On Location 2018 ASH Annual Meeting
Good News on the HORIZON: Melflufen Induces
Response in Heavily Refractory Myeloma
One-third of patients with relapsed/
refractory multiple myeloma (MM) that
was refractory to pomalidomide and/or
daratumumab responded to treatment
with melflufen, according to interim
data from the phase II HORIZON trial.
Paul Richardson, MD, from the Dana-
Farber Cancer Institute in Boston,
presented the results at the 2018 ASH
Annual meeting.
“Melflufen is a first-in-class drug that
is activated by aminopeptidases, which
are overexpressed in multiple cancers,
including myeloma,” T:7.75"
Dr. Richardson ex-
plained, adding that aminopeptidases play
S:7" cell prolifera-
a key role in DNA repair,
tion, programmed cell death, and tumor
angiogenesis.
WARNING: CAPILLARY LEAK SYNDROME
Capillary Leak Syndrome (CLS), which may be life-threatening or fatal if not properly
managed, can occur in patients receiving ELZONRIS. Monitor for signs and symptoms of
CLS and take actions as recommended [see Warnings and Precautions].
INDICATIONS AND USAGE
ELZONRIS™ is a CD123-directed cytotoxin for the treatment of blastic plasmacytoid
dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Capillary Leak Syndrome
Capillary leak syndrome (CLS), including life-threatening and fatal cases, has been
reported among patients treated with ELZONRIS. In patients receiving ELZONRIS in
clinical trials, the overall incidence of CLS was 55% (52/94), including Grade 1 or 2
in 46% (43/94), Grade 3 in 6% (6/94), Grade 4 in 1% (1/94) and 2 fatal events (2/94,
2%). Common signs and symptoms (incidence ≥ 20%) associated with CLS that were
reported during treatment with ELZONRIS include hypoalbuminemia, edema, weight
gain, and hypotension.
Before initiating therapy with ELZONRIS, ensure that the patient has adequate cardiac
function and serum albumin is greater than or equal to 3.2 g/dL. During treatment
with ELZONRIS, monitor serum albumin levels prior to the initiation of each dose of
ELZONRIS and as indicated clinically thereafter, and assess patients for other signs
or symptoms of CLS, including weight gain, new onset or worsening edema, including
pulmonary edema, and hypotension or hemodynamic instability. See table below for
CLS management guidelines.
CLS Management Guidelines
Time of
Presentation
Prior to first
dose of
ELZONRIS in
cycle 1
CLS
Sign/Symptom
ELZONRIS
Dosing
Management
Serum albumin
< 3.2 g/dL Administer ELZONRIS when serum albumin
≥ 3.2 g/dL.
Serum albumin
< 3.5 g/dL
Serum albumin
reduced by
≥ 0.5 g/dL from
the albumin value
measured prior to
ELZONRIS dosing
initiation of the
current cycle Administer 25g intravenous
albumin (q12h or more
frequently as practical)
until serum albumin is
≥ 3.5 g/dL AND not more
than 0.5 g/dL lower than
the value measured prior
to dosing initiation of the
current cycle.
A predose body
weight that is
increased by
≥ 1.5 kg over the
previous day’s
predose weight
During
ELZONRIS
dosing
Edema, fluid
overload and/or
hypotension
1
Recommended
Action
Administer 25g intravenous
albumin (q12h or more
frequently as practical),
and manage fluid status
as indicated clinically (e.g.,
generally with intravenous
fluids and vasopressors
if hypotensive and with
diuretics if normotensive
or hypertensive), until
body weight increase has
resolved (i.e. the increase
is no longer ≥ 1.5 kg greater
than the previous day’s
predose weight).
Administer 25g intravenous
albumin (q12h, or more
frequently as practical) until
serum albumin is ≥ 3.5 g/dL.
Administer 1 mg/kg
of methylprednisolone
(or an equivalent) per day,
until resolution of CLS
sign/symptom or as
indicated clinically.
Aggressive management
of fluid status and
hypotension if present,
which could include
intravenous fluids and/
or diuretics or other blood
pressure management,
until resolution of CLS
sign/symptom or as
clinically indicated.
