Articles

Daratumumab monotherapy in patients with heavily

pretreated relapsed or refractory multiple myeloma:
final results from the phase 2 GEN501 and SIRIUS trials
Saad Z Usmani, Hareth Nahi, Torben Plesner, Brendan M Weiss, Nizar J Bahlis, Andrew Belch, Peter M Voorhees, Jacob P Laubach,
Niels W C J van de Donk, Tahamtan Ahmadi, Clarissa M Uhlar, Jianping Wang, Huaibao Feng, Ming Qi, Paul G Richardson, Sagar Lonial

Summary
Background Daratumumab showed encouraging efficacy as monotherapy in patients with heavily pretreated multiple Lancet Haematol 2020;
myeloma in the GEN501 and SIRIUS studies. Here we report a pooled, post-hoc final analysis of these two studies. 7: e447–55
See Comment page e426
Methods GEN501 was an open-label, multicentre, phase 1–2, dose escalation and expansion study done in the Levine Cancer Institute/Atrium
Netherlands, the USA, Sweden, and Denmark. Eligible patients had multiple myeloma and had relapsed or were Health, Charlotte, NC, USA
(S Z Usmani MD,
refractory to 2 or more previous lines of treatment that included a proteasome inhibitor or an immunomodulatory Prof P M Voorhees MD);
drug. SIRIUS was an open-label, multicentre, phase 2 study done in Canada, Spain, and the USA, in which eligible Karolinska Institute, Karolinska
patients with multiple myeloma had received 3 or more previous lines of therapy, including a proteasome inhibitor or University Hospital at
Huddinge, Stockholm, Sweden
an immunomodulatory drug, or were double refractory. In both studies, eligible patients were aged 18 years or older
(H Nahi MD); Vejle Hospital and
and had an Eastern Cooperative Oncology Group performance status of 2 or less. In part 2 of GEN501, patients were University of Southern
given intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 8 doses, and then once per Denmark, Vejle, Denmark
month until disease progression. In part 2 of SIRIUS, patients received intravenous daratumumab 16 mg/kg once (Prof T Plesner MD); Janssen
Research & Development,
per week for 8 weeks, twice per month for 16 weeks, and once per month until disease progression. The primary
Spring House, PA, USA
endpoints (safety in GEN501 and overall response rate in SIRIUS) have previously been reported. These trials are (B M Weiss MD, C M Uhlar PhD,
registered on ClinicalTrials.gov, NCT00574288 (GEN501) and NCT01985126 (SIRIUS). J Wang PhD, H Feng PhD,
M Qi MD); Arnie Charbonneau
Cancer Research Institute,
Findings Patients were enrolled in GEN501 from March 27, 2008, until May 30, 2014, and in SIRIUS from Sept 30, 2013,
University of Calgary, Calgary,
until May 5, 2014. The combined analysis included 148 patients who received daratumumab 16 mg/kg (42 patients in AB, Canada (Prof N J Bahlis MD);
GEN501 part 2; 106 patients in SIRIUS), with a median follow-up of 36·6 months (IQR 34·5–38·2). Patients had Cross Cancer Institute,
received a median of 5 previous lines of therapy (IQR 4–7), and 128 (87%) of 148 patients were double refractory. The Edmonton, AB, Canada
(Prof A Belch MD); Dana Farber
overall response rate was 30·4% (95% CI 23·1–38·5), including 20 (14%) of 148 patients with very good partial
Cancer Institute, Harvard
response or better (8·5–20·1) and seven (5%) patients reporting complete response or better (1·9–9·5). Among Medical School, Boston, MA,
45 responders, the median duration of response was 8·0 months (95% CI 6·5–14·7). Median overall survival was USA (J P Laubach MD,
20·5 months (95% CI 16·6–28·1), with a 3-year overall survival rate of 36·5% (28·4–44·6). The most common Prof P G Richardson MD); VU
University Medical Center,
grade 3–4 treatment-emergent adverse events (TEAEs) were anaemia (grade 3, 26 [18%] of 148 patients; no grade 4 Amsterdam, Netherlands
events) and thrombocytopenia (grade 3, 13 [9%] of 148 patients; grade 4, 8 [5%] of 148 patients). Serious drug-related (N W C J van de Donk MD);
TEAEs occurred in 13 (9%) of 148 patients. There were no treatment-related deaths. Genmab A/S, Princeton, NJ,
USA (T Ahmadi MD); Winship
Cancer Institute, Emory
Interpretation In this analysis, daratumumab 16 mg/kg monotherapy showed durable responses and there were no University, Atlanta, GA, USA
new safety concerns with longer follow-up. (Prof S Lonial MD)
Correspondence to:
Funding Janssen Research & Development. Dr Saad Z Usmani, Levine Cancer
Institute, Charlotte, NC 28204,
USA
Copyright © 2020 Elsevier Ltd. All rights reserved. saad.usmani@atriumhealth.
org
Introduction heavily pretreated patients, including those refractory to
Outcomes for patients with multiple myeloma have treatment with both a proteasome inhibitor and an
improved as a result of an increase in treatment options, immunomodulatory drug.2–4 Patients with successive
including the introduction of proteasome inhibitors such relapses and those who are refractory to treatment have
as bortezomib, and immunomodulatory drugs such as poor survival.5 In a real-world analysis, overall survival
lenalidomide.1 However, most patients have disease was worse for patients with disease that was triple or
relapse, and the duration and depth of response decreases quadruple refractory to proteasome inhibitors and
with each successive line of therapy. Regimens containing immunomodulatory drugs (median overall survival
the second-generation proteasome inhibitors carfilzomib 5·1 months, 95% CI 2·6–8·7) than for those who were
and ixazomib have shown favourable response rates and double refractory to these classes of therapies (7·8 months,
prolonged survival in patients with previously treated 6·0–8·9).6 Effective therapies for patients with relapsed or
multiple myeloma, but outcomes remain poor for more refractory multiple myeloma remain a high unmet need.

