Role of Daratumumab in Combination With Standard Therapies in Patients With Relapsed and Refractory Multiple Myeloma

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by renal insufficiency, bone lesions, anemia, and hypercalcemia. In this modern era of medicine, even with the development of drugs like immunomodulatory agents (IMiDs) and proteasome inhibitors (PI), the treatment of MM prevails as a challenge. However, even after the attainment of total remission, relapse of MM and disease progression is frequent. That is why there is an urgent requirement to develop novel monoclonal antibody drugs. The latest drugs for the treatment of relapsed and refractory MM (RRMM) approved by the Food and Drug Administration (FDA) are elotuzumab and daratumumab. In this article, we will discuss daratumumab with different combination therapies. The literature exploration was done using PubMed, Medline, PubMed Central, and Research Gate. Keywords used to search are monoclonal antibodies, daratumumab, RRMM, and novel agents. Our review article, which includes 21 relevant articles, demonstrated that daratumumab in different combinations showed significant progression-free survival (PFS) without severe safety concerns. However, while observing all the studies, neither of them studied the combination therapies of daratumumab in end-stage renal disease (ESRD) patients. Hence, more randomized controlled clinical trials should be done to understand and compare the effect of the combination of daratumumab with the standard of care therapies in ESRD patients.

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Received 05/06/2021
Review began 05/16/2021
Review ended 05/30/2021
Published 06/04/2021
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Role of Daratumumab in Combination With
Standard Therapies in Patients With Relapsed
and Refractory Multiple Myeloma
Anusha Bapatla , Arunima Kaul , Paramvijay Singh Dhalla , Ana S. Armenta-Quiroga , Raheela Khalid
, Jian Garcia , Safeera Khan
1. Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA 2. Internal
Medicine, Detroit Medical Center/Wayne State University/Sinai Grace Hospital, Detroit, USA 3. Medicine, California
Institute of Behavioral Neurosciences & Psychology, Fairfield, USA 4. Internal medicine, California Institute of
Behavioral Neurosciences & Psychology, Fairfield, USA
Corresponding author: Anusha Bapatla, anushabapatla7@gmail.com
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by renal insufficiency, bone lesions,
anemia, and hypercalcemia. In this modern era of medicine, even with the development of drugs like
immunomodulatory agents (IMiDs) and proteasome inhibitors (PI), the treatment of MM prevails as a
challenge. However, even after the attainment of total remission, relapse of MM and disease progression is
frequent. That is why there is an urgent requirement to develop novel monoclonal antibody drugs. The
latest drugs for the treatment of relapsed and refractory MM (RRMM) approved by the Food and Drug
Administration (FDA) are elotuzumab and daratumumab. In this article, we will discuss daratumumab with
different combination therapies. The literature exploration was done using PubMed, Medline, PubMed
Central, and Research Gate. Keywords used to search are monoclonal antibodies, daratumumab, RRMM, and
novel agents. Our review article, which includes 21 relevant articles, demonstrated that daratumumab in
different combinations showed significant progression-free survival (PFS) without severe safety concerns.
However, while observing all the studies, neither of them studied the combination therapies of
daratumumab in end-stage renal disease (ESRD) patients. Hence, more randomized controlled clinical trials
should be done to understand and compare the effect of the combination of daratumumab with the standard
of care therapies in ESRD patients.
Categories: Internal Medicine, Oncology, Hematology
Keywords: daratumumab, relapsed and refractory multiple myeloma, monoclonal antibodies, novel agents,
mechanism of action
Introduction And Background
Multiple myeloma (MM) is defined as the abnormal proliferation of plasma cells (PCs) with increased
monoclonal antibody production. It is the second common hematological malignancy. MM is characterized
by organ dysfunction, including renal insufficiency, anemia, bone lesions, and hypercalcemia. The SEER
Data Registry, also known as US surveillance, epidemiology, and end results, estimated that new MM cases
in 2021 are 34,920, and estimated deaths in 2021 are 12,410 [1]. Relapsed myeloma is defined as previously
treated myeloma that progresses and needs salvage therapy initiation. It does not meet the criteria for either
Relapsed and Refractory MM (RRMM) categories or primary refractory myeloma [2]. When the disease is
nonresponsive while on salvage therapy or progresses within 60 days of the last cycle in patients who have
achieved minimal response or better at some point is defined as RRMM [2]. When the disease is
nonresponsive in patients who have never achieved a minimal response and neither got better with any
therapy is defined as primary refractory myeloma [2]. Despite enormous advances with the advent of
proteasome inhibitors (PI) and immunomodulatory agents (IMiDs), relapse of MM and disease progression is
very common even after achieving complete remission. Hence, the treatment of MM remains a challenge [3].
Patients' survival rate with frequent relapses or patients who are refractory to treatment is very low [4]. The
median overall survival (OS) in patients with three or more prior therapy lines including an IMiDs or PI or
double refractory to a combination of both PI and IMiDs was only about eight months, detailed in a recent
retrospective report of real-world survival outcomes [5]. Hence, new treatment combinations and therapies
are required urgently in patients with RRMM [4].
In 2015, the Food and Drug Administration (FDA) approved two monoclonal antibodies to treat RRMM,
elotuzumab, and daratumumab [6]. Despite the utilization of these novel agents, nearly all patients
experience relapsed disease [6], but comparatively prolonged survival with the use of these novel agents.
Daratumumab is a human IgGκ monoclonal antibody that targets CD38, expressed in abundance in
hematopoietic cell types, especially myeloma cells [7,8]. Daratumumab induces the death of PCs by
antibody-dependent phagocytosis, apoptosis, and cell-mediated cytotoxicity. In addition to that,
daratumumab works as an immunomodulator by increasing the activity of cytotoxic T‐lymphocytes by
inducing and decreasing CD38+ immunosuppressive myeloid and lymphoid cells [9,10].
