Drugs (2022) 82:683–690

https://doi.org/10.1007/s40265-022-01705-3

ADIS DRUG EVALUATION

Daratumumab: A Review in Newly Diagnosed Systemic Light Chain

Amyloidosis
Hannah A. Blair1

Published online: 13 April 2022

© Springer Nature Switzerland AG 2022

Abstract
Subcutaneous daratumumab (­DARZALEX®) co-formulated with recombinant human hyaluronidase (DARZALEX
­FASPRO®) is approved in several countries, including the USA and those of the EU, for use in combination with bortezomib,
cyclophosphamide and dexamethasone for the treatment of adult patients with newly diagnosed light chain (AL) amyloido-
sis. Daratumumab is a CD38-targeting, human IgG1κ monoclonal antibody. In the pivotal phase III ANDROMEDA trial in
adults with newly diagnosed systemic AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide and
dexamethasone significantly increased the proportion of patients achieving a haematological complete response relative to
bortezomib, cyclophosphamide and dexamethasone alone (primary endpoint). Daratumumab combination therapy produced
rapid and deep haematological responses which were associated with improved major organ deterioration progression-free
survival (PFS). The addition of daratumumab also led to higher cardiac and renal response rates at 6 and 12 months. Dara-
tumumab had an acceptable tolerability profile when used as combination therapy. Therefore, daratumumab in combination
with bortezomib, cyclophosphamide and dexamethasone represents an important emerging first-line treatment option for
patients with systemic AL amyloidosis.

Plain Language Summary

Systemic AL amyloidosis is a rare protein misfolding disease that causes serious damage to different organs, especially the
heart and kidneys. Daratumumab ­(DARZALEX®) is a human monoclonal antibody that targets CD38, a protein expressed
on clonal plasma cells. A subcutaneous formulation of daratumumab, co-formulated with recombinant human hyaluroni-
dase (DARZALEX F ­ ASPRO®), is approved for use in adult patients with newly diagnosed AL amyloidosis. When used in
combination with bortezomib, cyclophosphamide and dexamethasone, daratumumab was associated with higher rates of
haematological complete response and prolongation of major organ deterioration PFS compared with bortezomib, cyclo-
phosphamide and dexamethasone alone. The addition of daratumumab was also associated with near doubling of cardiac
and renal response rates at 6 and 12 months. Subcutaneous daratumumab had an acceptable tolerability profile when used as
combination therapy, with no new safety concerns. The combination of daratumumab with bortezomib, cyclophosphamide
and dexamethasone is an important emerging treatment option for patients with newly diagnosed systemic AL amyloidosis.

Digital Features for this Adis Drug Evaluation can be found at

https://​doi.​org/​10.​6084/​m9.​figsh​are.​19365​089. Daratumumab: clinical considerations in newly
diagnosed systemic AL amyloidosis
The manuscript was reviewed by: M. Beksac, Department
of Hematology, Ankara University, Ankara, Turkey; M. A. First-in-class CD38-targeting monoclonal antibody
Dimopoulos, Department of Clinical Therapeutics, National &
Kapodistrian University of Athens, Athens, Greece; G. Palladini, Associated with higher rates of haematological com-
Amyloidosis Research and Treatment Center, Fondazione IRCCS plete response and major organ deterioration PFS when
Policlinico San Matteo and Department of Molecular Medicine, combined with bortezomib, cyclophosphamide and
University of Pavia, Pavia, Italy.
dexamethasone
* Hannah A. Blair Acceptable tolerability profile
demail@springer.com
1
Springer Nature, Private Bag 65901, Mairangi Bay,
Auckland 0754, New Zealand