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 Articles
Research in context
Evidence before this study
We searched PubMed on June 6, 2019, with no date
restriction using the keywords “progression risk”, “overall
survival”, “multiple myeloma”, “relapsed”, and “refractory”
and identified 111 articles. Evidence suggests that, although
new agents have prolonged survival for patients with
previously treated multiple myeloma, outcomes remain poor
for most patients. Almost all patients have disease
progression, and treatments are also frequently associated
with substantial adverse events. Daratumumab is a human
CD38-targeting monoclonal antibody that gained initial
US Food and Drug Administration approval as monotherapy
for patients with multiple myeloma in 2015 on the basis of
the results of early-phase studies GEN501 and SIRIUS.
Subsequent studies have shown significant improvement in
progression-free survival and response rates for patients
treated with daratumumab in combination with standard-of-
care therapy in several treatment settings.
Daratumumab is a human IgG1 kappa (IgG1κ)
monoclonal antibody that binds with high affinity and
selectivity to CD38, inducing antitumour activity through
immunomodulation and directly targeting the tumour
cells.7 Following binding of daratumumab to CD38,
tumour cell death is induced by numerous mechanisms,
including complement-dependent cyto­ toxicity, antibody-
dependent cellular cytotoxicity, antibody-dependent phago­
cytosis, induction of apoptosis, and modulation of CD38
enzymatic activity.7 The immuno­ modulatory actions of
daratumumab include modulation of the tumour
microenvironment, clonal expansion of cytotoxic T cells,
increase in helper T cells, depletion of CD38+ immuno­
suppressive cells, and increase in granzyme B-positive
CD8+ T cells.8,9 Moreover, increase in myeloma cell survival
and proliferation via mitochondrial transfer from stromal
cells in the bone marrow micro­environment are inhibited
by a CD38-blocking antibody.10
The efficacy and safety of daratumumab monotherapy at
16 mg/kg in patients with heavily pretreated relapsed or
refractory multiple myeloma was investigated in two early-
phase open-label studies.11,12 Results of the first-in-human
phase 1–2 study GEN50111 showed a proportion of patients
receiving daratumumab 16 mg/kg with an objective
response rate (hereafter referred to as overall response
See Online for appendix rate) of 36% (95% CI 22–52) and a median progression-
free survival of 5·6 months (95% CI 4·2–8·1) at a median
follow-up of 10·2 months (range 1·2–16·0). In SIRIUS, a
phase 2 study,12 overall response rate was 29% (95% CI
20·8–38·9) and median progression-free survival was
3·7 months (95% CI 2·8–4·6) at a median follow-up of
9·3 months (range 0·5–14·4). In both studies, the depth of
responses improved for many patients. Responses were
also durable, with an analysis of pooled data from these
two studies showing an overall response rate of 31%
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Added value of this study
This study presents the combined analysis for patients receiving
daratumumab 16 mg/kg in monotherapy studies GEN501 and
SIRIUS at a median follow-up of approximately 3 years.
Daratumumab monotherapy in heavily pretreated patients with
multiple myeloma continues to show impressive efficacy, with
rapid and durable responses observed. More than one third of
patients were still alive 3 years after initiation of the two trials.
The safety profile of daratumumab has remained consistent
after extended follow-up, with no new concerns identified.
Implications of all the available evidence
These findings highlight the efficacy of daratumumab
monotherapy in patients with heavily pretreated multiple
myeloma. The rapid and durable responses and the manageable
safety profile of daratumumab support its use alone or in
combination with other therapies for patients with relapsed or
refractory multiple myeloma.
(95% CI 23·7–39·2) and a median duration of response of
7·6 months (95% CI 5·6 to not evaluable), after a median
follow-up of 20·7 months (range 0·5–27·1).13 Median
overall survival for the combined data was 20·1 months
(95% CI 16·6 to not evaluable), which could be attributed
in part to the immunomodulatory mechanism of action of
daratumumab or the inhibition of growth and survival
factor transfer from bone marrow stromal cells.
Daratumumab monotherapy is associated with a manage­
able safety profile and a low proportion of treatment
discontinuations due to adverse events.13 We present the
final safety and efficacy findings for patients receiving
daratumumab 16 mg/kg in GEN501 and SIRIUS in a
combined analysis, after a median follow-up of
approximately 3 years.
Methods
Study design and participants
The study design and patient populations for GEN501
and SIRIUS have been described previously.11–13 GEN501
was an open-label, multicentre, phase 1–2, dose escalation
and expansion study done in the Netherlands, the USA,
Sweden, and Denmark. SIRIUS was an open-label,
multicentre, phase 2 study done in Canada, Spain, and
the USA. Study sites information is included in the
appendix (pp 6–7) In both studies eligible patients were
adults aged 18 years or older, with documented secretory
multiple myeloma requiring systemic therapy, and an
Eastern Cooperative Oncology Group (ECOG) perfor­
mance status of 2 or less. In GEN501, eligible patients
were relapsed or refractory to at least 2 previous lines of
treatment, including proteasome inhibitors, immuno­
modulatory drugs, chemotherapy, and autologous stem-
cell trans­
plantation (ASCT). In SIRIUS, patients had
received an alkylating agent (alone or as part of