1, 2 1 3 1
1 4 1
Open Access Review
Article DOI: 10.7759/cureus.15440
How to cite this article
Bapatla A, Kaul A, Dhalla P, et al. (June 04, 2021) Role of Daratumumab in Combination With Standard Therapies in Patients With Relapsed and
Refractory Multiple Myeloma. Cureus 13(6): e15440. DOI 10.7759/cureus.15440

A pooled observation of two monotherapy studies produced a median OS of 20.1 months and an overall
response rate (ORR) of 31%. It showed a strong response and clinical benefit in patients with stable disease
responses or better [5]. Based on the above findings, daratumumab was approved in the United States for a
monotherapy drug (16 mg/kg) for treatment of MM patients who have received three or more than three
prior therapy lines, including a PI and an IMiDs, or who are double‐refractory to a PI and an IMiDs [5].
Daratumumab is extensively studied in various combinations with the standard of care therapies for RRMM.
Daratumumab-based combinations showed significant benefit in phase three and phase one/two clinical
trials [11-13]. But there is limited data on the complete role of daratumumab in a combination of the
standard of care therapies. This article discusses different combination therapies' efficacy and safety, and
the use of these combination therapies in different settings.
Review
We searched the databases PubMed, Medline, PubMed Central, and Research Gate using a combination of
keywords. Keywords used to search are daratumumab, RRMM, monoclonal antibodies, and novel agents. The
articles included are those from the last five years. Grey literature is not included in this review article. Only
articles with free full-text available are included in the study - no location specifications. Only articles in the
English language are included.
Mechanism of action of daratumumab
CD38 is a type II transmembrane glycoprotein involved in numerous intracellular and extracellular
functions. CD38 expression is at low levels in the normal lymphoid cell lineage and normal myeloid cell
lineage. However, CD38 is expressed at high levels on malignant myeloma cells [8]. Krejick et al., in their
flow cytometric analysis on 148 patients, confirmed the increased expression of CD38 on myeloma cells [14].
Daratumumab is an IgG1 human monoclonal antibody against CD38. Daratumumab kills myeloma cells via
different pathways include antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular
cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulatory
action.
Antibody-Dependent Cellular Phagocytosis
ADCP is one of the Fc component-medicated mechanisms that contribute to the anti-tumor activity of
daratumumab. Daratumumab (IgG1 monoclonal antibody) binds to CD38; the Fc component of
daratumumab binds to FcγRs on the macrophages and then phagocytosis of opsonized tumor cells [15,16].
This mechanism contributing to the anti-tumor activity of daratumumab is well demonstrated by Overdijik
et al. in their in vivo study [10]. It is one of the important mechanisms because of macrophages' ability to
engulf multiple opsonized tumor cells and the ability to engulf quickly. The efficacy and quick action of
macrophage-induced phagocytosis is demonstrated by time-lapse imaging microscopy [10].
Antibody-Dependent Cellular Cytotoxicity
This is one of the Fc component-mediated mechanisms of action. Fc component of daratumumab binds to
FcγRs on effector cells. Effector cells mainly release toxic components and thereby results in lysis of the
tumor cells [15,16]. Casneuf et al. demonstrated that even though there is a reduction in the number of
natural killer (NK) cells as these cells express CD38, there is no demonstrable change in the safety and
efficacy of daratumumab. This no change in safety and efficacy is because the remaining NK cells can
contribute to ADCC, other granulocytes contribute to ADCC, and other mechanisms of actions also play a
role in the efficacy of daratumumab [17].
Complement-Dependent Cytotoxicity
Fc binding to the complement activates complement and results in the production of membrane attack
complex, leading to increased permeability of membrane and damage to the cell [16].
Direct Apoptosis
Programed cell death is triggered by cross-linking CD38 by inhibitory FcγRIIb and activating FcγRs [16].
Immunomodulatory Action
Increased expression of CD38 is noted on B-regulatory cells and myeloma-derived suppressor cells. As
daratumumab is a monoclonal antibody to CD38, these cells are sensitive to daratumumab and hence
promote anti-tumor activity. Krejick et al. found that a shift towards positive versus negative immune cells
might contribute to anti-tumor activity. But further studies were required to prove whether this T-cell shift
results in actual anti-tumor activity or not [14]. The mechanism of action of daratumumab is illustrated in
Figure 1.
2021 Bapatla et al. Cureus 13(6): e15440. DOI 10.7759/cureus.15440 2 of 13

FIGURE 1: Mechanism of Action of Daratumumab
Modes of resistance
Resistance pattern to daratumumab may be primary or secondary resistance.
Mechanism of Primary Resistance to Daratumumab
The level of expression of CD38 itself affects the efficacy of daratumumab. MM cells with high levels of
CD38 expression are more sensitive to daratumumab than cells with a low level of CD38 expression [15].
Mechanism of Secondary Resistance to Daratumumab
Decreased expression of CD38 following daratumumab infusion causes decreased efficacy. Soluble CD38 and
antidrug antibodies might neutralize CD38 theoretically, but no clinical evidence till now [15]. ADCP
resistance is mainly caused by Fc receptor polymorphism; low monocyte to myeloma ratio decreases the
activity of daratumumab. CD47 expression inhibits phagocytosis of myeloma cells. ADCC resistance is
usually caused by increased NK cell destruction, an increased bone marrow stromal cells, and polymorphism
of the Fc receptor. CDC resistance is due to CD46, CD55, and CD59 are membrane-associated complement
inhibitors that protect normal cells from complement medicated damage. These inhibitors also protect
myeloma cells from complement-mediated damage. At the time of progression with daratumumab therapy,
increased expression of CD55 and CD59 is shown. Resistance to direct effects is due to a decrease in CD38
expression. Resistance to immunomodulatory action is due to a decrease in activated T cells [16].
Pharmacokinetics of daratumumab
Clemens et al., in their analysis of pharmacokinetics in 223 patients in Gen 501 and SIRUS study, showed
that daratumumab exhibits non-linear pharmacokinetic characteristics after intravenous administration.