Vol.:(0123456789)
684 H. A. Blair

1 Introduction cytotoxicity and antibody-dependent cellular phagocytosis

[5, 6]. Daratumumab also modulates CD38 enzymatic activ-
Systemic light chain (AL) amyloidosis is a rare systemic ity by inhibiting cyclase activity and stimulating hydrolase
disease characterized by the abnormal production of mono- activity [6]. Natural killer (NK) cells are known to express
clonal immunoglobulin light chains [1–4], proteins made by CD38, and daratumumab was associated with a decrease in
clonal plasma cells [4]. The light chains misfold and aggre- total and activated NK cells in peripheral whole blood and
gate to form insoluble amyloid fibrils that are deposited in bone marrow [5, 6].
tissues, causing progressive and largely irreversible organ The binding of daratumumab to CD38 on red blood cells
damage [1–3]. The clinical features of AL amyloidosis are (RBCs) may interfere with blood compatibility testing, result-
dependent on the organs involved [3, 4], with the heart and ing in a positive indirect antiglobulin test (indirect Coombs
kidneys being the most commonly affected [1, 2]. Treat- test) for up to 6 months after the last dose of daratumumab
ment of AL amyloidosis is generally based on a risk-adapted [5, 6]. As such, patients should be typed and screened before
approach, taking into account clone characteristics, comor- starting daratumumab therapy [6]. Strategies to mitigate
bidities and the severity of organ involvement [4]. daratumumab interference include treating reagent RBCs
Evidence suggests that CD138/38 plasma cells are with dithiothreitol [5, 6]. ABO and Rh typing are not affected
involved in the production of monoclonal light chains by daratumumab [6]. If an emergency blood transfusion is
[2]. CD38 is a transmembrane glycoprotein that is highly needed, non-cross-matched ABO/RhD-compatible RBCs can
expressed on the surface of various haematopoietic cells, be given according to local blood bank practices [5, 6].
including clonal plasma cells in AL amyloidosis [5, 6]. It is The pharmacokinetics of subcutaneous daratumumab are
involved in receptor-mediated adhesion, cell signaling and best described by a one-compartment model, with first-order
modulation of cyclase and hydrolase activity [5, 6]. There- absorption and parallel linear and non-linear elimination,
fore, CD38 represents a promising target for the treatment of according to a population pharmacokinetic analysis [11].
AL amyloidosis and other plasma cell disorders [2]. Following subcutaneous administration of daratumumab
Daratumumab ­(DARZALEX®) is a first-in-class human 1800 mg in patients with AL amyloidosis, the absolute bio-
IgG1κ monoclonal antibody against CD38. A subcutaneous availability of daratumumab was not estimated, the absorp-
formulation of daratumumab co-formulated with recombi- tion rate constant was 0.77/day and peak serum concentra-
nant human hyaluronidase PH20 (rHuPH20; DARZALEX tions were reached in ≈ 3 days [5, 6]. The estimated apparent
­FASPRO®) has been approved in the USA [5] and the EU [6] volume of distribution was 10.8 L [5, 6], indicating that
for use in combination with bortezomib, cyclophosphamide daratumumab is primarily distributed in the vascular system;
and dexamethasone in adult patients with newly diagnosed extravascular tissue distribution is limited [6]. The estimated
AL amyloidosis. This article reviews the clinical efficacy apparent clearance was 210 mL/day and the estimated mean
and tolerability of daratumumab in this setting, with a brief elimination half-life was 28 days [5, 6].
overview of its pharmacological properties. Discussion of Age (33–92 years), sex, renal impairment [creatinine
the use of daratumumab in other approved indications [i.e. clearance ­(CLCR) 15–89 mL/min] and mild hepatic impair-
relapsed and/or refractory multiple myeloma (MM) [7, 8], ment [total bilirubin 1–1.50 × upper limit of normal (ULN)
transplant-ineligible [9] and -eligible [10] newly diagnosed and AST > ULN] did not have clinically meaningful effects
MM] is outside the scope of this article. on daratumumab pharmacokinetics; therefore, no dosage
adjustments are required [5, 6]. The effect of moderate and
severe hepatic impairment on the pharmacokinetics of dara-
2 Pharmacological Properties tumumab is not known [5, 6]. In patients with AL amyloi-
of Daratumumab dosis, daratumumab exposure was higher in African-Amer-
icans and Asians than in whites [5]. Relative to patients
The majority of data on the effects of targeting CD38 have weighing 51–85 kg, daratumumab plasma concentrations
been derived from in vivo and in vitro studies on MM [2]. increased in patients with low bodyweight (≤ 50 kg) and
AL amyloidosis and MM are both plasma cell disorders and decreased in those with high bodyweight (> 85 kg) [5].
therefore have certain similarities [2]. Daratumumab binds
to the CD38 protein expressed on clonal plasma cells in
MM and AL amyloidosis, thereby inhibiting the growth of 3 Therapeutic Efficacy of Daratumumab
CD38-expressing tumour cells [5, 6]. Daratumumab induces
apoptosis directly via Fc-mediated cross-linking, as well as The efficacy of subcutaneous daratumumab in combina-
by immune-mediated tumour cell lysis through complement- tion with bortezomib, cyclophosphamide and dexametha-
dependent cytotoxicity, antibody-dependent cell-mediated sone in patients with newly diagnosed systemic AL amy-
loidosis was demonstrated in the randomized, open-label,
Daratumumab: A Review 685

