CLINICAL NEWS
treatment of young, fit patients,
about the new format and what
attendees can expect to take away
from the conversation.
How does this new session format differ
from previous annual meetings?
Typically, there are three didactic talks,
each about 20 to 25 minutes, in which a
speaker explains the new diagnostic tools or
methodology and therapeutic approaches in
a certain disease topic. This year, we wanted
to try something different; we wanted the
session to mirror the daily life of a clinician
who, when presented with a challenging
patient scenario, weighs the pros and cons
of a certain approach.
In this particular session, we will
present a case and two expert speakers
will walk us through their decision-
making process. They will present the
data supporting a certain treatment
approach sequentially – based on
how they would ask themselves these
questions in real-world practice. As
the moderator and as a clinician in
private practice (not a clinical trialist
or academic researcher), my job is to
speak for the audience. I’ll challenge the
speakers when they agree and, when
they disagree, try to uncover why their
recommendations differ.
It will be a somewhat freewheeling
REVLIMID [lenalidomide] capsules, for oral use
SPM, including squamous cell carcinoma and basal cell carcinoma,
occurred in 3.1% of patients receiving REVLIMID/dexamethasone,
compared to 0.6% in the dexamethasone alone arm.
Patients who received REVLIMID-containing therapy until disease
progression did not show a higher incidence of invasive SPM than
patients treated in the fixed duration REVLIMID-containing arms. Monitor
patients for the development of second primary malignancies. Take into
account both the potential benefit of REVLIMID and the risk of second
primary malignancies when considering treatment with REVLIMID.
5.7 Increased Mortality in Patients with MM When Pembrolizumab Is
Added to a Thalidomide Analogue and Dexamethasone
In two randomized clinical trials in patients with MM, the addition of
pembrolizumab to a thalidomide analogue plus dexamethasone, a use
for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in
increased mortality. Treatment of patients with MM with a PD-1 or PD-L1
blocking antibody in combination with a thalidomide analogue plus
dexamethasone is not recommended outside of controlled clinical trials.
5.8 Hepatotoxicity
Hepatic failure, including fatal cases, has occurred in patients treated with
lenalidomide in combination with dexamethasone. In clinical trials, 15%
of patients experienced hepatotoxicity (with hepatocellular, cholestatic
and mixed characteristics); 2% of patients with multiple myeloma and 1%
of patients with myelodysplasia had serious hepatotoxicity events. The
mechanism of drug-induced hepatotoxicity is unknown. Pre-existing
viral liver disease, elevated baseline liver enzymes, and concomitant
medications may be risk factors. Monitor liver enzymes periodically. Stop
REVLIMID upon elevation of liver enzymes. After return to baseline values,
treatment at a lower dose may be considered.
5.9 Severe Cutaneous Reactions Including Hypersensitivity Reactions
Angioedema and severe cutaneous reactions including Stevens-Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction
with eosinophilia and systemic symptoms (DRESS) have been reported.
DRESS may present with a cutaneous reaction (such as rash or exfoliative
dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic
complications such as hepatitis, nephritis, pneumonitis, myocarditis,
and/or pericarditis. These events can be fatal. Patients with a prior
history of Grade 4 rash associated with thalidomide treatment should not
receive REVLIMID. REVLIMID interruption or discontinuation should be
considered for Grade 2-3 skin rash. REVLIMID must be discontinued for
angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or
DRESS is suspected and should not be resumed following discontinuation
for these reactions.
5.10 Tumor Lysis Syndrome
Fatal instances of tumor lysis syndrome have been reported during
treatment with lenalidomide. The patients at risk of tumor lysis syndrome
are those with high tumor burden prior to treatment. These patients
should be monitored closely and appropriate precautions taken.
5.11 Tumor Flare Reaction
Tumor flare reaction has occurred during investigational use of
lenalidomide for CLL and lymphoma, and is characterized by tender
lymph node swelling, low grade fever, pain and rash. REVLIMID is not
indicated and not recommended for use in CLL outside of controlled
clinical trials.
Monitoring and evaluation for tumor flare reaction (TFR) is recommended
in patients with MCL. Tumor flare reaction may mimic progression of
disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR;
all reports were Grade 1 or 2 in severity. All of the events occurred in
cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide
may be continued in patients with Grade 1 and 2 TFR without interruption
or modification, at the physician’s discretion. Patients with Grade 1
and 2 TFR may also be treated with corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs) and/or narcotic analgesics for management
of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended
to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.