combination therapy) and at least 3 previous lines of
treatment that included a proteasome inhibitor and an
immuno­modulatory drug, or had disease confirmed as
double refractory to the most recent proteasome inhibitor
and immunomodulatory treatment. Evidence of disease
progression (on or within 60 days of the last dose of their
most recent treatment regimen) per International
Myeloma Working Group (IMWG) criteria was required.14
Eligible patients in GEN501 (but not SIRIUS) had a life
expectancy longer than 3 months. Additional eligibility
criteria are in the appendix (p 2).
All study participants provided written informed
consent before study entry. The studies were approved by
institutional review boards or ethics committees at all
participating institutions and were done in accordance
with the Declaration of Helsinki, the International
Conference on Harmonisation, and the guidelines for
Good Clinical Practice.
Procedures
GEN501 included a dose escalation phase (part 1) and a
dose expansion phase (part 2). In part 1, patients received
intravenous daratumumab at doses of 0·005 to 24 mg/kg.
After evaluation of safety and response at these doses,
patients in part 2 received daratumumab at 8 mg/kg or
16 mg/kg. Daratumumab 16 mg/kg was administered
once per week for the first seven doses after the initial
dose, which had a 3-week washout period to collect
pharmacokinetic data, twice per month for the subsequent
eight doses, and once per month thereafter until disease
progression. In SIRIUS, patients were randomly assigned
1:1 to receive intravenous daratumumab 8 mg/kg or
16 mg/kg in part 1 and, after interim analysis that assessed
the responses of patients in each treatment group,
additional patients were enrolled into the 16 mg/kg
cohort. Patients in part 2 of the SIRIUS study received
daratumumab 16 mg/kg once per week for 8 weeks, twice
per month for 16 weeks, and then once per month
thereafter. No daratumumab dose modifications were
permitted. To prevent or mitigate infusion-related
reactions, patients in both the GEN501 and SIRIUS
studies were given preinfusion and post-infusion
medications. Study treatment was discontinued for
unacceptable toxic effects, patient withdrawal, predefined
protocol deviation, disease progression, or if
daratumumab became commercially available (for
SIRIUS). Patients in GEN501 also discontinued treat­
ment if they started a new antimyeloma therapy or had
low platelet count. Reasons for study withdrawal were
loss to follow-up, patient withdrawal, study termination
by sponsor, or if daratumumab became commercially
available (for SIRIUS).
Outcomes
The primary endpoint of GEN501 was safety. In SIRIUS,
the primary endpoint was overall response rate. Other
endpoints of both studies included overall survival,
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Articles
progression-free survival, time to disease progression, and
duration of response. We report a combined analysis of
the GEN501 and SIRIUS studies including updated data
for response, overall survival, subsequent therapy, and
safety. There is no update on overall progression-free
survival, as these data were mature at the previously
published analysis.13 Complete definitions of primary and
secondary endpoints can be found in the appendix (pp 3–4);
although this is a post-hoc analysis, all endpoints were
defined as in the original study protocols.
Statistical analysis
Data from GEN501 and SIRIUS for patients who received
daratumumab monotherapy 16 mg/kg were pooled. All
patients who had received at least one dose of daratumumab
were included in the efficacy and safety analyses. No
formal statistical hypotheses were formulated or tested,
and no statistical power calculations were done. In both
studies, if patients developed progressive disease and
subsequently discontinued daratumumab treatment, their
subsequent therapies and best clinical responses to those
therapies were captured, when possible.
Responses were defined as per the IMWG criteria,14
evaluated with the use of a computerised algorithm,
and presented with two-sided exact 95% CIs. Previously
reported response results from SIRIUS were based on
assessment by the Independent Review Committee,
showing excellent agreement with the results of the
computerised algorithm (kappa coefficient 0·98).12
Time-to-event endpoints were analysed using the
Kaplan-Meier method. Adverse events were reported by
the patients at each study visit from informed content
to 30 days after the last dose of study drug for SIRIUS,
and from the first infusion to the end-of-treatment visit
for GEN501, and were defined as per National Cancer
Institute Common Terminology Criteria for Adverse
Events version 4.03.15
These trials are registered on ClinicalTrials.gov,
NCT00574288 (GEN501) and NCT01985126 (SIRIUS).
Role of the funding source
Janssen Research & Development. The study design and
analyses were devised by the investigators and sponsor.
Study data were collected by the investigators and their
research teams. Final data analysis and verification of
accuracy was done by the sponsor. The investigators were
not restricted by confidentiality agreements and had full
access to all the data. Medical writing and editorial
assistance were funded by Janssen Global Services.
Results
Patients were enrolled in GEN501 between March 27, 2008,
and May 30, 2014; the 72 patients included in part 2 were
followed up until the final clinical cutoff date of
March 31, 2017. 124 patients were enrolled in SIRIUS
between Sept 30, 2013, and May 5, 2014, who were
followed up until the final clinical cutoff date of
 Articles