Eligible patients randomized, stratified by cardiac stage,

Patients with newly availability of transplants in the local country and renal function
diagnosed systemic light (n = 388)
chain amyloidosis were VCd was given as six 28-day cycles. Daratumumab was Primary endpoint assessed Updated analysis (May
assessed for safety signals administered for a maximum of 24 cycles or until the start of (Feb 2020; median follow-up 2021; median follow-up
(n = 28) another therapy or disease progression 11.4 mo) 25.8 mo)

Safety Run-In Randomized Open-Label Treatment

Daratumumab + VCd (n = 195)

VCd only (n = 193)

Overall haematological complete response (% of patients)

Fig. 1  Trial design of the randomized, open-label, multinational details regarding treatment regimens. Efficacy results are reported in
phase III ANDROMEDA trial in adults with newly diagnosed sys- the animated figure (available online). VCd bortezomib + cyclophos-
temic light chain amyloidosis [12]. Refer to Sect. 3 and Table 1 for phamide + dexamethasone

active-controlled, multicentre, phase III ANDROMEDA intention-to-treat population. A haematological complete

trial [12]. Combination bortezomib, cyclophosphamide and response was defined as negative serum and urine immuno-
dexamethasone was used as the active comparator [12]. fixation and normalization of free light chain (FLC) levels
ANDROMEDA enrolled patients aged ≥ 18 years with and FLC ratios. However, if involved FLC (iFLC) was lower
a histopathological diagnosis of systemic AL amyloidosis than the upper limit of normal, normalization of uninvolved
affecting one or more organs, measurable haematological dis- FLC level and FLC ratio was not required to determine a
ease and an ECOG performance status of 0–2 [12]. Patients complete haematological response. If the primary endpoint
were also required to have an absolute neutrophil count of was significant, the major secondary endpoints [i.e. major
≥ 1.0 × ­109/L, a haemoglobin level of ≥ 8.0 g/dL, a platelet organ deterioration progression-free survival (PFS) and
count of > 50 × 1­ 09/L, ALT and AST levels of ≤ 2.5 × ULN, overall survival (OS)] were tested hierarchically [12].
a total bilirubin level of ≤ 1.5 × ULN (or ≤ 2 × ULN in Baseline demographic and clinical characteristics were
patients with Gilbert syndrome) and an estimated glomerular generally well balanced between treatment groups [12]. The
filtration rate of ≥ 20 mL/min/1.73 ­m2. Key exclusion criteria median time since diagnosis was 43 days and the median
included symptomatic MM, previous therapy for AL amy- patient age was 64 years. Most patients had an ECOG per-
loidosis, and evidence of a severe cardiovascular condition formance status of 0 or 1 (91%) and a cardiac stage of II or
including an N-terminal pro-B-type natriuretic peptide (NT- higher (77%). Overall, 66% of patients had involvement of
proBNP) level of > 8500 ng/L, a systolic BP of < 90 mmHg, two or more organs; 71% of patients had heart involvement
or a New York Heart Association (NYHA) classification of and 59% had kidney involvement [12].
IIIB or IV [12]. At the time of the primary analysis (median follow-up
After being stratified according to cardiac stage (I, II or 11.4 months; data cutoff date 14 February 2020), the pro-
IIIA on the basis of the European modification of the Mayo portion of patients achieving a haematological complete
Clinic Cardiac Staging System), availability of transplan- response was significantly greater with daratumumab com-
tation in the local country (yes or no) and renal function bination therapy than with the active comparator (primary
­(CLCR ≥ 60 or < 60 mL/min), 388 patients were randomized endpoint; Table 1) [12]. Daratumumab combination therapy
to receive daratumumab combination therapy or the active was also superior to the active comparator when haemato-
comparator (Fig. 1) [12]. After six cycles, patients in the logical complete response was defined according to Inter-
daratumumab group continued to receive daratumumab national Society of Amyloidosis (ISA) criteria (i.e. negative
monotherapy every 4 weeks for up to 24 cycles (see Table 1 immunofixation and FLC ratio normalization or abnormal
for dosage regimens) and those in the active comparator FLC ratio, if uninvolved FLC is higher than iFLC; Table 1)
group completed their treatment. The median duration of [12]. Prespecified subgroup analyses for the primary end-
treatment was 9.6 and 5.3 months in the daratumumab and point favoured daratumumab combination therapy over the
active comparator groups. Pre- and post-medications were active comparator in most subgroups, including sex, age,
given with daratumumab to prevent administration-related bodyweight, race, cardiac stage [13], availability of trans-
reactions. The primary endpoint was overall haematologi- plantation, ­CLCR, cardiac involvement, renal stage, alkaline
cal complete response at the time of clinical cutoff in the phosphatase level, ECOG performance status, cytogenetic
686 H. A. Blair

