (1-11) treatment cycles prior to stem cell harvest, and 15 (68%) patients had

a best response of ≥VGPR prior to stem cell harvest. A total of 14 (64%) patients underwent >1

collection attempt; 3 (14%) patients underwent >5 collection attempts. None of the 3 patients

18
who required 5 collection attempts underwent ASCT; 2 of these patients completed all 13

treatment cycles, while the remaining 1 patient had discontinued treatment due to an adverse

event of pulmonary embolism by Cycle 2 Day 1. Failed collection attempts (to obtain targeted

numbers of harvested stem cells during a session) only occurred in 2 patients, with 5 failed

collection attempts in 1 patient and 2 failed collection attempts in the second patient. The median

(range) number of CD34+ cells collected was 11.4 (3.5-447.6) × 106 cells/kg. A total of 10

patients underwent ASCT; best responses of patients who discontinued treatment to pursue

elective ASCT or completed treatment and proceeded to ASCT are shown in Table 4. Stem cell

mobilization agents are also presented; no patients received cyclophosphamide for stem cell

mobilization.

DISCUSSION

This study demonstrates that D-KRd quadruplet therapy, with carfilzomib administered weekly,

is well tolerated, with a safety profile consistent with previous reports of KRd triplet therapy,

with carfilzomib administered twice weekly.7-9 The split first dose regimen for daratumumab was

well tolerated, and was recently approved in the United States and Europe.38, 39 Responses

deepened with longer follow-up, with D-KRd showing evidence of encouraging efficacy. The

vast majority of patients responded to therapy (95%); responses were deep, including 86% of

patients with ≥VGPR and 67% of patients with ≥CR. The MRD-negativity rate at a sensitivity

threshold of 10–5 was 75% (6 out of 8 patients) among patients who achieved a ≥CR and

underwent MRD testing.

19
Deep responses (4 sCRs and 3 VGPRs) were achieved pre-transplant for the 8 patients who

discontinued treatment to undergo elective ASCT. Additionally, 2 patients who completed

treatment (13 cycles) proceeded to ASCT. As patients were censored at the time of

discontinuation of protocol treatment and responses were not assessed following ASCT, further

deepening of responses induced by D-KRd could not be captured in patients undergoing ASCT.

However, these results are consistent to favorable with those observed in the 12 cycle twice-

weekly carfilzomib 36 mg/m2 plus Rd treatment arm of the FORTE study in patients with

transplant-eligible NDMM (≤65 years of age; N = 157) and the MMRC study of twice-weekly

carfilzomib 20-36 mg/m2 plus Rd treatment for 24 cycles with deferred transplant.9, 40 Patients

treated with 12 cycles of KRd in FORTE demonstrated a ≥VGPR rate of 87%, a ≥CR rate of

61%, and an MRD-negativity rate (10–5 sensitivity threshold) of 54%; and an at least near CR

rate of 72% and a ≥VGPR rate of 86% was reported in patients (n = 29) who received ≥12

treatment cycles in the MMRC study.9, 40 Here, the ≥VGPR rate (92%) with D-KRd after 13

treatment cycles was similar to KRd in FORTE (87%) and MMRC (86%) studies, while the ≥CR

rate (83%) was higher than what was reported for ≥CR in FORTE (61%) and near CR or better

(72%) in the MMRC study. In the randomized phase 2 GRIFFIN study, patients with transplant-

eligible NDMM underwent induction and consolidation with daratumumab plus VRd (D-VRd)

versus VRd alone.41 Findings from the study showed a ≥VGPR rate of 72% and a ≥CR rate of

19% with D-VRd at the end of induction (4, 21-day cycles), which are lower than what is

reported here; however, the rates of ≥VGPR and ≥CR continued to deepen over time following

ASCT and consolidation and were 96% and 80%, respectively, with a median follow-up of 22.1

months.