Maximum concentration (C max) increase is in proportion to an increase in dose after initial infusion. After
subsequent infusions, the C max increase is greater than the dose-proportional increase. The reason for this
increase in C max is postulated either due to target-mediated saturation or due to a decrease in CD38
containing cells by decreasing tumor burden [18]. This study also studied the dose-effect and confirmed that
16 mg/kg is a better target saturation and ORR than 8 mg/kg. Based on the consideration of pharmacokinetic
characteristics, the suggested daratumumab dose is 16 mg/kg weekly for eight weeks, every two weeks for 16
weeks, and four weeks after that [18].
Although daratumumab was proven as an effective drug, it is also associated with infusion-related reactions
(IRR) in 50% of patients. Most of them are mild and related to early infusions. Usmani et al., in their study,
mainly focused on the safety and pharmacokinetics of subcutaneous delivery of daratumumab with
2021 Bapatla et al. Cureus 13(6): e15440. DOI 10.7759/cureus.15440 3 of 13

hyaluronidase. Two doses were tested in this study, the first dose is 1,200 mg, which is equivalent to the
daratumumab IV dose of 16 mg/kg, and the second dose is 1,800 mg, which is equivalent to the
daratumumab IV dose of 24 mg/kg. The second dose is tested considering the bioavailability of less than
100% for subcutaneous delivery. Serum daratumumab concentrations in the 1,800 mg subcutaneous group
are almost similar to daratumumab 16 mg/kg infusion. Treatment site reactions include pain, erythema, and
induration. Most of them were resolved without intervention. IRR is less common than IV infusion. As there
are considerably fewer side effects with maintaining efficacy, subcutaneous daratumumab can be considered
an alternative [19]. Mechanism of action, modes of resistance and pharmacokinetics are mentioned in Table
1.
Author &
Year of
Publication
Number
of
patients
Type of the
study
Purpose of the
study Results Conclusions
Krejcik et
al. 2016
[14]
148 Clinical trial
Role of
immunomodulatory
effect of
daratumumab in
RRMM
Immunosuppressive cells, including MDSCs and B
regs, showed increased CD38 expression, and
daratumumab decreases the number of these
cells. T regs, which showed increased CD38
expression, are more immunosuppressive and
decreased following daratumumab. Daratumumab
effect on T regs also have anti-tumor activity
Observed changes were in ratios of CD8:CD4 and
CD8: T regs with the treatment of daratumumab.
But their exact contribution to the mechanism
needs further evaluation and treatment.
Along with the
direct effect of
daratumumab on
myeloma cells, the
Immunomodulatory
effect of
daratumumab on
anti-tumor activity
is proposed in this
study. Further
studies were
needed to evaluate
the change in T
cells contributes to
the anti-tumor
activity of
daratumumab or
not.
Overdijk et
al. 2015
[10]
12 Clinical trial
To study the
contribution of
macrophage-
mediated antibody-
dependent
phagocytosis to
the mechanism of
action of
daratumumab
To study the macrophage-mediated phagocytosis,
double-positive macrophages and percentage
reduction in target cells were studied in vivo. Flow
cytometry phagocytosis assay showed an increase
in double-positive macrophages and reduced the
number of target cells. Time-lapse imaging
microscopy showed fast and effective
phagocytosis by macrophages.
This study
demonstrated the
contribution of
macrophage-
mediated ADCP in
anti-tumor activity
by eliminating
ADCC and CDCC.
ADCP is one of the
fast and effective
mechanisms that
contribute to
daratumumab anti-
tumor activity.
Donk et al.
2018 [15] Review
A review
describing different
modes of action. It
also describes
host and tumor-
related factors that
affect
daratumumab
efficacy Various
mechanisms that
cause resistance to
CD 38 antibodies
Described mechanism of action as Fc mediated
effects includes ADCP, ADCC, and CDCC. Others
described are immune effects, direct apoptosis,
and Immunomodulatory effects were reviewed.
Primary Resistance depends on the level of
expression of CD38 on MM cells. Cells with high
expression are more sensitive, and cells with low
expression are less sensitive. Various factors
contribute to secondary resistance. The
downregulation of CD38 is another factor that
contributes to resistance. CD38 antibodies and
soluble CD38 might inactivate but clinically haven't
proven that they decrease activity. Divided
resistance as ADCP resistance, ADCC resistance,
CDC resistance, resistance to direct effects,
resistance to immunomodulatory effects
Various host-
related and drug-
related factors are
involved in the
therapeutic
efficacy of the
drug. A better
understanding of
these factors helps
in the
individualization of
the treatment and
thus increases the
efficacy
Along with other immunotherapeutic agents This study
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Morandi et
al. [16] Review Review article on
Immunotherapeutic
approaches in MM
against CD8, this study also reviewed
daratumumab. Added an important point of
daratumumab in the prevention of bone resorption
by killing osteoclasts
concludes CD38 as
a good target for
anti-tumor therapy
in MM
Casneuf et
al 2017 [17] 148 Clinical trail
Effect of
daratumumab
monotherapy on
NK cells and NK
cells dynamics on
efficacy and safety
of daratumumab
This study demonstrated CD38 mediated reduction
in NK cells after daratumumab treatment. In vivo
studies showed a decrease in ADCC mediated
lysis, and the remaining PBMCs showed some
ADCC mediated lysis of cells.
Although there is a
reduction in the
number of NK cells
with daratumumab,
no effect on
efficacy and safety
was observed.
There is no effect
on efficacy
because other
effector cells may
carry out ADCC,
and other
mechanisms act.
Clemens et
al 2017 [18]
223 Clinical trail
Characterize the
pharmacokinetics
of daratumumab
This study showed that daratumumab exhibits
non-linear pharmacokinetic characteristics after
Intravenous administration. C max increase is in
proportion to an increase in dose after initial
infusion. However, after subsequent infusions, the
C max increase is greater than the dose-
proportional increase. The reason for this increase
in C max is postulated either due to target
mediated saturation or due to a decrease in CD38
containing cells by decreasing tumor burden.
The dose regimen
suggested from
this study is
daratumumab 16
mg/kg weekly for
eight weeks, every
two weeks for 16
weeks, and four
weeks after that.