Table 1  Efficacy of daratumumab combination therapy in adults with newly diagnosed systemic light chain amyloidosis in the phase III
ANDROMEDA trial
Endpoint DARA​a + ­VCdb VCdb RRR (95% CI) OR or HR (95% CI)
(n = 195) (n = 193)

Primary analysis (median follow-up 11.4 months) [12]

Haematological response (% pts) 92 77
­CRc 53 18 2.9 (2.1–4.1)** OR 5.1 (3.2–8.2)**
CR by ISA ­criteriad 54 27 2.0 (1.5–2.6)** OR 3.1 (2.1–4.8)**
≥ VGPR 79 49 1.6 (1.4–1.9) OR 3.8 (2.4–5.9)
VGPR 25 31
PR 13 28
iFLC level ≤ 20 mg/L (% pts) 71 20
dFLC level < 10 mg/L (% pts) 63 30
Major organ deterioration ­PFSe (% pts) HR 0.58 (0.36–0.93)*
Haematological progression 4 13
Major organ deterioration 1 4
Death 13 11
Updated analysis (median follow-up 25.8 months) [21]
Haematological response (% pts)
CR 60 19 OR 6.03 (3.80–9.58)***
≥ VGPR 79 50 OR 3.74 (2.39–5.86)***

CR complete response, DARA​ daratumumab, dFLC difference between involved and uninvolved FLC, FLC free light chains, HR hazard ratio,
iFLC involved FLC, ISA International Society of Amyloidosis, IV intravenous, OR odds ratio, PFS progression-free survival, PR partial
response, pts patients, qxw every × weeks, RRR​ relative risk ratio, SC subcutaneous, VCd bortezomib + cyclophosphamide + dexamethasone,
VGPR very good partial response
*p = 0.02, **p < 0.001, ***p < 0.0001
a
SC DARA 1800 mg (co-formulated with hyaluronidase) q1w (cycles 1 and 2) then q2w (cycles 3–6) then q4w until disease progression, the
start of subsequent therapy, or for a maximum of 24 cycles, whichever occurs first
b
SC bortezomib (1.3 mg/m2) + oral or IV cyclophosphamide 300 mg/m2 (maximum 500 mg) + oral or IV dexamethasone 40 mg [or 20 mg in
pts who were > 70 years of age, underweight (body mass index < 18.5 kg/m2), or had hypervolaemia, poorly controlled diabetes, or previous
unacceptable side effects associated with glucocorticoid therapy] q1w for 6 cycles of 28 days each
c
Primary endpoint
d
Defined as negative immunofixation and FLC ratio within the reference range or abnormal FLC ratio, if uninvolved FLC is higher than iFLC
e
Composite endpoint of haematological progression, end-stage cardiac or renal failure, or death, whichever occurs first