Pooled analysis Response, n (%) 95% CI*

(n=148)
sCR 2 (1%) 0·2–4·8
Sex CR 5 (3%) 1·1–7·7
Male 69 (47%) VGPR 13 (9%) 4·8–14·6
Female 79 (53%) PR 25 (17%) 11·2–23·9
Age Minimal response 9 (6%) 2·8–11·2
Median age, years 64 (58–70) Stable disease 70 (47%) 39·0–55·7
65 to <75 years 52 (35%) Progressive disease 18 (12%) 7·4–18·5
≥75 years 16 (11%) Not evaluable 6 (4%) 1·5–8·6
ECOG performance status OR (sCR + CR + VGPR + PR) 45 (30%) 23·1–38·5
0 41 (28%) VGPR or better (sCR + CR + VGPR) 20 (14%) 8·5–20·1
1 97 (66%) CR or better (sCR + CR) 7 (5%) 1·9–9·5
2 10 (7%)
All patients received daratumumab 16 mg/kg. CR=complete response. OR=overall
Years since diagnosis 5·1 (3·9–7·8) response. PR=partial response. sCR=stringent complete response. VGPR=very
≥1 extramedullary plasmacytomas 18 (12%) good partial response. *Calculated by use of an exact CI.
Creatinine clearance
Table 2: Best responses in 148 patients combined from GEN501 part 2
≥60 mL/min 89 (60%) and SIRIUS
≥30 to <60 mL/min 54 (37%)
<30 mL/min 5 (3%)
Bone marrow plasma cells (%) follow-up of 36·6 months (IQR 34·5–38·24). All patients
≤30 85 (57%) who received 16 mg/kg daratumumab from the primary
>30 to ≤60 26 (18%) analyses11,12 are included in this pooled analysis with
>60 35 (24%) longer follow-up.
Number of previous lines of therapy 5 (4–7) Patient demographics and baseline characteristics for
>3 previous lines of therapy 113 (76%) 148 patients receiving daratumumab 16 mg/kg in the
Previous ASCT 116 (78%) combined analysis are presented in table 1. Patients were
Previous proteasome inhibitor* heavily pretreated, with a median of 5 (IQR 4–7) previous
Any 148 (100%) lines of therapy, and 113 (76%) of 148 patients having
Bortezomib 147 (99%) received more than 3 previous lines of therapy. 128 (87%)
Carfilzomib 61 (41%) of 148 patients were refractory to both a proteasome
Previous immunomodulatory drug* inhibitor and an immunomodulatory drug; 124 (84%)
Any 146 (99%) patients were refractory to lenalidomide, 82 (55%) patients
Lenalidomide 145 (98%) were refractory to pomalidomide, and 58 (39%) patients
Pomalidomide 82 (55%) were refractory to carfilzomib (table 1).
Thalidomide 66 (45%)
In GEN501, median duration of treatment was
Refractory to treatment
5·4 months (IQR 1·6–13·6), and patients received a
Last line of therapy 135 (91%)
median of 14·5 infusions (6–23). In SIRIUS, median
duration of treatment was 2·8 months (1·7–6·7), and
Both a proteasome inhibitor and 128 (87%)
an immunomodulatory drug patients received a median of 11·0 infusions (8–18). At
Proteasome inhibitor and immunomodulatory 100 (68%) clinical cutoff for both studies, most patients had
drug and alkylating agent discontinued treatment with daratumumab because of
Bortezomib 125 (85%) progressive disease (32 [76%] of 42 patients in GEN501
Carfilzomib 58 (39%) part 2; 96 [91%] of 106 patients in SIRIUS). Discon­
Lenalidomide 124 (84%) tinuations as a result of adverse events were infrequent,
Pomalidomide 82 (55%) with only one (2%) of 42 patients in GEN501 and five (5%)
Thalidomide 41 (28%) of 106 patients in SIRIUS discontinuing treatment
Alkylating agent only 107 (72%) because of adverse events, none of which were considered
Data are n (%) or median (IQR). ASCT=autologous stem-cell transplantation.
related to daratumumab. Among the 148 patients from
ECOG=Eastern Cooperative Oncology Group. *Patients could have received more GEN501 and SIRIUS, 14 (9%) died within 30 days of the
than one of these therapies. last daratumumab dose: 11 (7%) because of progressive
Table 1: Patient characteristics at baseline
disease and three (2%) because of adverse events (not
considered related to daratumumab).
In the combined analysis, the overall response rate
May 30, 2017. The combined analysis included 148 patients was 30·4% (95% CI 23·1–38·5), with 20 (14%) of
who received daratumumab 16 mg/kg (42 patients in 148 patients reporting a very good partial response
GEN501 part 2; 106 patients in SIRIUS), with a median (8·5–20·1) or better and seven (5%) patients reporting

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complete response or better (1·9–9·5; table 2). Responses

PR
improved with continued daratumumab treatment for PR CR
VGPR CR
14 (31%) of 45 patients with a response across both PR sCR
PR
studies (figure 1). Of the 45 patients with a response, VGPR CR
PR VGPR
34 (76%) had an initial partial response. Seven (21%) of VGPR
VGPR
CR

34 patients went on to have very good partial response, PR

VGPR sCR
VGPR CR
one (3%) to complete response, and one (3%) to stringent PR
PR
complete response. Five (46%) of 11 patients with an PR VGPR
PR VGPR
initial response of VGPR had responses deepen, four PR
PR
(36%) to complete response and one (9%) to stringent PR
VGPR
VGPR
complete response. The median duration of response PR
PR

Patient
was 8·0 months (95% CI 6·5–14·7) for the combined PR
PR VGPR
VGPR
population of 45 responders. PR
PR
In patients with a partial response or better, the PR
VGPR
proportion of patients with progression-free survival at PR
VGPR
36 months was 19·6% (95% CI 9·0–33·2), 19·6% at PR
PR
24 months (9·0–33·2), and 40·6% at 12 months PR VGPR
PR
(26·1–54·6). For all patients, median overall survival was PR
PR
PR
20·5 months (95% CI 16·6–28·1) with a 3-year overall PR
PR
survival of 36·5% (28·4–44·6; figure 2A) at clinical cutoff. PR
PR VGPR
An analysis of median overall survival by response status VGPR SIRIUS
PR
is presented in figure 2B. The median overall survival for PR GEN501 part 2

responders (partial response or better) was not reached 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