Usmani et
al. 2019
[19]
88
patients
Phase one,
open-label,
multicenter,
dose-
escalation
two-part
study
The purpose of the
study is to see
whether
daratumumab can
be given SQ
without affecting
efficacy to
minimize
complications and
discomfort
associated with IV
daratumumab
Daratumumab concentrations in the 1800 mg
Subcutaneous group are almost similar to
daratumumab 16mg per kg infusion. One patient
was positive for daratumumab antibody, but it
seems like it's not affecting pharmacokinetics.
Treatment site reactions include pain, erythema,
paraesthesia, and induration. Most of them were
resolved without intervention. IRR is less common
than IV infusion. If present, it easily gets treated
with supportive treatment.
Low risk of
immunogenicity,
low IRR, Low
TEAE, and almost
equal efficacy are
proven with SQ
Dara. However, as
there are
considerably fewer
side effects with
maintaining
efficacy,
subcutaneous
daratumumab can
be considered an
alternative.
TABLE 1: Mechanism of Action, Modes of Resistance, and Pharmacokinetics of Daratumumab
MDSC – myeloma derived suppressor cells, B regs – B regulatory cells, T regs – T regulatory cells, NK cells – natural killer cells, ADC P – antibody-
dependent cellular phagocytosis, ADCC – antibody-dependent cellular cytotoxicity, CDCC – complement-dependent cellular cytotoxicity, IRR –
infusion-related reaction, TEAEs – treatment effective adverse events.
Combination therapy
Daratumumab monotherapy at a dose of 16mg/kg was studied in Gen 501 and SIRUS study and showed
significant ORR in one-third of the population. In addition, treatment efficacy and side effect profile of
daratumumab combined with various standards of care regimens in RRMM were studied in different phase
clinical trials. Those results from different clinical studies are reviewed here in this article.
Therapeutic Eff icacy of Daratumumab in Different Combinations
Daratumumab with bortezomib and dexamethasone (D-Vd): The CASTOR study is multicenter, randomized
controlled trial (RCT). Patients included in the study were the patients with RRMM, those who had at least
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some positive response to previous therapy, and those who got at least one dose previously. The patients
excluded from the CASTOR study had significant side effects to bortezomib or patients who were refractory
to bortezomib therapy. They were randomly distributed into two groups. One group got bortezomib and
dexamethasone (Vd), and another group got D-Vd. Progression-free survival (PFS) was the primary endpoint
that was being studied. After a median follow-up of about eight months, pre-specified interim analysis was
done by Palumbo et al. The estimated one-year PFS with the daratumumab group is 60.7% (95% Confidence
interval [CI], 51.2 to 69.0) while comparing with the control group, which was 28.8% (95% CI, 17.1 to 37.5).
This significant PFS was maintained in all subgroups divided based on age, sex, type of myeloma, number of
the previous line of therapy, previous bortezomib therapy, and disease refractory to prior therapy. But the
PFS was not studied in subgroups based on cytogenetic risk. The OS benefit was unable to assess as it is a
shorter duration of follow-up. From this short-term follow-up published by Palumbo et al., D-Vd is more
effective than Vd concerning rates of excellent partial response or better and/or overall complete response or
better. This interim analysis showed that D-Vd is superior to Vd in every subgroup of the population was
studied [20].
Spencer et al. conducted an updated analysis of the CASTOR study after an extended follow-up of another 12
months (total of 19.4 months). Patients showed significant PFS in the treatment group compared to the
control group. An 18-month PFS rate of 48.0% in the D-Vd group compared with the Vd group, which is
7.9%. ORR was significantly improved with D-Vd versus Vd (83.8% versus 63.2%; P<0.0001). This clinical
benefit is consistent with all subgroups, including the subgroups based on cytogenetic risk, which was not
evaluated in the interim analysis. This extended follow-up showed a deeper response with the D-Vd group
with minimum MRD negative rates. OS is still immature to comment on during this study [21]. Mateos et al.
did subgroup analysis on efficacy and safety of D-Vd based on age group. Two groups were studied, one is 65
to 74 years, and another is more than or equal to 75. PFS was significantly prolonged in two age groups (age
more than 75 and age from 65 to 74). The 18-month PFS in patients with age more than 75 years is 48.0%
versus 7.9%, comparable with the 18-month PFS of the updated CASTOR study analysis. Among patients
with the age group of 65 to 74, the PFS rate was 45.8% versus 0%, comparable with the 18-month PFS of
updated castor study analysis [22].
Daratumumab with lenalidomide and dexamethasone (D-Rd): POLLUX study is a multicenter, RCT, phase
three clinical trial. Patients with RRMM, according to the International myeloma workgroup, those who
received at least one prior therapy were included in this study. Those who were refractory to lenalidomide or
had unacceptable adverse events (AEs) with lenalidomide were excluded from the study. The patients were
randomly assigned into two groups. One group received D-Rd, and another group received lenalidomide and
dexamethasone (Rd). Pre-specified Interim analysis of this study was done by Dimpolous et al. after a
median follow-up of 13.5 months, which showed significant PFS. The time to event analysis of PFS after 12
months was 83.2% in the D-Rd versus Rd is 60.1%. Significant PFS is maintained in all subgroups stratified
based on the number of the previous therapy line, whether the patient is exposed to lenalidomide or not, a
timeline of previous therapy, and age. ORR in the D-Rd was 92.9% versus 76.4% in the control group. A
significantly higher ORR, deeper responses, and longer response duration were shown in this study. The
daratumumab group showed a 63% lower risk of death or disease progression than the control group [12].
Dimpolous et al. conducted their updated analysis of the POLLUX study with additional 12 months of
follow-up (total of 25.5 months), which showed a significantly reduced risk of progression or death than the
control group. A 24-month PFS rate was 68.0% in the treatment group versus 40.9% in the control group.