20
The current study lacked a control group and assessed the safety and efficacy of D-KRd in a

small number of patients with NDMM; nevertheless, stem cell collection was successful in the

majority (20 of 22; 91%) of patients treated with D-KRd, providing further evidence that the use

of daratumumab is feasible as part of pre-transplant induction therapy. A median of 11.4 × 106

CD34+ cells/kg were collected, although 3 patients required >5 collection attempts. These

findings are consistent with stem cell collection data reported in other studies evaluating

daratumumab combination therapies in patients with NDMM.30, 41, 42

D-KRd was well tolerated in patients with NDMM. The AE profile was consistent with previous

studies of both daratumumab and twice-weekly carfilzomib (20-36 mg/m2) plus Rd.7-9, 23, 24, 26, 27

A once-weekly 70 mg/m2 carfilzomib dosing schedule was used in this study. In the phase 3

A.R.R.O.W. study in patients with RRMM, the overall safety of 70 mg/m2 weekly dosing was

similar to a 27 mg/m2 twice-weekly carfilzomib dosing schedule, but showed improved efficacy.

Carfilzomib was recently approved in combination with dexamethasone for once-weekly dosing

using a 20/70 mg/m2 dosing schedule based on these results.11, 43 In our study, only 1 patient

discontinued treatment due to a TEAE, no patients died due to TEAEs, and patients were able to

proceed to elective ASCT. Cardiac TEAEs were limited, with only a single grade 3 event which

resolved with carfilzomib dose interruption and subsequent dose reduction. A total of 5 (23%)

patients experienced a treatment-emergent thrombolic event, all of which resolved. All but 1 of

these patients received prophylactic treatment (aspirin) per study protocol, which was based on

guidelines available at the time. All pulmonary embolisms were attributed to lenalidomide,

consistent with previous reports showing an association between lenalidomide and an increased

risk of thrombosis and subsequent pulmonary embolisms.44 Pulmonary embolisms and venous

21
thromboembolisms have also been noted in previous studies of KRd, but not studies of D-Kd or

daratumumab monotherapy in RRMM.7, 33, 45-47 To decrease the rate of venous

thromboembolisms with KRd (with or without daratumumab), consideration should be given to

dosing of carfilzomib; if given weekly, carfilzomib should be limited to 56 mg/m2 and use of

more aggressive anticoagulants should be considered.48-51

Peripheral neuropathy was infrequent (3 [14%] patients) and no grade 3/4 events were observed,

occurring at a rate similar to previous trials of carfilzomib.52 In contrast, bortezomib is frequently

associated with peripheral neuropathy, which is a common reason for treatment

discontinuation.53 Grade 3/4 infections were reported in 5 (23%) patients, consistent with

previous reports of daratumumab-combination regimens.26, 29, 30, 33, 54, 55

IRRs were mild (grade 1/2) and occurred mainly during the first infusion. Splitting the first dose

over 2 days was feasible, and reduced the duration of the first infusion, with an overall IRR rate

of 41%. In a separate arm of this study, this split first dose protocol was employed in 75 patients

with RRMM treated with daratumumab plus weekly carfilzomib 70 mg/m2 and dexamethasone

and resulted in an IRR rate of 43%, with most occurring during the first infusion.33 Patients

treated with daratumumab plus CyBorD in the LYRA phase 2 study also received a split first

dose over Days 1 and 2. IRRs occurred in 53% of patients; 49% were during the first infusion.42

Recently, a subcutaneous version of daratumumab co-formulated with recombinant human

hyaluronidase PH20 (ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA,

USA) was approved that was demonstrated to be non-inferior to the intravenous formulation of

daratumumab in terms of efficacy and pharmacokinetics and to reduce administration time and

22
the rate of IRRs.56-58 Although there have been no studies assessing subcutaneous daratumumab

in combination with KRd in patients with NDMM, the use of subcutaneous daratumumab in this

combination would be expected to reduce administration time as well as the rate of IRRs.