profile [12, 14] and presence of t(11;14) mutations [12]. comparator (relative risk ratio 3.5, 95% CI 2.4–5.2; odds
The benefit of daratumumab combination therapy in the ratio 6.1, 95% CI 3.7–10.0). Deep haematological responses,
subgroup of Asian patients (Chinese, Japanese or Korean; including a very good partial response (VGPR) or better, an
n = 60) was consistent with that seen in the overall study iFLC level of ≤ 20 mg/L, and a difference between involved
population [15]. and uninvolved FLC (dFLC) level of < 10 mg/L, were
For secondary endpoints, major organ deterioration PFS numerically higher in daratumumab combination therapy
(Table 1) favoured daratumumab combination therapy over recipients than in active comparator recipients (Table 1)
the active comparator [12]. Similar results were seen in sup- [12]. Further analyses demonstrated that rapid haemato-
portive analyses, including without censoring for subsequent logical responses (complete response and VGPR at 1 and
treatment (HR 0.57; 95% CI 0.37–0.87). At the time of the 3 months) [16] and deep haematological responses (iFLC
primary analysis, OS did not differ significantly between the ≤ 20 mg/L and dFLC < 10 mg/L, regardless of FLC ratio)
two treatment groups (HR 0.90; 95% CI 0.53–1.53) [12]. [17] were associated with improved major organ deteriora-
The median time to haematological complete response tion PFS.
was 60 days with daratumumab combination therapy and Daratumumab combination therapy recipients were more
85 days with the active comparator [12]. The haematologi- likely than those in the active comparator group to have a
cal complete response rate at 6 months was 50% with dara- cardiac or renal response at 6 and 12 months [12]. Cardiac
tumumab combination therapy versus 14% with the active response was defined as NT-proBNP response (> 30% and
Daratumumab: A Review 687