ORR is 92.9% in the D-Rd group versus 76.4% in the Rd group. This study is focused on minimal residual
disease and clinically relevant subgroups. Also analyzed parameters in the subgroup analyses were
conducted based on the number of prior lines of therapy, prior treatment exposure, and a treatment-free
period after the last dose, and cytogenetic risk. The efficacy is maintained in all subgroups, including those
with cytogenetically high risk [23]. Bahlis et al. did efficacy and safety analysis after an extended follow-up
of 44.3 months. The study showed that the daratumumab combination was shown to cause significant PFS
benefit [24]. Mateos et al. did a subgroup analysis of the efficacy and safety of D-Rd based on age group. Two
groups are studied 65 to 74 and more than or equal to 75 after an extended follow-up of POLLUX study for
25.4 months. PFS was significantly prolonged in patients aged more than 75 years and patients between 65
and 74 years. In patients aged more than 75 years, the 18-month PFS rate of D-Vd versus Vd was 86.2%
versus 36.9%. In patients aged 65 to 74 years, the 18-month PFS rate was 72.0% versus 48.7%. Both the
groups showed good ORR and very good partial response (VGPR) or better and CR or better. Mateos et al.
demonstrated that efficacy and tolerability are almost the same events in the patents more than 75. So
daratumumab can be used even in patients above 75 as the general population [22]. Suzuki et al. performed a
subgroup analysis on the East Asian population. This subgroup analysis was performed to check for any
change in the D-Rd efficacy and safety in the East Asian population (Japanese, Korean, and Taiwanese). In
the East Asian population, 24-month PFS was 65.69% (D-Rd) versus 35.2% (Rd). ORR with the East Asian
population was 90.2% versus 72.1 %. ORR with the Japanese population was 90.0% versus 60.0%. This
efficacy is maintained in all subgroups, including the cytogenetic group, and consistent with the overall
population [25].
Daratumumab with pomalidomide and dexamethasone: Chari et al. discussed the results of the
daratumumab plus pomalidomide and dexamethasone (pom-dex) arm from the EQUULEUS study, which
includes 103 patients. This study is phase one; an open-label, the non-randomized study focused on dose-
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limiting toxicities of the daratumumab and pom-dex. This study also focuses on daratumumab and pom-dex
safety and tolerability. Those who received at least two lines of therapy were included in this study. The
patients were eligible who have progressive disease on lenalidomide or bortezomib or a combination of
lenalidomide and bortezomib. The ORR was 60%. ORR was maintained in all subgroups stratified based on
various parameters. ORR in subgroups were 64%, 65%, and 55% in patients who received two, three, or more
than three lines of prior therapy. Median survival was about nine months. This study showed that pom-dex
could be safely combined with daratumumab. This study might complement the POLLUX study. In the
POLLUX study, the addition of daratumumab for lenalidomide, which is immunomodulatory, showed
significant ORR. The addition of pomalidomide also showed significant ORR, but this is a non-randomized
study and needs a very extensive study to prove the combination of daratumumab with pom-dex to be
effective. APOLLO study is an on-going study to determine the actual benefit from the RCT. This regimen is
approved based on the phase one/two clinical trials without the phase three trial. This regimen is really
helpful in people who are refractory to lenalidomide [26].
Hussain et al. did a retrospective cohort study to see the combination of daratumumab and pomalidomide
helps overcome the resistance of either of them, considering their mechanism of action. This study showed
that a combination of daratumumab and pomalidomide helps overcome resistance in some cases. But this is
a retrospective cohort study with a limited population, needs a randomized controlled trial to confirm the
association that has been shown in this study [27]. Siegel et al. in their clinical trial mainly focused on
patients who are refractory or relapsed with lenalidomide. One-year PFS in those who relapsed after
lenalidomide was 83.2%. One-year PFS for those who are refractory to lenalidomide treatment was 72.4%.
PFS in patients with one or two prior lines of therapy was 78.8 % versus 69.0%. ORR was achieved
irrespective of several prior therapy lines, refractoriness to lenalidomide, or previous bortezomib exposure.
These findings demonstrate that pomalidomide, low-dose dexamethasone, and daratumumab combination
is a safe and effective treatment for patients with RRMM immediately following disease progression on or
after lenalidomide [28].
Daratumumab with carfilzomib and dexamethasone (D-Kd): Safety, pharmacokinetics, and preliminary
efficacy from the D-Kd arm of the EQUULEUS were studied by Chari et al. The patients included in this study
are RRMM, lenalidomide refractory patients, who had received one to three prior lines of therapy. The 12-
month PFS in patients who received D-Kd was 74%. In lenalidomide refractory patients, 12-month PFS was
65%, and bortezomib refractory patients, 12-month PFS was 60%. Median PFS was not reached in all
patients. In the treatment group, the 12-month OS rate was 82%. ORR was 84% in lenalidomide refractory
patients, and in bortezomib refractory patients ORR was 84%. Median OS was not achieved. The 12-month
OS rate for all treated populations was 82%, lenalidomide refractory patients were 75%, and bortezomib
refractory patients was 76% as it is a phase one study. Phase three trials are necessary to find out the efficacy
of this combination and check the side effect profile. This regimen would be a helpful regimen for those with
refractoriness to lenalidomide. There is one study going for D-Kd in lenalidomide-exposed patients [13].
Daratumumab with bortezomib, cyclophosphamide, and dexamethasone (D-VCd): D-VCd was studied in a
multicenter, open-label, single-arm study which includes 14 RRMM patients along with 87 patients of
NDMM. This study is limited as they involve only 14 patients and the main population in NDMM. The ORR
after the completion of four cycles was 71.4 %. Median PFS was 13.3%, and 12-month PFs were 66.2%.
12month OS rate was 54.5%. As this study is a phase two study and no set of controls and a limited number
of the population included in this study, it needs an extensive clinical trial to prove the efficacy [29].
Influence of Disease Characteristics, Patient Characteristics, and Other Monoclonal Antibodies in Combination
Therapy
Except for the type of myeloma, there is no influence of disease and patient characteristics on the
concentration of daratumumab. Daratumumab concentration is less in IgG type compared to non-IgG.
Regarding efficacy, there is no change in the efficacy of IgG MM and non-IgG MM. No patient and disease
factors analyzed by Yan et al. showed a statistically significant difference [30].