The new agent is designed to overcome
resistance pathways of existing MM treat-
ments, making it a promising therapy
for patients with relapsed and refractory
disease, the authors noted, citing earlier
phase I/II results in which melflufen was
associated with an overall response rate
(ORR) of 31 percent and a progression-free
survival (PFS) of 5.7 months.
In the present study, an open-label,
phase II trial, researchers evaluated the
Hypersensitivity Reactions
ELZONRIS can cause severe hypersensitivity reactions. In patients receiving
ELZONRIS in clinical trials, hypersensitivity reactions were reported in 46% (43/94)
of patients treated with ELZONRIS and were Grade ≥ 3 in 10% (9/94). Manifestations
of hypersensitivity reported in ≥ 5% of patients include rash, pruritus, stomatitis,
and wheezing. Monitor patients for hypersensitivity reactions during treatment with
ELZONRIS. Interrupt ELZONRIS infusion and provide supportive care as needed if a
hypersensitivity reaction should occur.
Hepatotoxicity
Treatment with ELZONRIS was associated with elevations in liver enzymes. In patients
receiving ELZONRIS in clinical trials, elevations in liver enzymes occurred in 88%
(83/94) of patients, including Grade 1 or 2 in 48% (45/94), Grade 3 in 36% (34/94),
and Grade 4 in 4% (4/94). Monitor alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) prior to each infusion with ELZONRIS. Withhold ELZONRIS
temporarily if the transaminases rise to greater than 5 times the upper limit of normal
and resume treatment upon normalization or when resolved.
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 30%) are capillary leak syndrome,
nausea, fatigue, peripheral edema, pyrexia and weight increase. Most common
laboratory abnormalities (incidence ≥ 50%) are decreases in albumin, platelets,
hemoglobin, calcium, and sodium, and increases in glucose, ALT and AST.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates observed in practice.
Safety of ELZONRIS was assessed in a single-arm clinical trial that included 94 adults
with newly diagnosed or relapsed/refractory myeloid malignancies, including 58 with
BPDCN, treated with ELZONRIS 12 mcg/kg daily for 5 days of a 21-day cycle. The
overall median number of cycles administered was 2 (range, 1-43), and 4 in patients
with BPDCN (range, 1-43). Two (2%) patients had fatal adverse reaction, both capillary
leak syndrome. Overall, 10 (11%) patients discontinued treatment with ELZONRIS due
to an adverse reaction; the most common adverse reactions resulting in treatment
discontinuation were hepatic toxicities and CLS.
Table below summarizes the common (≥ 10%) adverse reactions with ELZONRIS in
patients with myeloid malignancies. The rate of any given adverse reaction or lab
abnormality was derived from all the reported events of that type.
Adverse Reactions in ≥ 10% of Patients Receiving 12 mcg/kg of ELZONRIS
N=94
All Grades
% Grade ≥ 3
%
Capillary leak syndrome 1 55 9
Hypotension 29 9
Hypertension 15 6
Nausea 49 0
Constipation 23 0
Vomiting 21 0
Diarrhea 20 0
Vascular Disorders
Gastrointestinal disorders
Interrupt
ELZONRIS
dosing until the
relevant CLS
sign/symptom
has resolved 1 .
ELZONRIS administration may resume in the same cycle if all CLS signs/symptoms have resolved and the
patient did not require measures to treat hemodynamic instability. ELZONRIS administration should be held
for the remainder of the cycle if CLS signs/symptoms have not resolved or the patient required measures to
treat hemodynamic instability (e.g., required administration of intravenous fluids and/or vasopressors to treat
hypotension) (even if resolved), and ELZONRIS administration may only resume in the next cycle if all CLS signs/
symptoms have resolved, and the patient is hemodynamically stable.
General disorders and administration
site conditions
Fatigue 45 7
Peripheral edema 43 1
Pyrexia 43 0
Chills 29 1
31 0
Headache 29 0
Dizziness 20 0
24 0
20 18
Back pain 20 2
Pain in extremity 10 2
Investigations
Weight increase
Nervous system disorders
Metabolism and nutrition disorders
Decreased appetite
Blood and lymphatic system disorders
Febrile neutropenia
Musculoskeletal and connective
tissue disorders