On May 7, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the U.S. Food and Drug Administration (FDA) has approved DARZALEX (daratumumab) in combination with VELCADE (bortezomib)*, a proteasome inhibitor (PI); melphalan, an alkylating agent; and prednisone – VMP –for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) (Press release, Johnson & Johnson, MAY 7, 2018, View Source [SID1234526259]). DARZALEX is the first monoclonal antibody approved for newly diagnosed patients with this disease. Clinical trial results showed DARZALEX in combination with VMP reduced the risk of disease progression or death by 50 percent compared to treatment with VMP alone.

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"This approval is significant as we now have the first antibody-based regimen for treating newly diagnosed multiple
myeloma patients who are not eligible for a stem cell transplant," said Andrzej Jakubowiak, M.D., Ph.D., Director of
the Multiple Myeloma Program at University of Chicago Medical Center, Chicago, Illinois and a DARZALEX
clinical study investigator. "In clinical studies, patients who received treatment with daratumumab experienced a
lower risk of disease progression and higher rates of response."

The FDA approval of DARZALEX in combination with VMP is supported by data from the randomized, open-label,
multicenter Phase 3 ALCYONE (MMY3007) study, recently published in the New England Journal of Medicine.
The combination of DARZALEX with VMP reduced the risk of disease progression or death by 50 percent,
compared to treatment with VMP alone (Hazard Ratio [HR] = 0.50; 95 percent CI [0.38-0.65], p<0.0001).1 The
median progression-free survival (PFS) for DARZALEX-VMP had not yet been reached, compared to a median
PFS of 18.1 months for patients who received VMP alone.1

"A patient’s best chance at lasting remission often begins with a durable response to frontline therapy, because
multiple myeloma can become more difficult to treat after relapse," said Maria-Victoria Mateos, M.D., Ph.D.,
Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain and ALCYONE
primary investigator. "Combination therapy with daratumumab resulted in deep and durable responses in newly
diagnosed patients with multiple myeloma who are transplant ineligible, supporting this regimen as an important
new treatment option for these patients."