Patients with Grade 3 or 4 TFR may be treated for management of
symptoms per the guidance for treatment of Grade 1 and 2 TFR.
5.12 Impaired Stem Cell Mobilization
A decrease in the number of CD34+ cells collected after treatment
(> 4 cycles) with REVLIMID has been reported. In patients who are ASCT
candidates, referral to a transplant center should occur early in treatment
to optimize the timing of the stem cell collection. In patients who
received more than 4 cycles of a REVLIMID-containing treatment or for
whom inadequate numbers of CD 34+ cells have been collected with
G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF
with a CXCR4 inhibitor may be considered.
5.13 Thyroid Disorders
Both hypothyroidism and hyperthyroidism have been reported [see
Adverse Reactions (6.2)]. Measure thyroid function before start of
REVLIMID treatment and during therapy.
5.14 Early Mortality in Patients with MCL
In another MCL study, there was an increase in early deaths (within
20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm.
On exploratory multivariate analysis, risk factors for early deaths include
high tumor burden, MIPI score at diagnosis, and high WBC at baseline
(≥10 x 10 9 /L).
6 ADVERSE REACTIONS
The following adverse reactions are described in detail in other sections
of the prescribing information:
• Embryo-Fetal Toxicity [see Boxed Warning, Warnings and
Precautions (5.1, 5.2)]
• Hematologic Toxicity [see Boxed Warning, Warnings and
Precautions (5.3)]
• Venous and Arterial Thromboembolism [see Boxed Warning,
Warnings and Precautions (5.4)]
• Increased Mortality in Patients with CLL [see Warnings and
Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Increased Mortality in Patients with MM When Pembrolizumab Is
Added to a Thalidomide Analogue and Dexamethasone [see
Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Severe Cutaneous Reactions Including Hypersensitivity Reactions
[see Warnings and Precautions (5.9)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.10)]
• Tumor Flare Reactions [see Warnings and Precautions (5.11)]
• Impaired Stem Cell Mobilization [see Warnings and Precautions
(5.12)]
• Thyroid Disorders [see Warnings and Precautions (5.13)]
• Early Mortality in Patients with MCL [see Warnings and Precautions
(5.14)].
6.1 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.
Newly Diagnosed MM - REVLIMID Maintenance Therapy Following
Auto-HSCT:
Data were evaluated from 1018 patients in two randomized trials who
received at least one dose of REVLIMID 10 mg daily as maintenance
therapy after auto-HSCT until progressive disease or unacceptable
toxicity. The mean treatment duration for REVLIMID treatment was
30.3 months for Maintenance Study 1 and 24.0 months for Maintenance
Study 2 (overall range across both studies from 0.1 to 108 months). As
of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance
Study 1 REVLIMID arm were still on treatment and none of the patients
in the Maintenance Study 2 REVLIMID arm were still on treatment at the
same cut-off date
The adverse reactions listed from Maintenance Study 1 included events
reported post-transplant (completion of high-dose melphalan /auto-
HSCT), and the maintenance treatment period. In Maintenance Study 2,
the adverse reactions were from the maintenance treatment period only.
In general, the most frequently reported adverse reactions (more than
20% in the REVLIMID arm) across both studies were neutropenia,
thrombocytopenia, leukopenia, anemia, upper respiratory tract infection,
bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash,
fatigue, asthenia, muscle spasm and pyrexia. The most frequently
reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm)
included neutropenia, thrombocytopenia, and leukopenia. The serious
adverse reactions lung infection and neutropenia (more than 4.5%)
occurred in the REVLIMID arm.
For REVLIMID, the most common adverse reactions leading to dose
interruption were hematologic events (29.7%, data available in
Maintenance Study 2 only). The most common adverse reaction leading
to dose reduction of REVLIMID were hematologic events (17.7%,
data available in Maintenance Study 2 only). The most common
adverse reactions leading to discontinuation of REVLIMID were
thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia
(2.4%) in Maintenance Study 2.
The frequencies of onset of adverse reactions were generally highest in
the first 6 months of treatment and then the frequencies decreased over
time or remained stable throughout treatment.
Table 5 summarizes the adverse reactions reported for the REVLIMID and
placebo maintenance treatment arms.
conversation about the patient case that at-
tendees can listen in on. There won’t be the
usual three separate talks at a podium – just
three clinicians sitting together as they talk
about how they decide to treat a patient.
In this scenario of a young, fit person
with myeloma, what do you expect the
greatest areas of disagreement will be?
Obviously, there are many recently ap-
proved therapeutic options for induction,