Hoylman et al. did a retrospective cohort study to find out the optimal sequence of daratumumab and
elotuzumab. The effect of one monoclonal antibody on another monoclonal antibody was never studied
before; ORR to initial monoclonal antibody was unchanged. ORR is higher in the cohort where
daratumumab received a second dose compared to elotuzumab as a second dose. PFS for daratumumab when
daratumumab first received was about three months. PFS for elotuzumab when elotuzumab first received
was about six and half months. Median PFS for daratumumab when received second dose was about ten
months. The median PFS for elotuzumab when elotuzumab received the second dose was about two months.
Use of daratumumab before elotuzumab was associated with decreased cumulative PFS. Daratumumab
retains activity whether it was used as first or second after elotuzumab. But elotuzumab did not retain
activity when used after daratumumab [6].
AEs Associated With Daratumumab in Different Combinations
Although AEs associated with a combination of medications are high, most of them are manageable and
2021 Bapatla et al. Cureus 13(6): e15440. DOI 10.7759/cureus.15440 7 of 13

almost similar to the AEs associated with individual medication involved in combination therapy. In the
interim analysis of the CASTOR study, although there were more hematological and non-hematological AEs
reported in the D-Vd group, the treatment discontinuation because of side effects is almost similar. No cases
of immunogenicity or no cases of hemolysis were reported in the treatment group [20]. Increased incidence
of IRR in the daratumumab group and most of them were associated with the first dose of daratumumab
infusion. Most of them are grade one or two [20]. Even with an extended follow-up of another 12 months,
the safety profile remains unchanged. No new cases were reported [21]. AEs with D-Rd are similar to
knowing Rd complications demonstrated in POLLUX study [12]. AEs related to the D-Rd group with extended
follow-up are higher than the control group, but the discontinuation rate is low [23]. A higher incidence of
infusion reaction is evident in the daratumumab group over 75 years in a study by Mateos et al. [22]. Side
effects profiles were similar in both the East Asian and Japanese groups, consistent with the overall
population in the study by Suzuki et al. [25]. Though higher neutropenia rates were observed in the
daratumumab plus pom-dex group, febrile neutropenia and grade three/four infections are comparable with
pom-dex alone [26]. Yimer et al., in their study, show that AEs are more common in RRMM than NDMM in
patients receiving D-VCd [30]. Daratumumab therapeutic efficacy and safety as combination therapies are
mentioned in Table 2.
Author &
year of
publication
Number of
patients
Type of the
study Purpose of the study Intervention studied Results/Conclusion
Palumbo et
al. 2016
[20]
498 Phase three,
RCT
Effect of D-Vd vs. Vd
in patients with
RRMM
The primary endpoint
is PFS. Secondary
efficacy endpoints are
ORR, OS, the duration
of response, the time
of response, time of
disease progression,
the percentage of
people with great
partial response
After 12 months in the D-Vd group, the
percentage of patients free from disease
progression was 65.4%, whereas, in the control
group, it was 28.8%. This study showed that the
PFS of the D-Vd group was elevated co mpared
with the Vd group, and statistically significant
PFS was maintained in all subgroups. Increased
complications with D-Vd compared with Vd
group.
Spencer et
al. 2018
[21]
498 Phase three,
RCT
Efficacy and safety
analysis of D-Vd with
extended follow up
of another 12 months
New PFS with
updated analysis in
comparison with the
primary analysis
The 18-month PFS rate of 48.0% in the study
group compared with the control group, which
is 7.9%. ORR was significantly prolonged with
study group is 83.8 % in comparison with the
control group
Mateos et
al. 2020
[22]
539
Phase three,
RCT,
subgroup
analysis of
CASTOR and
POLLUX
based on age
group
Subgroup analysis of
efficacy and safety of
D-Vd and D-Rd
based on age group
with an extended
period of follow-up.
Two age groups
studied were one
more than 75 years
and the second group
is the age between 65
to 74 years The
Median follow-up for
the POLLUX study is
25.4 months, and the
CASTOR study is 19.4
months
PFS was significantly prolonged in patients age
more than 75 years and patients between 65
and 74 years in POLLUX and CASTOR study In
patient’s age, more than 75 years, the 18-month
PFS rate of D-Vd versus Vd was 86.2% versus
36.9%. In Patients age 65 to 74 years, the 18-
month PFS rate was 72.0% versus 48.7% . In
patients age more than 75 years, the 18-month
PFS rate of D-Rd versus Rd was 48.0% versus
7.9%. Age more than 75 years, 18-month PFS
rate of D-Rd versus Rd were 45.8% versus 0%.
In the POLLUX study, both the groups showed
good ORR and VGPR or better and CR or better.
In CASTOR study showed TEAEs were similar in
both groups. Higher Rate of IRR in patients
more than 75 years compared to 65 to 74 yrs.
Dimpolous
et al. 2016
[12]
569 RCT
In this study, the
effect of combination
therapy of D-Rd was
being studied in
RRMM patients
compared to Rd
The primary endpoint
was PFS The
secondary endpoint
studied was
percentage of
patients with the good
response or better,
ORR, percentage of
patients with complete
response or better,
percentage of patients
with results below the
Treatment group showed a result of 63%
reduction outcome in the risk of disease
progression or death. It was also seen that there
was a significantly higher ORR (92.9 % versus
76.4%) and a significantly higher minimal
residual disease.
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alone threshold for minimal
residual disease,
studies were time to
disease progression,
duration of response,
time of response, and
OS
Dimpolous
et al. 2018
[23]
569 Phase three,
RCT
To study efficacy and
safety of D-Rd with
extended follow-up
The primary efficacy
endpoint studied was
PFS. Secondary
efficacy endpoint
studied were MRD,
ORR, OS, time of
response, Rate of
VGPR or better and
complete or better
Showed prolonged PFS in agreement with the
primary analysis. Significantly improved the
ORR (92.9% versus 76.4%) respectively In
subgroup analysis based on the number of prior
therapies, no difference is found in PFS based
on the number of prior therapies one, two, or
three. Response to daratumumab grou p is equal
in all independent of cytogenetic status. No
change in side effect profile from the prim ary
study reinforce the durable response data.