> 300 ng/L decrease in patients with baseline NT-proBNP daratumumab combination therapy than with the active com-
≥ 650 ng/L) or NYHA class response (≥ 2-class decrease parator (53 vs 24% and 58 vs 26%) [21].
in patients with baseline NYHA class III or IV), and renal
response was defined as ≥ 30% decrease in proteinuria or
drop in proteinuria below 0.5 g/24 h in the absence of renal 4 Tolerability and Safety of Daratumumab
progression. Among patients who were evaluated for cardiac
response (n = 235), the cardiac response rate at 6 months Subcutaneous daratumumab in combination with bort-
was 42% with daratumumab combination therapy and 22% ezomib, cyclophosphamide and dexamethasone had an
with the active comparator. Cardiac progression (i.e. NT- acceptable tolerability profile in patients with newly
proBNP, cardiac troponin or ejection fraction progression) diagnosed systemic AL amyloidosis participating in the
occurred in 3 and 8% of patients, respectively. Among ANDROMEDA trial discussed in Sect. 3 [12]. Subcutaneous
patients who were evaluated for renal response (n = 230), daratumumab was well tolerated when used as combination
the renal response rate at 6 months was 53% with daratu- therapy during the safety run-in phase of ANDROMEDA
mumab combination therapy and 24% with the active com- (n = 28), and no new safety concerns were identified com-
parator. Renal progression (i.e. ≥ 25% decrease in eGFR) pared with intravenous or subcutaneous daratumumab mon-
was seen in 4 and 12% of patients, respectively [12]. otherapy or the active comparator [22].
Daratumumab combination therapy was associated In ANDROMEDA, the safety profiles of daratumumab,
with some benefits over the active comparator in terms of bortezomib, cyclophosphamide and dexamethasone were
health-related quality of life (HR-QOL), as assessed by the consistent with their known profiles and with the underlying
European Organization for Research and Treatment of Can- disease [12]. In the safety population (n = 381), the exposure-
cer Quality of Life Questionnaire Core 30-item (EORTC adjusted incidence rates of overall adverse events (AEs) and
QLQ-C30), the EuroQol 5-dimensions 5-level (EQ-5D-5L) grade 3 or 4 AEs were lower with daratumumab combi-
visual analogue scale (VAS) and the 36-Item Short-Form nation therapy than with the active comparator (154.23 vs
Health Survey (SF-36) mental component summary (MCS) 217.92 and 10.55 vs 18.96 per 100 patient-months at risk,
[18]. For EORTC QLQ-C30 global health status (GHS) respectively). The most common (≥ 20% incidence) AEs
and fatigue scales and EQ-5D-5L VAS, the median time of any grade were peripheral oedema, diarrhoea, constipa-
to improvement was shorter and the median time to wors- tion, peripheral sensory neuropathy, fatigue, nausea and
ening was longer with daratumumab combination therapy upper respiratory tract infection (Fig. 2). The most common
versus the active comparator. Least squares mean scores for (≥ 10% incidence) grade 3 or 4 AEs were infections (17%
EORTC QLQ-C30 GHS and fatigue, EQ-5D-5L VAS and with daratumumab combination therapy vs 10% with the
SF-36 MCS remained stable with daratumumab combination active comparator) and lymphopenia (13 vs 10%). Serious
therapy and worsened with the active comparator, with the AEs occurred in 43% of daratumumab combination therapy
greatest between-group differences seen at week 16 (cycle recipients and 36% of active comparator recipients, with the
4). Improvements in GHS and fatigue were reported after most common of these being pneumonia (7 vs 5%). AEs led
cycle 6 in the daratumumab combination therapy group [18]. to treatment discontinuation in 4% of patients in each treat-
Similar improvements in fatigue-related symptoms (e.g. ment group. Fatal AEs (in the absence of disease progres-
shortness of breath, feeling weak and tired) were observed sion) occurred in 12% of patients receiving daratumumab
with daratumumab combination therapy in the subgroups combination therapy and 7% of those receiving the active
of patients with cardiac (n = 277) [19] or renal (n = 229) comparator [12].
[20] involvement.
4.1 Adverse Events of Special Interest
3.1 Updated Analysis
Serious or fatal cardiac AEs have been reported in patients
Improvements in clinical outcomes with daratumumab with newly diagnosed AL amyloidosis receiving daratu-
combination therapy relative to the active comparator were mumab combination therapy [5, 6]. In ANDROMEDA,
maintained over the longer term [21]. At the time of the serious cardiac disorders (including cardiac failure, car-
updated analysis (median follow-up of 25.8 months; data diac arrest and atrial fibrillation [6]) occurred in 16% of
cutoff date May 2021), when 11% of patients in the dara- patients receiving daratumumab combination therapy and
tumumab group were still receiving treatment, the rates of 13% of those receiving the active comparator; correspond-
haematological complete response and VGPR or better were ing rates of grade 3 or 4 cardiac disorders were 11 and 10%,
higher in the daratumumab combination therapy group than respectively [5, 6]. Patients with NYHA class IIIA or Mayo
in the active comparator group (Table 1). Cardiac and renal stage IIIA disease may be at greater risk for cardiac toxicity
response rates at 18 months were numerically higher with [5]. In the USA, daratumumab is not indicated and is not
688 H. A. Blair

Like all therapeutic proteins, daratumumab has the

potential for immunogenicity [5]. However, < 1% of
patients receiving daratumumab in clinical trials devel-
oped treatment-emergent anti-daratumumab antibodies [5,
6]. Although 7% of patients developed treatment-emergent
anti-rHuPH20 antibodies, these did not appear to affect dara-
tumumab exposure [5, 6].

