Schmidt-Wolf et al (2014)
reviewed the development in the treatment of relapsed/refractory multiple
myeloma (MM) during the past 10 years. The present standard-of-care in
progressive or refractory MM was elaborated by the Working Group "Refractory
Multiple Myeloma" using an extensive literature search for studies published
between 2003 and 2013. Outside of clinical trials, high-dose chemo-therapy
(HDCT) with stem cell transplantation (SCT) is recommended in physically fit
patients (up to 75 years of age) without significant co-morbidities. Ongoing
studies address the question regarding the least toxic and the most effective
treatment; thus, inclusion of patients in therapeutic trials and use of novel
agent combinations is highly recommended (e.g., with 3rd generation
immunomodulatory drugs [Pomalidomide], new proteasome inhibitors [PIs] such as
Carfilzomib, Ixazomib or Oprozomib, antibodies, such as Elotuzumab, Daratumumab
or SAR650984, Siltuximab, Tabalumab, Denosumab, Romosozumab, Bruton`s tyrosine
kinase [BTK]-, heat shock protein [HSP]-inhibitors and other innovative agents).
El-Amm and Tabbara (2015)
stated that the treatment of MM has evolved significantly over the past 2
decades as a consequence of the use of HDCT and autologous SCT, and the
subsequent introduction of the immunomodulatory agents (thalidomide and
Lenalidomide) and the PI (Bortezomib). The median overall survival (OS) of MM
patients has increased significantly with patients younger than 50 years of age
experiencing a 10-year survival rate of approximately 40 %. However, despite
the increased effectiveness of the 1st-line agents, the majority of patients
will eventually relapse and become drug-resistant. Promising novel therapies
have recently emerged and are being used to treat relapsed and refractory
patients. These researchers examined the clinical data regarding these emerging
therapies that include new generation of PIs (e.g., Carfilzomib, Ixazomib,
Oprozomib, and Marizomib), immunomodulatory drugs (Pomalidomide), monoclonal
antibodies (mAbs) (Elotuzumab and Daratumumab), signal transduction modulator
(Perifosine), and histone deacetylase inhibitors (Vorinostat and Panobinostat).
Daratumumab is an IgG1κ human mAb that binds to cluster of differentiation 38
(CD38; also known as cyclic ADP ribose hydrolase) and inhibits the growth of
CD38-expressing tumor cells by inducing apoptosis directly through Fc-mediated
cross-linking as well as by immune-mediated tumor cell lysis through complement
dependent cytotoxicity, antibody dependent cell mediated cytotoxicity, and
antibody dependent cellular phagocytosis. Myeloid derived suppressor cells and
a subset of regulatory T cells (CD38+Tregs) express CD38 and are susceptible to
Daratumumab-mediated cell lysis.
In a phase I/II clinical
trial, Lokhorst et al (2015) examined the safety and effectiveness of
Daratumumab in patients with relapsed MM or relapsed MM that was refractory to 2
or more prior lines of therapy. In part 1, the dose-escalation phase, these
researchers administered Daratumumab at doses of 0.005 to 24 mg/kg body weight.
In part 2, the dose-expansion phase, 30 patients received 8 mg/kg of Daratumumab
and 42 received 16 mg/kg, administered once-weekly (8 doses), twice-monthly (8
doses), and monthly for up to 24 months. End-points included safety,
effectiveness, and pharmacokinetics. No maximum tolerated dose (MTD) was
identified in part 1; in part 2, the median time since diagnosis was 5.7 years.
Patients had received a median of 4 prior treatments; 79 % of the patients had
disease that was refractory to the last therapy received (64 % had disease
refractory to PIs and immunomodulatory drugs and 64 % had disease refractory to
Bortezomib and Lenalidomide), and 76 % had received autologous SCT.