Bahlis et
al. 2020
[24]
569 Phase three,
RCT
Long-term safety and
efficacy after a
median follow up of
3.5 years
The primary efficacy
endpoints were PFS
Secondary efficacy
endpoints were
duration of response,
percentage of VGPR
or better and CR or
better, minimal
residual disease, ORR,
response time, and
OS. Subgroup
analysis was done
based on the number
of lines of therapy,
prior treatment with
lenalidomide,
bortezomib
refractoriness,
achievement of CR or
better MRD has
assessed at CR three
mths, six months after
complete response.
Median PFS with the D-Rd group is 44.5 months
versus 17.5 months in the Rd group. D-Rd group
showed significant PFS compared to Rd in the
subgroup of patients who received at least one
prior therapy. Forty-two months PFS rates were
57.3% versus 27.8%. The subgroup of patients
who received one to three prior therapies
showed significant PFS than the Rd gro up. For
example, 42-month PFS rates were 73.6%
versus 59.6%. In the subgroup of prior
Lenalidomide therapy and Bortezomib refractory
group, significantly prolonged progression-free
survival. ORR was significantly higher in the D-
Rd group versus the Rd group. ORR was higher
among all the subgroups. With extended follow-
up, no other safety issues were reported. TEAEs
were similar in both treatment and groups.
TEAEs leading to treatment discontinuation are
pneumonia, pulmonary embolism, and shock.
Suzuki et
al. 2018
[25]
96
Multicenter,
open-label,
RCT
This study is
specially performed
to see the efficacy
safety of D-Rd in the
East Asian
population and the
specific Japanese
population.
The primary endpoint
was PFS The
secondary endpoint
was ORR
Twenty-four months PFS in East Asia population
was 65.6 9 in D-Rd group versus 35.2 in R d
group. In Japanese patients was not estimable.
ORR in East Asia population, D-Rd vers us Rd
was 90.2 versus 72.1. In Japanese patients, ORR
in D-Rd versus RD was 90.0% versus 60.0%.
The response is maintained in all subgro up
analyses, including cytogenetic group, p rior line
of therapy. The side effects profile was similar in
both the East Asian and Japanese groups,
consistent with the overall population. S afety
and efficacy are consistent with the overall
population in East Asia and the Japanese
population
Chari et al.
2017 [26] 103
Equlleus -
Phase one,
open-label,
non-
randomized
study. This
study
Equlleus study –on
safety and tolerability
of various
combinations. This
arm focuses on
adverse effects with
The primary endpoint
assessed was the
maximum tolerated
dose of daratumumab.
Secondary endpoints
studied were efficacy
Though higher neutropenia rates were observed
in dartumumab plus pom-dex group, febrile
neutropenia and grade three/four infections are
comparable with pom-dex alone. Infusion
reactions has happened in 50% of patients who
were receiving daratumumab. However, most of
them were able to manage by slowing the
infusion rate or discontinuing the infusion. The
ORR was 60%. ORR 64, 65, and 55% in the
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published the
arm that
received pom-
dex with
daratumumab.
patients receiving
combination therapy
with daratumumab
plus Pom-dex
parameters which
include ORR and Rate
of complete response.
subgroup of patients received two, three or
more than three lines of prior therapy. 12
months PFS rate is 42%. Response with
daratumumab with pom-dex is rapid, d eep, and
durable without any increase in safety issues
than pom-dex alone except an increase in the
incidence of neutropenia
Hussain et
al. 2018
[27]
19 patients
Eight were
pomalidomide
refractory
Three were
refractory to
daratumumab
Eight were
refractory to
both
daratumumab
and
pomalidomide
Retrospective
cohort
The purpose of this
study is to see
whether the
combination of
daratumumab and
pomalidomide
combination helps in
overcoming the
resistance to either
of them or both of
them, taking into
consideration their
mechanism of action.
The endpoints studied
are PFS. ORR, CR
ORR was 54.6% in daratumumab or
pomalidomide refractory cohort and 12.5% in
daratumumab and pomalidomide refractory
cohort. CR was 63.6 % in daratumumab or
pomalidomide refractory cohort and 50% in
daratumumab and pomalidomide refractory
cohort. Median PFS was about four months for
the daratumumab or pomalidomide refractory
group and about four and half months for the
daratumumab and Pomalidomide refractory
group. This study proposed that daratumumab
and pomalidomide's combination help s
overcome resistance for either agents or both
the agents in some cases. Limitations to his
study were high and advising for further studies
regarding the use of combination in refractory
patients
Siegel et
al. 2020
[28]
112 Phase two,
clinical trial
The purpose of this
study is to see the
effect of
daratumumab plus
pom-dex in
Lenalidomide
refractory patients.
Three cohorts were
studied. Cohort A
included patients
who were given
pomalidomide and
low dose
dexamethasone In
cohort B,
pomalidomide, low
dose
dexamethasone, and
daratumumab were
given. Cohort C in
Japanese people
received
pomalidomide, low
dose
dexamethasone, and
daratumumab
Major inclusion criteria
are those who
relapsed or refractory
to lenalidomide. Major
exclusion criteria are
those who received
prior pomalidomide or
dexamethasone
One-year PFS for those who relapsed after
lenalidomide is 83.2%. One-year PFS for those
who are refractory to treatment is 72.4%. PFS in
patients with one or two prior lines of therapy is
78.8 % versus 69.0%. ORR is achieved
irrespective of the refractoriness to
lenalidomide, number of prior lines of therapy,
or previous bortezomib exposure This
combination is approved based on these results
exhibit that pomalidomide, low-dose
dexamethasone, and daratumumab are effective
and a safe treatment modality for RRMM
patients just after the disease progression
on/after lenalidomide.
Chari et al.
2019 [13] 85
Phase one,
open-label,
non-
randomized
study
Safety,
pharmacokinetics,
and preliminary
efficacy of D-Kd
PFS and ORR in
lenalidomide
refractory and
bortezomib refractory
patients
In lenalidomide refractory patients, 12 months
PFS was 65%, and bortezomib refractory
patients, 12-month PFS was 60%. Mainly in
lenalidomide refractory patient efficacy is
maintained, and this regimen would be a helpful
regimen for those with refractoriness to
lenalidomide.