5 Dosage and Administration

of Daratumumab

In the USA [5] and the EU [6], daratumumab (in combina-

tion with bortezomib, cyclophosphamide and dexametha-
sone; 4-week cycle regimens) is indicated for the treatment
of adult patients with newly diagnosed AL amyloidosis. The
US approval of daratumumab in this indication was acceler-
ated based on response rates, and continued approval may
be contingent upon verification and description of clinical
benefit in further confirmatory trials [5]. The recommended
Fig. 2  The most common adverse events of any grade (≥ 20% inci- dosage is 1800 mg daratumumab and 30,000 units hyaluro-
dence in either treatment group) in ANDROMEDA [12]. DARA​
nidase (HuPH20) administered as a subcutaneous injection
daratumumab, PSN peripheral sensory neuropathy, URTI upper res-
piratory tract infection, VCd bortezomib + cyclophosphamide + dex- into the abdomen (over ≈ 3–5 min) weekly from weeks 1
amethasone to 8 (total of 8 doses), every 2 weeks from weeks 9 to 24
(total of 8 doses) and every 4 weeks from week 25 onwards
until disease progression (or for a maximum of 2 years [5])
recommended for the treatment of patients with AL amyloi- [5, 6]. Local prescribing information should be consulted
dosis who have NYHA class IIIB or IV cardiac disease or for detailed information regarding preparation, storage and
Mayo stage IIIB outside of controlled clinical trials. Patients administration procedures, pre- and post-medication recom-
with cardiac involvement of AL amyloidosis should be fre- mendations, warnings and precautions, drug interactions,
quently monitored for cardiac toxicity, and appropriate sup- and use in specific populations.
portive care should be administered [5].
Daratumumab may increase neutropenia and thrombocy-
topenia induced by background therapy [5, 6]. In ANDROM- 6 Place of Daratumumab
EDA, daratumumab combination therapy was associated in the Management of Newly Diagnosed
with numerically higher rates of neutropenia (11 vs 6%) and Systemic Light Chain Amyloidosis
thrombocytopenia (17 vs 12%) than the active comparator
[12]. Complete blood counts should be monitored throughout The goals of treatment in systemic AL amyloidosis are to
the treatment period, and patients should be observed for signs eliminate the misfolded immunoglobulin light chains, to
of infection [5, 6]. Daratumumab dose delays may be required support the function of damaged organs, and to minimize
to allow recovery of neutrophils and platelets [5, 6]. toxicity [23]. Conventional systemic treatment options have
Severe and/or serious infusion-related reactions (IRRs) included alkylator-based chemotherapy, including the com-
and local injection-site reactions (ISRs) can occur with bination of cyclophosphamide, bortezomib and dexametha-
daratumumab [5, 6]. In ANDROMEDA, 7% of patients had sone [3]. In the most recent NCCN [23] and mSMART [24]
systemic administration-related reactions to daratumumab guidelines, daratumumab in combination with bortezomib,
[12]. Most (86%) of these reactions occurred during the cyclophosphamide and dexamethasone is recommended as
first administration, and the median time to onset was 1.3 the preferred (category 1 [23]) regimen for the treatment of
h (range 0.2–7.3 h). Local ISRs to daratumumab occurred newly diagnosed AL amyloidosis.
in 11% of patients. All systemic and local reactions were Approval of daratumumab combination therapy in
grade 1 or 2 in severity [12]. To reduce the risk of reactions, patients with newly diagnosed AL amyloidosis was based
patients should receive pre-medication (e.g. antihistamines, on data from the pivotal phase III ANDROMEDA trial, in
antipyretics and corticosteroids) and post-medication (e.g. which the addition of daratumumab to bortezomib, cyclo-
corticosteroids) [5, 6]. phosphamide and dexamethasone significantly improved
Daratumumab: A Review 689