Infusion-related reactions in part 2 were mild (71 % of patients had an event of
any grade, and 1 % had an event of grade 3), with no dose-dependent adverse
events. The most common adverse events of grade 3 or 4 (in greater than or
equal to 5 % of patients) were pneumonia and thrombocytopenia. The overall
response rate (ORR) was 36 % (95 % confidence interval [CI]: 21.6 % to 52.0 %)
in the cohort that received 16 mg/kg (15 patients had a partial response [PR] or
better, including 2 with a complete response [CR] and 2 with a very good PR
[VGPR]) and 10 % in the cohort that received 8 mg/kg (3 had a PR). In the
cohort that received 16 mg/kg, the median progression-free survival (PFS) was
5.6 months (95 % CI: 4.2 to 8.1), and 65 % (95 % CI: 28 to 86) of the patients
who had a response did not have progression at 12 months. The authors concluded
that Daratumumab monotherapy had a favorable safety profile and encouraging
efficacy in patients with heavily pre-treated and refractory MM.
Lonial et al (2015)
reported the findings of an open-label trial evaluating Daratumumab monotherapy
in patients with relapsed or refractory MM who had received at least 3 prior
lines of therapy including a PI and an immunomodulatory agent or who were
double-refractory to a PI and an immunomodulatory agent. In 106 patients,
Daratumumab 16 mg/kg was administered with pre- and post-infusion medication.
Treatment continued until unacceptable toxicity or disease progression. The
median patient age was 63.5 years (range of 31 to 84 years), 49 % were male, and
79 % were Caucasian. Patients had received a median of 5 prior lines of
therapy; 80 % of patients had received prior autologous SCT. Prior therapies
included Bortezomib (99 %), Lenalidomide (99 %), Pomalidomide (63 %), and
carfilzomib (50 %). At baseline, 97 % of patients were refractory to the last
line of treatment, 95 % were refractory to both, a PI and an immunomodulatory
agent, and 77 % were refractory to alkylating agents. Efficacy results were
based on ORR as determined by the Independent Review Committee assessment using
the International Myeloma Working Group (IMWG) criteria. Overall response rate
was 29.2 % (2.8 % stringent CR [sCR], 0 % CR, 9.4 % VGPR, and 10 % PR) (95 % CI:
20.8 % to 38.9 %). The median time to response was 1 month (range of 0.9 to 5.6
months). The median duration of response was 7.4 months (range of 1.2 to 13.1+
November 16, 2015, the Food and Drug Administration (FDA) approved Daratumumab
(Darzalex) for the treatment of patients with MM who have received at least 3
prior treatments. The safety and effectiveness of Darzalex were reported in 2
open-label studies (Lokhorst et al, 2015 and Lonial et al, 2015). This
indication was approved under accelerated approval based on response rate.
Continued approval for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trials. The most common side
effects of Darzalex were back pain, cough, fatigue, fever, nausea and
infusion-related reactions. Darzalex may also result in anemia, leukopenia,
lymphopenia, neutropenia, as well as thrombocytopenia.
The warnings and
precautions for Darzalex include infusion reactions, interference with
serological testing and interference with determination of complete response.
The most frequently reported adverse reactions (incidence ≥20%) were: fatigue,
nausea, back pain, pyrexia, cough and upper respiratory tract infection.
In data from three pooled
clinical studies including a total of 156 patients, four percent of patients
discontinued treatment due to adverse reactions. Infusion reactions were
reported in approximately half of all patients treated with Darzalex. Common (≥5
percent) symptoms of infusion reactions included nasal congestion, chills,
cough, allergic rhinitis, throat irritation, dyspnea (shortness of breath) and
nausea, severe infusion reactions including bronchospasm, dyspnea, hypoxia and
hypertension (<2 percent each).
Darzalex (Daratumumab) has
not been evaluated in patients with moderate to severe hepatic impairment. Mild
hepatic impairment and renal impairment do not require dosage adjustments.