These safety data that included a once weekly carfilzomib dosing schedule, taken together with

the high response rate, suggest a favorable benefit-risk profile for D-KRd, particularly when

compared with other triplet and quadruplet therapies. Recent results from the phase 3

ENDURANCE trial demonstrated that KRd failed to show PFS improvement over VRd in

standard-risk NDMM patients who were not intended for immediate ASCT or were ineligible for

ASCT.12 A significantly higher rate of a composite measure of cardiopulmonary and renal

toxicity was observed with KRd versus VRd, which was largely driven by dyspnea. These results

suggest that VRd continues to be a suitable backbone regimen for 4 drug combinations, as is

being investigated in the phase 2 GRIFFIN41 and PLEIADES59 trials and phase 3 PERSEUS

(NCT03710603) and CEPHEUS (NCT03652064) trials with D-VRd. Of note, a twice-weekly 36

mg/m2 carfilzomib dosing schedule was used in the ENDURANCE trial, therapy was limited to

36 weeks for both triplets, and rates of peripheral neuropathy were higher with VRd.12 The

relatively short durations of KRd and VRd treatment, both planned and delivered, may have

limited the comparison between these two regimens,60 especially given the important role of

duration of treatment in achieving deep responses.8, 41

Results from the D-Kd and D-Pd treatment arms of the MMY1001 study have been previously

reported.26,33 In addition to the current study, D-KRd is being evaluated in 3 open-label phase 2

trials. The MASTER trial is assessing D-KRd (weekly carfilzomib dose escalated to 56 mg/m2)

23
in patients with NDMM administered over four 28-day cycles as induction therapy prior to

ASCT and as consolidation, according to MRD status at each phase of therapy. D-KRd therapy

in this trial was shown to be tolerable, with rapid responses and a high proportion of patients

achieving CR/sCR and MRD negativity.51 A study of up to 8 cycles of weekly D-KRd (weekly

carfilzomib dose escalated to 56 mg/m2) has demonstrated an 83% MRD-negativity rate in

patients with NDMM who had not received ASCT, with no additional toxicity compared with

twice-weekly D-KRd (twice-weekly carfilzomib dose escalated to 36 mg/m2).49 The IRB17-1097

trial (NCT03500445) is assessing 24 cycles of D-KRd (twice-weekly carfilzomib dose escalated

to 36 mg/m2) in patients with NDMM regardless of transplant eligibility. Transplant will be

deferred for transplant-eligible patients using a similar study design and eligibility criteria as the

published KRd regimen,9 with the objective of evaluating the impact on efficacy with the

addition of daratumumab to KRd.

Although the results of the present trial are encouraging, the limitations of this study include a

small sample size and available baseline characteristics, early discontinuation of patients for

ASCT, and lack of a comparator arm. As responses were not evaluated following ASCT, further

deepening of responses with D-KRd could not be assessed in patients undergoing ASCT.

However, taken together, the depth of responses observed and ability to proceed to ASCT may

provide a rationale for further investigation.

CONCLUSION

In summary, compared with studies of daratumumab and KRd alone, no new safety concerns

were observed when daratumumab was combined with KRd. Despite the limitations of the study,

24
promising activity suggestive of benefit was observed with D-KRd. The use of split dosing was

feasible and reduced infusion time for the first daratumumab dose, which may provide a more

convenient option for patients and healthcare providers. In addition, in the majority of patients,

stem cell collection was successful during treatment with D-KRd. Nearly all treated patients

responded to therapy, and responses continued to deepen over time. These results suggest that a

larger clinical trial of D-KRd may show similar benefits to those observed with daratumumab

plus PI, IMiD, and steroid combinations in other studies in NDMM.

CLINICAL PRACTICE POINTS

 Triplet regimens with a proteasome inhibitor, immunomodulatory drug, and steroids

(with or without autologous stem cell transplant [ASCT]) are now established as

standards of care for newly diagnosed multiple myeloma (NDMM)

 Among triplet regimens, carfilzomib, lenalidomide, and dexamethasone (KRd) has shown

high activity for patients with NDMM

 The addition of daratumumab, a human immunoglobulin Gκ monoclonal antibody, to

standard of care regimens has improved outcomes across lines of therapy in multiple

myeloma

 Here, in a phase 1b study, we show that the addition of daratumumab to KRd is well

tolerated, with encouraging efficacy

 These results support further investigation of daratumumab-based quadruplet therapies

for NDMM

25
ACKNOWLEDGMENTS

This study was sponsored by Janssen Research & Development, LLC. The authors thank the

patients who participated in the MMY1001 study and their families, as well as the study co-

investigators, research nurses, and coordinators at each of the clinical sites. Medical writing and

editorial support were provided by Elise Blankenship, PhD and J. Matthew Kuczmarski, PhD of

MedErgy and were funded by Janssen Global Services, LLC.