(95% CI 29·2–not estimable), and 36-month overall
survival was 60·2% (43·9–73·2). Patients with a minimal
response or stable disease had a median overall survival
of 18·5 months (95% CI 15·1–22·4) and 36-month overall
survival of 29·5% (19·1–40·6). Patients with progressive
disease or without an evaluable response had median
overall survival of 3·5 months (95% CI 1·5–6·6) and
36-month overall survival of 12·5 % (3·1–28·7).
119 (80%) of 148 patients received subsequent therapy
for multiple myeloma. The most common (given to
>20% of patients) subsequent therapies included
dexamethasone (96 [65%] patients), pomalidomide
(62 [42%]), cyclophosphamide (54 [36%]), carfilzomib
(48 [32%]), bortezomib (44 [30%]), and lenalidomide
(31 [21%]). 28 (19%) of 148 patients received daratumumab
as subsequent therapy. Of the 119 patients receiving
subsequent therapy, 44 (37%) had a partial response or
better on their first subsequent line of therapy, including
14 (12%) patients with a very good partial response,
three (3%) patients with a complete response, and
three (3%) patients with a stringent complete response.
147 (99%) of 148 patients had at least one treatment-
emergent adverse event (TEAE; table 3). The most
frequently reported any-grade TEAEs were fatigue
(62 [42%] of 148 patients), nausea (44 [30%]), anaemia
(42 [28%]), back pain (40 [27%]), and cough (38 [26%]).
Infections of any grade occurred in 87 (59%) of
148 patients, with a grade 3 event in 13 (9%) of 148 patients
and a grade 4 event in two (1%) patients. TEAEs were
generally mild (grade 1–2); anaemia (26 [18%] patients)
was the only grade 3 TEAE reported in more than 10% of
patients, and the only grade 4 TEAE occurring in 5% or
more of patients was thrombocytopenia (8 [5%] patients).
Serious drug-related adverse events occurred in 13 (9%)
Time from first dosing date (months)
Figure 1: Swim-lane plot of responders in 148 patients who received daratumumab at 16 mg/kg from
GEN501 part 2 and SIRIUS
CR=complete response. PR=partial response. sCR=stringent complete response. VGPR=very good partial response.
of 148 patients. Three patients died during the studies
because of TEAEs, which were not considered to be drug-
related (one each of viral H1N1 infection, pneumonia,
and aspiration pneumonia). Infusion-related reactions
occurred in 71 (48%) of 148 patients. 68 (96%) of
71 patients with an infusion-related reaction had an event
occur during the first infusion, five (7%) patients had an
event during the second infusion, and five (7%) patients
had an event during subsequent infusions. The most
common infusion-related reactions included nasal
congestion (17 [11%] of 148 patients), cough (12 [8%]),
allergic rhinitis (10 [7%]), chills (10 [7%]), throat irritation
(9 [6%]), dyspnoea (8 [5%]), and nausea (8 [5%]).
Immunoparesis (defined as uninvolved immunoglobulin
<lower limit of normal) at baseline occurred among
37 (88%) of 42 patients in GEN501 and 103 (97%) of
106 patients in SIRIUS. Within 30 days of last study
treatment, immunoparesis was seen in 41 (98%) of
42 patients in GEN501 part 2, including among all
15 responders. For SIRIUS, postbaseline immunoglobulins
were not available.
Patient samples to evaluate the potential immuno­
genicity of daratumumab were collected predose, during
study treatment, and after completion of therapy.11,12 In
both studies, none of the patients with samples appropriate
for analysis (39 patients in GEN501 part 2 and 95 patients
in SIRIUS) were positive for antidaratumumab antibodies,
suggesting a low risk for immunogenicity.

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A
100

80
Overall survival (%)

60

Median overall survival 20·5 months

(95% CI 16·6–28·1)
40

20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Number at risk 148 136 125 119 108 103 96 90 82 77 70 64 60 58 55 52 50 43 30 14 9 2 0
(number censored) (0) (0) (4) (5) (6) (6) (7) (7) (8) (9) (9) (11) (12) (12) (12) (12) (13) (19) (30) (44) (49) (56) (58)

B
100 Patients with PR or better
Patients with minimal response
or stable disease
Patients with progressive disease
80

Median overall survival NR

(95% CI 29·2–not estimable)
Overall survival (%)

60

40 Median overall survival 18·5 months

(95% CI 15·1–22·4)

20 Median overall survival 3·5 months

(95% CI 1·5–6·6)

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time from start of treatment (months)
Number at risk
(number censored)
Patients with PR 45 45 44 42 42 40 39 34 33 30 28 26 18 7 2 0
or better (0) (0) (1) (1) (1) (1) (1) (2) (2) (2) (2) (3) (10) (20) (25) (27)
Patients with minimal 79 73 65 58 50 45 35 28 24 23 21 18 10 4 0 0
response or stable disease (0) (1) (4) (5) (6) (6) (8) (8) (10) (10) (10) (12) (19) (24) (28) (28)
Patients with 24 14 10 5 4 3 3 3 3 3 3 3 2 0 0 0
progressive disease (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (1) (3) (3) (3)

Figure 2: Overall survival in 148 patients who received daratumumab at 16 mg/kg from GEN501 part 2 and SIRIUS
(A) All patients. (B) Patients stratified by response. Patients with progressive disease include those whose response was not evaluable. NR=not reached. PR=partial
response.

Discussion clinical trials, daratumumab-based regimens were

This pooled, final analysis among patients with refractory associated with significant reductions in the risk of
multiple myeloma shows that daratumumab 16 mg/kg progression or death by 44–63% and increased minimal
monotherapy provides durable responses; no new safety residual disease negativity, such as in the CASTOR and
concerns were identified with longer follow-up. POLLUX studies (patients with ≥1 previous lines of
Daratumumab was initially approved as a monotherapy treatment),17,18 and the ALCYONE and MAIA studies
in heavily treated patients on the basis of the GEN501 and (ASCT-ineligible, newly diagnosed patients).19,20 Therefore,
SIRIUS phase 2 studies.16 Across a series of phase 3 in many regions, patients treated with daratumumab are