the proportion of patients achieving a haematological active comparator (Sect. 4). Although IRRs and ISRs to
complete response (Sect. 3). Results of an updated anal- daratumumab were observed, these were of mild or moder-
ysis were generally consistent with that of the primary ate severity, typically occurred during the first infusion, and
analysis (Sect. 3.1). It should be noted that the primary may be mitigated with the use of pre- and post-medication
endpoint of haematological complete response used in (Sect. 4.1).
ANDROMEDA was a study-specific endpoint. However, In conclusion, daratumumab is an effective addition
the superiority of daratumumab combination therapy to bortezomib, cyclophosphamide and dexamethasone
was also evident for haematological complete response in patients with newly diagnosed systemic AL amyloi-
defined according to ISA criteria (Sect. 3). This is impor- dosis, with an acceptable tolerability profile. Therefore,
tant, given that the ISA response criteria are validated and daratumumab combination therapy represents an impor-
are widely used as surrogate endpoints in other studies of tant emerging first-line treatment option in this patient
AL amyloidosis [25]. population.
Organ dysfunction and damage are serious complica-
tions of systemic AL amyloidosis [4]. Daratumumab com-
bination therapy produced rapid and deep haematological Data Selection Daratumumab: 156 records
responses which were associated with improved major identified
organ deterioration PFS (Sect. 3). When this endpoint
was analysed without censoring for subsequent mainte- Duplicates removed 43
nance therapy, daratumumab combination therapy was still
Excluded during initial screening (e.g. press releases; 55
associated with prolonged major organ deterioration PFS news reports; not relevant drug/indication; preclinical
(Sect. 3). The addition of daratumumab was associated study; reviews; case reports; not randomized trial)
with near doubling of 6-month cardiac and renal response Excluded during writing (e.g. reviews; duplicate data; 33
rates (Sect. 3), a crucial finding considering that organ small patient number; nonrandomized/phase I/II trials)
response rates are an important predictor of improved sur- Cited efficacy/tolerability articles 13
vival [12].
Cited articles not efficacy/tolerability 12
Achievement of both haematological and organ
responses is expected to translate into improved OS in Search Strategy: EMBASE, MEDLINE and PubMed from 1946
to present. Clinical trial registries/databases and websites were
patients with systemic AL amyloidosis [3]. In ANDROM- also searched for relevant data. Key words were Daratumumab,
EDA, there were no differences in OS between daratu- Darzalex, light-chain amyloidosis, AL amyloidosis. Records were
mumab combination therapy and the active comparator limited to those in English language. Searches last updated 14
after a median of 11.4 months (Sect. 3). Longer follow- March 2022
up is needed to determine the effect of long-term dara-
tumumab therapy on OS [12] and its potential role in
patients with more severe cardiac or renal impairment.
When comparing long-term results, it is important to Supplementary Information The online version contains supplemen-
consider that in ANDROMEDA, daratumumab could be tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40265-0​ 22-0​ 1705-3.
continued for up to 2 years in the combination therapy
Acknowledgements During the peer review process, the manufacturer
group. Additional data are awaited with interest and will of daratumumab was also offered an opportunity to review this article.
be important in further elucidating the place of daratu- Changes resulting from comments received were made on the basis of
mumab in patients with systemic AL amyloidosis. scientific and editorial merit.
Daratumumab had an acceptable tolerability profile when
used in combination with bortezomib, cyclophosphamide Declarations
and dexamethasone (Sect. 4). The overall safety profile of
daratumumab combination therapy was consistent with the Funding The preparation of this review was not supported by any
external funding.
known safety profiles of the individual agents and with the
underlying disease. Daratumumab combination therapy was Authorship and Conflict of interest Hannah Blair is a salaried employee
well tolerated during the safety run-in phase of ANDROM- of Adis International Ltd/Springer Nature, and declares no relevant
EDA (Sect. 4), providing support for its use in the subse- conflicts of interest. All authors contributed to the review and are
responsible for the article content.
quent randomized portion of the trial [22]. When adjusted
for treatment exposure, daratumumab combination therapy Ethics approval, Consent to participate, Consent to publish, Availability
was associated with a lower incidence of AEs than with the of data and material, Code availability Not applicable.
690 H. A. Blair

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