Darzalex (Daratumumab) can
cause severe infusion reactions. Most reactions occur during the first
administration. Darzalex (Daratumumab) should be administered with pre‐infusion
medications including intravenous corticosteroids, oral antipyretics, and an
oral or intravenous antihistamine. An oral corticosteroid should be administered
Prophylaxis for herpes zoster reaction should be initiated.
Safety and efficacy in pediatric patients has not been established.
Safety and efficacy in
pregnancy has not been established.
There is no information
regarding the presence of Daratumumab in human milk, the effects on the
breastfed infant, or the effects on milk production.
Guidelines on multiple
myeloma from the National Comprehensive Cancer Network (NCCN, 2016) recommend
Daratumumab for the treatment of patients who have received at least three prior
therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent
or who are double refractory to a PI and immunomodulatory agent.
Overdijk and colleagues
(2015) examined the contribution of antibody-dependent, macrophage-mediated
phagocytosis to Daratumumab`s mechanism of action. Live cell imaging revealed
that Daratumumab efficiently induced macrophage-mediated phagocytosis, in which
individual macrophages rapidly and sequentially engulfed multiple tumor cells.
Using a range of MM and Burkitt`s lymphoma cell lines, Daratumumab-dependent
phagocytosis by mouse and human macrophages was also observed in an in-vitro
flow cytometry assay. Phagocytosis contributed to Daratumumab`s anti-tumor
activity in-vivo, in both a subcutaneous and an intravenous leukemic xenograft
mouse model. Furthermore, Daratumumab was shown to induce macrophage-mediated
phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable
levels of CD38 expression. The authors concluded that they showed that
phagocytosis is a fast, potent and clinically relevant mechanism of action that
may contribute to the therapeutic activity of Daratumumab in MM and potentially
other hematological tumors.
Wang et al (2015) stated
that no standard chemotherapeutic regimens have been defined yet for extra-nodal
natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with
advanced or relapsed disease is very poor. Daratumumab has been of great
interest in the treatment of CD38-expressing malignancies, especially MM. In
this study, these investigators reviewed the clinical data of 94 patients with
ENKTL, investigated the expression of CD38, and analyzed the prognostic value of
CD38 expression; 47 patients had weak expression of CD38, and the other 47
patients had strong expression. The CR rate was significantly higher in
patients who were treated with Asparaginase-based therapy (83.8 % versus 59.6 %,
p = 0.025). There was a trend towards higher CR rate in CD38 weak expression
group (78.7 % versus 59.6 %, p = 0.074). At a median follow-up time of 42
months, the 2-year and 5-year PFS rates were 53.0 % and 39.0 %, respectively,
and the 2-year and 5-year OS rates were 68.0 % and 58.0 %, respectively. In
multi-variate survival analysis including CD38 expression status, International
Prognostic Index (IPI) score, local tumor invasion, and chemotherapeutic
regimens, it was found that strong expression of CD38 and non-Asparaginase-based
chemo-regimens were independent adverse prognostic factors for PFS (p = 0.009
and 0.027, respectively), while local tumor invasion and higher IPI score were
independent adverse prognostic factors for OS (p = 0.002 and 0.035,
respectively). In subgroup analysis, strong expression of CD38 significantly
correlated with inferior survival outcomes in patients without local tumor
invasion (p = 0.011) or with stage I-II disease (p = 0.008). The authors
concluded that they found that the majority of ENKTL cases were CD38-positive,
with 50 % had strong expression of CD38, which significantly correlated with
poor outcomes, indicating the potential role of CD38 as a therapy target for
is also being investigated for use in (i) relapsed/refractory mantle cell
lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, and (ii)
phase II clinical trial on “An Efficacy and Safety Proof of Concept Study of
Daratumumab in Relapsed/Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell
Lymphoma, and Follicular Lymphoma” is currently recruiting participants (last
verified December 2015).
Smoldering Multiple Myeloma
phase II clinical trial on “A Study to Evaluate 3 Dose Schedules of Daratumumab
in Participants With Smoldering Multiple Myeloma” is currently recruiting
participants (last verified December 2015).