Yimer et al.
2019 [29] 14
Multicenter,
Open-label
Phase two
The purpose of this
study is to study
about efficacy and
safety of the
daratumumab in
combination with
The primary endpoint
studied is the rate of
complete response
plus VGPR in the
The study shows that TEAEs are more common
in RRMM than NDMM.
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study bortezomib,
cyclophosphamide,
and Dexamethasone
(D-VCd)
RRMM
Yan et al.
2017 [30] 223 Exploratory
analysis
To study the effects
of disease
characteristics and
patient
characteristics on
daratumumab
pharmacokinetics,
efficacy, and safety.
Combined data from
SIRUS and GEN501
were collected.
Disease factors are
type of myeloma, prior
lines of therapy,
refractory status,
ECOG performance
status at baseline.
Patient factors are
age, race, sex, body
weight, renal and
hepatic function.
ORR was similar to both IgG and non-Ig G
myelomas. This study concluded that n one of
the factors studied showed statistically
significant differences.
Hoylman et
al. 2019 [6]
19 patients.
Eight were
pomalidomide
refractory.
Three were
refractory to
daratumumab
Eight patients
were
refractory to
both
daratumumab
and
pomalidomide
Retrospective
cohort. Two
cohorts were
included in
this study.
Cohort one
received
daratumumab
before
elotuzumab
Cohort two
received
elotuzumab
before
daratumumab
To find out the
optimal sequence of
daratumumab and
elotuzumab. The
effect of one
monoclonal antibody
on another
monoclonal antibody
was never studied.
This study to see any
effect of
daratumumab and
elotuzumab on each
other.
The primary outcome
looked at was
cumulative PFS.
Secondary outcomes
were PFS for the first
monoclonal antibody,
PFS for the second
monoclonal antibody.
Efficacy outcomes – In both the cohort, ORR to
the initial monoclonal antibody was unchanged.
The ORR in the cohort receiving the second
dose of daratumumab was higher than
elotuzumab as the second dose. PFS for
daratumumab when daratumumab first received
was about three months. PFs for elotuzumab
when elotuzumab first received was about six
and half months. Median PFS for daratumumab
when received second dose was about 10
months. The median PFS for elotuzumab when
elotuzumab received a second dose was about
two months. Use of daratumumab before
elotuzumab was associated with decreased
cumulative PFS. Daratumumab retain activity
irrespective of whether it was used as first or
second after elotuzumumab but elotuzumab did
not retain activity when used after daratu mumab
Cejalvo et
al. 2019
[31]
15 Retrospective
study
Retrospective study
of safety and efficacy
of daratumumab
among patients with
RRM and end-stage
renal disease
requiring dialysis
The primary endpoints
studied were ORR,
PFS, and OS
ORR was 40% that included one CR plus four
VGPR. Median PFS was about nine months. OS
was 12.19. Hematological TEAEs observed
were anemia, thrombocytopenia, neutro penia
and non-hematological TEAEs were asthesia
and hypotension. TEAEs causing death in this
study were pulmonary infection,
gastrointestinal hemorrhage, and ventricular
fibrillation. The best treatment regimen for
RRMM for patients with end-stage renal
disease requiring hemodialysis was sing le-
agent daratumumab.
TABLE 2: Therapeutic Efficacy and Safety of Daratumumab in Combination Therapies
RCT - Randomized controlled trial, D-Vd - daratumumab, bortezomib, and dexamethasone, Vd - bortezomib and dexamethasone PFS -
progression-free survival, OS - overall survival, ORR - overall response rate, , D-Rd - daratumumab, lenalidomide, and dexamethasone, Rd -
lenalidomide and dexamethasone, Pom -dex - pomalidomide and dexamethason e, D-Kd - daratumumab, carfilzomib, and dexamethasone, D-VCd –
Daratumumab, bortezomib, cyclophosphamide and dexamethasone, TEAEs - treatment effective adverse events, MRD – minimum residual disease,
CR – complete response, VGPR – very g ood partial response
Our study has some limitations; only articles in the English language and the free text available articles are
included. Most of the studies are performed on Caucasians and African Americans but not on Asians except
the study by Suzuki et al. on the East Asian population. Patients in these studies are followed for a limited
time and need more follow-up to assess OS rate. There are no RCTs found on daratumumab use as
combination therapies in end-stage renal disease (ESRD) patients, which is an important association with
MM. Only one study by Cejalvo et al. did a retrospective analysis that showed a single agent is safe in ESRD
patients. However, this study has limitations; this is a small observational retrospective study [31]. RCTs are
2021 Bapatla et al. Cureus 13(6): e15440. DOI 10.7759/cureus.15440 11 of 13

necessary to assess the safety and efficacy of single-agent and combination therapies.
Conclusions
The main objective of this research article is to study the safety and efficacy of daratumumab with the
current standard regimes for MM. D-Vd compared to Vd exhibited prolonged PFS in interim and long-term
follow-up data. While observing the extended follow-up, all subgroups maintained the prolonged PFS
including a subgroup based on cytogenetic risk. Prolonged PFS was observed in the interim and extended
follow-up in the D-Rd group. While considering all subgroups (including high cytogenetic risk), notable
prolonged PFS was maintained on the D-Rd group compared to the Rd group. Therefore, D-Vd and D-Rd
were approved for the treatment of RRMM. During phase ½, clinical trial efficacy and safety were observed
with daratumumab plus pom-dex, especially useful in patient's refractory to lenalidomide. During phase one
clinical trials, D-Kd and D-VCd also showed promising efficacy. More RCTs are necessary to prove the
efficacy and safety of D-Kd and D-VCd. While observing all the studies, none of them mentioned the
combination therapies of daratumumab for ESRD patients. Hence, more RCTs are necessary to understand
and compare the effect of combinations of daratumumab with the standard of care therapies in ESRD
patients.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
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