ROLE OF THE FUNDING SOURCE

This trial was designed by the study sponsor, Janssen Research & Development, LLC. Patients

were assigned to a treatment regimen in MMY1001 in a non-randomized manner based upon the

investigator’s judgment and the recruitment status of available treatment regimens as

communicated by the sponsor. The sponsor and an independent data monitoring committee

reviewed safety data during the study. Data were collected by the investigators and analyzed by

the Janssen trial team. All authors, including those from Janssen, were responsible for data

interpretation and the development of the article, and approved the final version. Professional

medical writers who were funded by the sponsor prepared the manuscript. The lead author had

full access to all data in the study and had final responsibility for the decision to submit for

publication.

AUTHOR CONTRIBUTIONS

AJ, SZU, AK, and JMS participated in conception and design of the work being described in the

publication, acquisition/collection of data, and analysis or interpretation of data. SL and CdB

participated in conception and design of the work being described in the publication and analysis

26
or interpretation of data. RC participated in acquisition/collection of data. JW participated in

analysis or interpretation of data. WD, BMW, and AC participated in acquisition/collection of

data and analysis or interpretation of data. All named authors had full access to all of the data in

this study, meet the International Committee of Medical Journal Editors (ICMJE) criteria for

authorship for this article, take responsibility for the integrity of the work as a whole, and have

given their approval for this version to be published.

DATA SHARING

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available

at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access

to the study data can be submitted through Yale Open Data Access (YODA) Project site at

http://yoda.yale.edu.

27
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36
Table 1. Demographics and Baseline Disease Characteristics

N = 22

Age

Median (range), years 59.5 (34-74)

<65 years, n (%) 15 (68.2)

65 to <75 years, n (%) 7 (31.8)

Sex, n (%)

Male 12 (54.5)

Female 10 (45.5)

Race, n (%)

White 19 (86.4)

Othera 3 (13.6)

ECOG performance status, n (%)

0 12 (54.5)

1 9 (40.9)

2 1 (4.5)

Type of measurable disease, n (%)

IgGb 18 (81.8)

IgAc 1 (4.5)

Serum FLC only 1 (4.5)

Urine only 2 (9.1)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; FLC, free

light chain.

37
Note that additional baseline characteristics (including International Staging System stage,

lactate dehydrogenase, and cytogenetic risk) are not available.

a
Other includes black/African American, American Indian/Alaska Native, and race not reported.
b
Determined via serum testing only for 17 patients; 1 patient confirmed via serum and urine

testing.
c
Determined via serum testing only.

38
Table 2. Most Common (>30%) Hematologic and Nonhematologic TEAEs

N = 22

Event, n (%) Any grade Grade 3/4

Hematologic TEAEs

Lymphopenia 14 (63.6) 13 (59.1)

Anemia 10 (45.5) 2 (9.1)

Thrombocytopenia 9 (40.9) 0

Neutropenia 8 (36.4) 4 (18.2)

Leukopenia 8 (36.4) 1 (4.5)

Nonhematologic TEAEs

Diarrhea 15 (68.2) 4 (18.2)

Upper respiratory tract infection 12 (54.5) 0

Cough 13 (59.1) 1 (4.5)

Insomnia 11 (50.0) 2 (9.1)

Fatigue 11 (50.0) 1 (4.5)

Constipation 11 (50.0) 0

Dyspnea 10 (45.5) 0

Nausea 9 (40.9) 0

Back pain 9 (40.9) 0

Rash 9 (40.9) 0

Muscle spasms 9 (40.9) 0

Vomiting 8 (36.4) 0

Increased ALT 7 (31.8) 2 (9.1)

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 Pain in extremity 7 (31.8) 0

Hyperglycemia 7 (31.8) 1 (4.5)

Abbreviations: TEAE, treatment-emergent adverse event; ALT, alanine aminotransferase.