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 Articles

likely to receive the drug as a component of a combination

Any grade Grade 1–2 Grade 3 Grade 4
regimen with standard-of-care therapies.7,21 However,
understanding the effects of long-term treatment with Fatigue 62 (42%) 59 (40%) 3 (2%) 0
daratumumab monotherapy is of value, as daratumumab- Nausea 44 (30%) 44 (30%) 0 0
based combinations are not available to many patients Anaemia 42 (28%) 16 (11%) 26 (18%) 0
and single-agent therapy is often the only option for Back pain 40 (27%) 36 (24%) 4 (3%) 0
disease refractory to multiple drug classes. Cough 38 (26%) 38 (26%) 0 0
Survival outcomes in similarly heavily pretreated patients Upper respiratory tract infection 33 (22%) 32 (22%) 1 (1%) 0
have typically been poor.5 Here, we report a median overall Thrombocytopenia 31 (21%) 10 (7%) 13 (9%) 8 (5%)
survival of 20·5 months (95% CI 16·6–28·1) for dara­ Neutropenia 31 (21%) 16 (11%) 11 (7%) 4 (3%)
tumumab monotherapy after median follow-up of Pyrexia 29 (20%) 28 (19%) 1 (1%) 0
36·6 months (IQR 34·5–38·24). The median overall Nasal congestion 29 (20%) 29 (20%) 0 0
survival and differences in overall survival observed when Arthralgia 28 (19%) 28 (19%) 0 0
stratified by response status are consistent with an earlier Diarrhoea 28 (19%) 27 (18%) 1 (1%) 0
pooled analysis of these studies.13 The progression-free Pain in extremity 26 (18%) 25 (17%) 1 (1%) 0
survival data were mature at the earlier pooled analysis, Dyspnoea 25 (17%) 24 (16%) 1 (1%) 0
with median progression-free survival of 4·0 months Nasopharyngitis 24 (16%) 24 (16%) 0 0
(95% CI 2·8–5·6), and median progression-free survival Constipation 23 (16%) 23 (16%) 0 0
data remain unchanged in this updated analysis.13 Decreased appetite 23 (16%) 22 (15%) 1 (1%) 0
In studies of other single-agent therapies (eg, without Vomiting 21 (14%) 21 (14%) 0 0
the addition of dexamethasone), similar or lower Musculoskeletal chest pain 19 (13%) 17 (11%) 2 (1%) 0
proportions of patients with overall response have been Hypercalcaemia 18 (12%) 13 (9%) 3 (2%) 2 (1%)
reported, with varying effects on overall survival. Headache 18 (12%) 16 (11%) 2 (1%) 0
Isatuximab, a CD38 monoclonal antibody in clinical Musculoskeletal pain 16 (11%) 15 (10%) 1 (1%) 0
development, showed an overall response of 21% in a Bone pain 15 (10%) 14 (9%) 1 (1%) 0
phase 1 study at a dose of 20 mg/kg (every 1 or 2 weeks).22 Chills 15 (10%) 15 (10%) 0 0
In a larger phase 2 study23 of 20 mg/kg isatuximab every Hypertension 15 (10%) 8 (5%) 7 (5%) 0
2 weeks in patients with a median of 4 previous lines of
Data are n (%). All patients received daratumumab 16 mg/kg.
therapy, the proportion of patients with overall response
was 26%, median progression-free survival was 4·9 months Table 3: Treatment-emergent adverse events reported in 10% or more of 148 patients combined from
(95% CI 3·8–7·7), and 16-month overall survival was 57% GEN501 part 2 and SIRIUS
(median not reached, 95% CI 14·7–not estimable).23
Treatment with a different CD38 monoclonal antibody,
MOR202, as monotherapy in a phase 1–2a study24 resulted response at 56 days, and further deepened to stringent
in an overall response of 31% in patients with heavily complete response at 194 days. Approximately 2 years
pretreated relapsed or refractory multiple myeloma. after enrolment, the patient showed no minimal residual
Monotherapy studies have also been done with next- disease, and after more than 3 years had not had disease
generation proteasome inhibitors. In a population of relapse.27 Three patients enrolled in GEN501 who had a
266 patients,25 in whom 82% had received 4 or more best response of stringent complete response remained
lines of previous therapy, patients given single-agent on daratumumab monotherapy for more than 4·5 years
carfilzomib had an overall response of 24% (95% CI (durations of 54 months, 56 months, and 59 months); all
18·7–29·4), with median overall survival of 15·6 months remain minimal residual disease negative at a 10–⁶
(13·0–19·2).25 A phase 1 study26 of ixazomib monotherapy sensitivity threshold.28 High proportions of minimal
in patients with a median of 4 lines of previous residual disease negativity have been shown in multiple
treatment resulted in an overall response of just 15% studies of daratumumab-based combinations.17–20 Analysis
(95% CI 6–27). Although many new therapies are under of minimal residual disease negativity in this pooled
investigation, the efficacy and favourable tolerability population would be of interest, but minimal residual
profile make single-agent daratumumab a useful disease data were not routinely evaluated in GEN501 and
treatment option for patients with heavily pretreated SIRIUS.
disease, particularly in patients who cannot tolerate Deep responses driven by daratumumab could be
combination therapy or where com­bination therapy is associated with changes in immune cell phenotype and
not available. function. Rapid and sustained decreases in immuno­
In this analysis, responses continued to improve in suppressive CD38+ regulatory B and T cells were observed
some patients. A case report27 of a patient enrolled in in GEN501 and SIRIUS.9 Of note, a shift in T-cell
SIRIUS who was triple refractory (including bortezomib, phenotype in blood samples obtained after eight infusions
lenalidomide, and pomalidomide) described a partial of daratumumab occurred, with an increased proportion
response at 28 days, which improved to very good partial of CD8+ cells associated with an increase in granzyme B