Treatment with DARZALEX in combination with VMP significantly improved overall response rates (91 vs. 74
percent) compared to VMP alone.
1 Additionally, measures of stringent complete response (18 vs. 7 percent),
complete response or better (43 vs. 24 percent) and very good partial response or better (71 vs. 50 percent) all
showed marked improvement.
1 Patients receiving DARZALEX in combination with VMP achieved a more than
three-fold increase in the minimal residual disease (MRD) negativity rate (22 vs. 6 percent) compared to those who
received VMP alone.1
In the ALYCONE study, the most frequent adverse reactions (>20 percent) with at least 5 percent greater
frequency in the DARZALEX
-VMP arm were upper respiratory tract infection (48 vs. 28 percent), infusion
reactions (28 vs. 0 percent) and peripheral edema (21 vs. 14 percent).1 Serious adverse reactions with at least a 2
percent greater incidence in the DARZALEX
-VMP arm vs. VMP were pneumonia (11 vs. 4 percent), upper
respiratory tract infection (5 vs.1 percent) and pulmonary edema (2 vs. 0 percent).1 The most common Grade 3/4
treatment-emergent hematology laboratory abnormalities for DARZALEX
-VMP vs. VMP were lymphopenia (58 vs.
53 percent), neutropenia (44 vs. 43 percent) and thrombocytopenia (38 vs. 42 percent).
1 The warnings and
precautions for DARZALEX include infusion reactions, interference with cross-matching and red blood cell
antibody screening, neutropenia and thrombocytopenia (see Important Safety Information).1
"Slowing the progression of myeloma translates to more time in remission for those battling the disease. This latest
approval for DARZALEX in combination with VMP is an exciting step forward for newly diagnosed patients and
the healthcare teams who treat them," said Paul Giusti, President and CEO of the Multiple Myeloma Research
Foundation (MMRF). "The MMRF congratulates Janssen, our long-time collaborator in myeloma research, the
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dedicated healthcare providers in the myeloma community as well as the patients who donate their time and data
on clinical trials, for making this critical new combination therapy possible."
Today’s FDA approval marks the fifth indication for DARZALEX
, the first CD38-directed antibody approved
anywhere in the world and the first antibody approved for newly diagnosed patients with multiple myeloma who are
transplant ineligible.
1 DARZALEX was first approved by the FDA in November 2015 as a monotherapy for
patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an
immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.2 DARZALEX
received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or
bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least
one prior therapy.3 In June 2017, DARZALEX received approval in combination with pomalidomide and
dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies,
including lenalidomide and a PI.4
"We are grateful to the patients and physicians who participated in the clinical program that enabled today’s
important approval of DARZALEX combination therapy as a treatment option for newly diagnosed patients with
multiple myeloma who are transplant ineligible," said Peter Lebowitz, M.D., Ph.D, Global Therapeutic Area Head,
Oncology, Janssen Research & Development, LLC. "DARZALEX has redefined how we approach the treatment
of multiple myeloma, and we continue to evaluate its potential in combination with other regimens, with the aim of
arresting the disease at its earliest stages."
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen
an exclusive license to develop, manufacture and commercialize DARZALEX
.
5 Janssen Biotech, Inc.
commercializes DARZALEX in the U.S. For full Prescribing Information, please visit www.DARZALEX.com.
About DARZALEX (daratumumab) Injection, for Intravenous Infusion
DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed antibody approved anywhere
in the world.1 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of
disease stage.6 DARZALEX is believed to induce tumor cell death through multiple immune-mediated
mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated
cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which
a series of molecular steps in a cell lead to its death.1 Subsets of myeloid derived suppressor cells (MDSCs),
CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by DARZALEX
.
1 DARZALEX is
being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple
myeloma, such as in frontline and relapsed settings.
7,8,9,10,11,12,13,14 Additional studies are ongoing or planned to
assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such
4
as smoldering myeloma, as well as in solid tumors.
15,16,17 DARZALEX is the first and only CD38-directed antibody
to receive regulatory approval to treat multiple myeloma.1
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the
bone marrow.18,19 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of
multiple myeloma, patients progress within 60 days of their last therapy.20,21 Relapsed cancer means the disease
has returned after a period of initial, partial or complete remission.22 In 2018, it is estimated that 30,700 people will
be diagnosed and 12,770 will die from the disease in the United States.23 While some patients with multiple
myeloma have no symptoms at all, most patients are diagnosed due to symptoms, which can include bone fracture
or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.24
IMPORTANT SAFETY INFORMATION1
CONTRAINDICATIONS – None
WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients
experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent
infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the
introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion.
Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema
and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion,
cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic
rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.
Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during
the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed.
Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3
reactions, reduce the infusion rate when re-starting the infusion.
To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following
DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional
post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting
bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.
5
Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in
a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin
test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks
detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh
blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and
inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting
DARZALEX.
Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood
cell counts periodically during treatment according to manufacturer’s prescribing information for background
therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to
allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with
growth factors.
Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor
complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for
background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction
of DARZALEX is recommended. Consider supportive care with transfusions.
Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal
antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE)
assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination
of complete response and of disease progression in some patients with IgG kappa myeloma protein.
Adverse Reactions –
In patients who received DARZALEX in combination with bortezomib, melphalan, and prednisone, the most
frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion
reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% greater compared to the VMP
arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment
emergent grade 3-4 hematology laboratory abnormalities ≥20% were thrombocytopenia (38%), neutropenia
(44%), and lymphopenia (58%).
In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently
reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper
respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle
spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse
6
reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%),
influenza (3%) and pyrexia (3%).
In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently
reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral
sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%),
cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions
was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial
fibrillation (2%).
In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions
(incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%),
nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%).
Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions
were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).
In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequent
adverse reactions (≥20%) were infusion reactions (50%), diarrhea (38%), constipation (33%), nausea (30%),
vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%),
back pain (25%), arthralgia (22%), dizziness (21%), insomnia (23%), cough (43%) and dyspnea (33%). The
overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients
included pneumonia (7%).
DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with
DARZALEX did not affect the pharmacokinetics of daratumumab.
Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib or pomalidomide
did not affect the pharmacokinetics of bortezomib.