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Table 3. Infusion-related Reactions

N = 22

Event, n (%) Total Grade 1 Grade 2 Grade 3/4

Total patients with an IRR 9 (40.9) 2 (9.1) 7 (31.8) 0

Throat irritation 2 (9.1) 1 (4.5) 1 (4.5) 0

Cough 2 (9.1) 1 (4.5) 1 (4.5) 0

Nausea 2 (9.1) 1 (4.5) 1 (4.5) 0

Headache 1 (4.5) 1 (4.5) 0 0

Productive cough 1 (4.5) 0 1 (4.5) 0

Throat tightness 1 (4.5) 1 (4.5) 0 0

Chest pain 1 (4.5) 1 (4.5) 0 0

Influenza-like illness 1 (4.5) 1 (4.5) 0 0

Hypertension 1 (4.5) 1 (4.5) 0 0

Rash pruritic 1 (4.5) 0 1 (4.5) 0

Tachycardia 2 (9.1) 0 2 (9.1) 0

Tremor 1 (4.5) 1 (4.5) 0 0

Back pain 1 (4.5) 0 1 (4.5) 0

Bronchospasm 1 (4.5) 1 (4.5) 0 0

Exertional dyspnea 1 (4.5) 0 1 (4.5) 0

Sinus tachycardia 1 (4.5) 0 1 (4.5) 0

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Table 4. Stem Cell Harvest and ASCT

Stem cell Last cycle Time from last treatment to Total CD34+ cells Cycle at Best

Patient mobilization agent before harvest harvest (days) (x 106/kg body weight) ASCT responsea

Discontinued treatment to pursue ASCT

1 NA 8 19 13.6 12 VGPR

2 Filgrastim and Plerixafor 6 15 3.6 12 VGPR

3 Filgrastim and Plerixafor 5 21 12 5 VGPR

4 Filgrastim 4 17 6.5 4 SD

5 Filgrastim and Plerixafor 9 29 30 9 sCR

6 Filgrastim and Plerixafor 4 36 28 4 sCR

7 Filgastrim 4 51 38 4 sCR

8 Filgrastim and Plerixafor 5 49 10.4 5 sCR

Completed treatment and proceeded to ASCT

9 Plerixafor 4 30 6.5 13 PR

10 Filgrastim and Plerixafor 4 21 7.2 13 CR

Abbreviations: ASCT, autologous stem cell transplant; NA, not available; VGPR, very good partial response; SD, stable disease; sCR,

stringent complete response; PR, partial response; CR, complete response.

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a
Best response prior to ASCT per validated computer algorithm.

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FIGURE LEGENDS

Figure 1. Overall best response and response rates after 4, 8, and 13 treatment cycles in the

response-evaluable population.a

ORR, overall response rate; CR, complete response; VGPR, very good partial response; sCR,

stringent complete response; PR, partial response; ASCT, autologous stem cell transplant; PD,

progressive disease.
a
The response-evaluable analysis set included 21 patients who received ≥1 dose of study drug

and had ≥1 post-baseline disease assessment and was used to calculate the ORR and duration of

response. One patient was not included in the response-evaluable analysis set because they

discontinued treatment (due to pulmonary embolism) before post-baseline disease assessment.

b
Six patients were excluded: 5 due to ASCT and 1 due to PD in Cycle 7.
c
Nine patients were excluded: 7 due to ASCT, 1 due to an adverse event (pulmonary embolism),

and 1 due to PD in Cycle 7.

Figure 2. MRD-negativity rates.a

MRD, minimal residual disease; CR, complete response.

a
MRD negativity was assessed in patients who achieved ≥CR and had a post-screening MRD

evaluation.
b
Samples were indeterminate at a 10–6 sensitivity threshold.

Figure 3. PFS in patients receiving D-KRd.

PFS, progression-free survival; D-KRd, daratumumab plus carfilzomib, lenalidomide, and

dexamethasone.

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