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positivity; this was most pronounced in patients who
responded to treatment.9 Inhibition of CD38 has been
shown to prevent the transfer of mitochondria through
nanotubes from bone marrow stromal cells to myeloma
cells, thereby interfering with myeloma cell survival and
proliferation.10
Although daratumumab is increasingly administered
as part of combination therapy, this analysis showed that
long-term use as a monotherapy is well tolerated. In
addition to its use as a monotherapy in heavily pretreated
patients, daratumumab is used as a single-agent
maintenance treatment after a period of combination
therapy, on the basis of the CASTOR and ALCYONE
studies.17,19
No new safety concerns were identified relative to the
initial reports for the two individual studies (at approxi­
mately 10 months of follow-up),11,12 or the previously
published pooled analysis (at approximately 20 months of
follow-up).13 The rate of infusion-related reactions was
similar to previous publications, and these reactions were
well managed with preinfusion and postinfusion
medications.11–13,29 Cytopenias were among the most
common TEAEs, as were infections of any grade,
consistent with other daratumumab studies.11–13,19,20,30–32
Immunoparesis was observed in nearly all patients, both at
baseline and post-treatment, consistent with the nature of
advanced disease in this patient population. Daratumumab
can deplete natural killer (NK) cells, but there is no
relationship between the safety profile and NK cell count
reduction.33 The safety results reported here are also
consistent with those observed in an early access
programme in the USA for daratumumab in heavily
pretreated patients with relapsed or refractory multiple
myeloma.34 Results from this early access programme also
showed consistent health-related quality of life based on
patient-reported outcomes after initiation of daratumumab
treatment, further supporting the good tolerability of
daratumumab monotherapy. That there does not seem to
be cumulative or progressive toxicity with long-term
daratumumab monotherapy is encouraging.
A limitation of this analysis is that clinical trials might
not reflect real-world populations and outcomes can differ.
Daratumumab monotherapy was less efficacious in a
study of 41 patients from a single centre in a real-world
study than in clinical trial data.35 Patients were treated per
the approved indication, namely 3 previous treatment
lines including a proteasome inhibitor and an immuno­
modulatory drug, or were double refractory. An overall
response of 24% was associated with median progression-
free survival of 1·9 months (95% CI 1·4–2·5) and median
overall survival of 6·5 months (3·1–10·0). However, 44% of
these patients did not receive subsequent therapy after
daratumumab. In GEN501 and SIRIUS, 119 (80%) of
148 patients received subsequent therapy, of whom
44 (37%) had a response (partial response or better). The
authors also noted that compared with GEN501 and
SIRIUS, the patients were older, 20% had worse functional
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status (ECOG 3 and 4), and 10% had severe renal
impairment. An additional limitation of GEN501 and
SIRIUS is that the sample size did not allow for
comparisons of patient subgroups, such as by cytogenetic
risk status or those with a sustained response (>2 years). In
a previous report of patients in SIRIUS, subgroup analysis
of overall response by baseline characteristics showed that
responses were observed across all subgroups regardless
of the number or type of previous lines of therapy,
refractory status, renal function, or baseline percentage of
plasma cells in the bone marrow (appendix p 5).12
After a median 3 years of follow-up, daratumumab
monotherapy continued to show a favourable safety profile
with no new safety concerns. Meaningful responses were
observed in patients with a median of 5 previous lines of
therapy, suggesting that daratumumab could address an
unmet need in patients for whom other available treatment
options have been exhausted. The encouraging efficacy
results observed with daratumumab monotherapy in
heavily pretreated patients, in addition to its manageable
safety profile, support its use for patients with relapsed or
refractory multiple myeloma. Ongoing studies are
addressing the efficacy and safety of daratumumab in
combination regimens across lines of therapy, and
potential re-treatment, as daratumumab becomes more
frequently used in newly diagnosed patients.
Contributors
All authors drafted and reviewed the manuscript, approved the final
version, and decided to publish this report, and vouch for data accuracy
and completeness. SL, HN, TP, NJB, TA, and PGR participated in the
conception and design of the work being described in the publication,
acquisition or collection of data, and analysis or interpretation of data.
SZU, BMW, AB, PMV, NWCJvdD, CMU, and JW participated in the
acquisition or collection of data and analysis or interpretation of data.
JPL participated in the conception and design of the work being
described in the publication. HF and MQ participated in analysis or
interpretation of data.
Declaration of interests
SZU served in a consulting or advisory role for Onyx, Sanofi, Takeda,
Celgene, Skyline, Millennium, Amgen, and Janssen; served on a speakers’
bureau for Takeda, Celgene, and Amgen; and received research funding
from Onyx, Sanofi, Array BioPharma, Pharmacyclics, Takeda, Celgene,
and Bristol-Myers Squibb. TP received honoraria from Janssen; served in
a consulting or advisory role for Janssen, Celgene, Takeda, and AbbVie;
received research funding from Janssen, Genmab, Amgen, Takeda,
Roche, and Celgene; and had travel, accommodations, or other expenses
paid or reimbursed by Janssen. BMW received research funding and
honoraria from and is an employee of Janssen. NJB received honoraria
from Celgene, Janssen, AbbVie, and Amgen; served in a consulting or
advisory role for Celgene, Janssen, and AbbVie; received research funding
from Celgene; and had travel, accommodations, or other expenses paid or
reimbursed by Celgene and Janssen. PMV served in a consulting or
advisory role for Adaptive Biotechnologies, Bristol-Myers Squibb, Celgene,
Janssen, Novartis, and Oncopeptides; and received research funding from
Amgen, Celgene, GlaxoSmithKline, and Janssen. JPL received research
funding from Bristol-Myers Squibb, Takeda, and Celgene. NWCJvdD
served in a consulting or advisory role for Celgene, Janssen, Bristol-Myers
Squibb, Bayer, Servier, and Novartis; and received research funding from
Celgene, Janssen, and Bristol-Myers Squibb. TA is an employee of and
owns stocks or has other ownership in Genmab. CMU, JW, HF, and MQ
are employees of Janssen. PGR received honoraria from and served in a
consulting or advisory role for Karyopharm, Oncopeptides, Celgene,
Takeda, Amgen, and Janssen; and received research funding from
Oncopeptides, Celgene, Takeda, and Bristol-Myers Squibb. SL received

consulting fees or honoraria from Celgene, Novartis, Bristol-Myers
Squibb, Amgen, Janssen, GlaxoSmithKline, Merck, Karyopharm, and
Takeda; and received grants from or has pending grants with Celgene,
Janssen, and Takeda. HN and AB declare no competing interests.
Data sharing
The data sharing policy of Janssen Pharmaceutical Companies of Johnson
& Johnson is available online. Requests for access to the study data can be
submitted through the Yale Open Data Access (YODA) Project site.
Acknowledgments
This study was sponsored by Janssen Research & Development.
The authors thank the patients who participated in the GEN501 and
SIRIUS (MMY2002) studies and their families; and 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, of MedErgy, and were funded by Janssen Global Services.
References
1 Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE.
Recent trends in multiple myeloma incidence and survival by age,
race, and ethnicity in the United States. Blood Adv 2017; 1: 282–87.
2 Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in
overall survival with carfilzomib, lenalidomide, and dexamethasone
in patients with relapsed or refractory multiple myeloma.
J Clin Oncol 2018; 36: 728–34.
3 Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib
or bortezomib in relapsed or refractory multiple myeloma
(ENDEAVOR): an interim overall survival analysis of an open-label,
randomised, phase 3 trial. Lancet Oncol 2017; 18: 1327–37.
4 Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide,
and dexamethasone for multiple myeloma. N Engl J Med 2016;
374: 1621–34.
5 Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival
in multiple myeloma relapsing after therapy with IMiDs and
bortezomib: a multicenter international myeloma working group
study. Leukemia 2012; 26: 149–57.
6 Usmani S, Ahmadi T, Ng Y, et al. Analysis of real-world data on
overall survival in multiple myeloma patients with ≥3 prior lines
of therapy including a proteasome inhibitor (PI) and an
immunomodulatory drug (IMiD), or double refractory to a PI
and an IMiD. Oncologist 2016; 21: 1355–61.
7 Syed YY. Daratumumab: a review in combination therapy for
transplant-ineligible newly diagnosed multiple myeloma. Drugs
2019; 79: 447–54.
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: 384–94.
9 Adams HC 3rd, Stevenaert F, Krejcik J, et al. High-parameter mass
cytometry evaluation of relapsed/refractory multiple myeloma
patients treated with daratumumab demonstrates immune
modulation as a novel mechanism of action. Cytometry A 2019;
95: 279–89.
10 Marlein CR, Piddock RE, Mistry JJ, et al. CD38-driven
mitochondrial trafficking promotes bioenergetic plasticity in
multiple myeloma. Cancer Res 2019; 79: 2285–97.
11 Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with
daratumumab monotherapy in multiple myeloma. N Engl J Med
2015; 373: 1207–19.
12 Lonial S, Weiss BM, Usmani S, et al. Daratumumab monotherapy
in patients with treatment-refractory multiple myeloma (SIRIUS):
an open-label, randomised, phase 2 trial. Lancet 2016; 387: 1551–60.
13 Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of
daratumumab monotherapy in patients with heavily pretreated
relapsed or refractory multiple myeloma. Blood 2016; 128: 37–44.
14 Rajkumar SV, Harousseau JL, Durie B, et al. Consensus
recommendations for the uniform reporting of clinical trials: report
of the International Myeloma Workshop Consensus Panel 1.
Blood 2011; 117: 4691–95.
15 US Department of Health and Human Services, National Institutes
of Health, National Cancer Institute. Common Terminology Criteria
for Adverse Events (CTCAE). Version 4.036/14/2010, 2010.
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_
QuickReference_5x7.pdf (accessed May 11, 2014).
www.thelancet.com/haematology Vol 7 June 2020 e455
Downloaded for Anonymous User (n/a) at Cadila Pharmaceuticals Ltd from ClinicalKey.com by Elsevier on August 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
Articles
16 McKeage K. Daratumumab: first global approval. Drugs 2016;
76: 275–81.
17 Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus
bortezomib and dexamethasone versus bortezomib and
dexamethasone in relapsed or refractory multiple myeloma:
updated analysis of CASTOR. Haematologica 2018; 103: 2079–87.
18 Dimopoulos M, San Miguel J, Belch A, et al. Daratumumab plus For more on the data sharing
lenalidomide and dexamethasone versus lenalidomide and policy of Janssen
dexamethasone in relapsed or refractory multiple myeloma: Pharmaceutical Companies of
updated analysis of POLLUX. Haematologica 2018; 103: 2088–96. Johnson & Johnson see
19 Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus https://www.janssen.com/
bortezomib, melphalan, and prednisone for untreated myeloma. clinical-trials/transparency
N Engl J Med 2018; 378: 518–28.
For requests for access to the
20 Facon T, Kumar S, Plesner T, et al. Daratumumab plus study data see
lenalidomide and dexamethasone for untreated myeloma.
http://yoda.yale.edu
N Engl J Med 2019; 380: 2104–15.
21 Blair HA. Daratumumab: a review in relapsed and/or refractory
multiple myeloma. Drugs 2017; 77: 2013–24.
22 Martin T, Strickland S, Glenn M, et al. Phase I trial of isatuximab
monotherapy in the treatment of refractory multiple myeloma.
Blood Cancer J 2019; 9: 41.
23 Dimopoulos M, Bringhen S, Anttila P, et al. Results from a phase II
study of isatuximab as a single agent and in combination with
dexamethasone in patients with relapsed/refractory multiple
myeloma. Blood 2018; 132 (suppl 1): 155 (abstr).
24 Raab MS, Chatterjee M, Goldschmidt H, et al. A phase I/IIa study
of the CD38 antibody MOR202 alone and in combination with
pomalidomide or lenalidomide in patients with relapsed or
refractory multiple myeloma. Blood 2016; 128 (suppl): 1152 (abstr).
25 Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent
carfilzomib (PX-171-003-A1) in patients with relapsed and refractory
multiple myeloma. Blood 2012; 120: 2817–25.
26 Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly
ixazomib, an oral proteasome inhibitor, in relapsed/refractory
multiple myeloma patients. Blood 2014; 124: 1038–46.
27 Usmani SZ, Khan I, Chiu C, et al. Deep sustained response to
daratumumab monotherapy associated with T-cell expansion in
triple refractory myeloma. Exp Hematol Oncol 2018; 7: 3.
28 Szabo AG, Minnema MC, Nahi H, Plesner T. Long-lasting
remissions for myeloma patients on daratumumab therapy from
the GEN501 and GEN503 trials. Blood 2018;
132 (suppl 1): 3308 (abstr).
29 Voorhees PM, Weiss B, Usmani S, et al. Management of infusion-
related reactions following daratumumab monotherapy in patients
with at least 3 lines of prior therapy or double refractory multiple
myeloma (MM): 54767414MMY2002 (Sirius). Blood 2015;
126 (suppl): 1829 (abstr).
30 Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab,
lenalidomide, and dexamethasone for multiple myeloma.
N Engl J Med 2016; 375: 1319–31.
31 Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab,
bortezomib, and dexamethasone for multiple myeloma.
N Engl J Med 2016; 375: 754–66.
32 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: 29–38.
33 Casneuf T, Xu XS, Adams HC 3rd, et al. Effects of daratumumab on
natural killer cells and impact on clinical outcomes in relapsed
refractory multiple myeloma. Blood Advances 2017; 1: 2105–14.
34 Chari A, Lonial S, Mark TM, et al. Results of an early access
treatment protocol of daratumumab in United States patients with
relapsed or refractory multiple myeloma. Cancer 2018; 124: 4342–49.
35 Jullien M, Trudel S, Tessoulin B, et al. Single-agent daratumumab
in very advanced relapsed and refractory multiple myeloma
patients: a real-life single-center retrospective study. Ann Hematol
2019; 98: 1435–40.