Introduction
Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy worldwide,
with more than 700,000 cases per year in the United States.
1
Cemiplimab, a programmed cell death (PD)-1 inhibitor, was approved by the US Food
and Drug Administration in 2018 as the first drug specifically to treat patients with
locally advanced or metastatic cSCC who are not candidates for curative surgery or
curative radiation. Phase 1 (n = 26) and phase 2 (n = 59) open-label, multicenter
clinical trials showed a 50% overall response rate in advanced cSCC, with median duration
of response exceeding 6 months.
2
However, these studies excluded participants with comorbid conditions affecting the
immune system such as multiple myeloma (MM). Because MM patients have 2.44 times higher
incidence of cSCC than patients without MM,
3
exploring the potential benefits and risks of PD-1 inhibitors for advanced cSCC in
MM patients is clinically important. The effectiveness and safety of PD-1 inhibitors
for cSCC in patients with MM is not well known, and it is possible that T-cell responses
necessary for PD-1 inhibitor effectiveness are not sufficient in MM patients. Here
we report a case of clinically complete response of metastatic cSCC on cemiplimab
in a patient with known MM.
Case report
A man in his 60s with a 16-year history of IgG MM managed with multiple medications
presented to the dermatology clinic with a forehead lesion found by biopsy to be a
desmoplastic cSCC with perineural and subcutaneous invasion. The patient's MM had
previously involved his pelvic bone and had been treated with radiation, then revlimid
with dexamethasone 12 years ago, with resolution of his M spike and normalization
of activity on positron emission tomography/computed tomography (PET-CT) imaging (Fig
1, A). His MM remained quiescent until 2 years before presentation, when his κ-free
light chain levels started to increase, and he was started on combination therapy
consisting of daratumumab and dexamethasone with improvement.
Fig 1
PET-CT scans of the case patient. A, Patient with multiple areas of MM involvement
prior to his cSCC diagnosis. B, Seven months after the previous PET-CT in (A), new
areas of uptake in the preauricular region and lungs (blue arrows) were detected,
indicative of metastatic cSCC. C, Three month after starting cemiplimab, PET-CT found
clinically complete response of preauricular and pulmonary cSCCs, with sustained response
12 months after cemiplimab start.
Because the patient had high-risk cSCC, magnetic resonance imaging of the orbits was
performed, which did not show any perineural spread or osseous invasion. The patient
underwent Mohs micrographic surgery with plan for local adjuvant radiation. However,
during radiation planning, computed tomography (CT) imaging showed 10 pulmonary nodules
in the lungs, with CT-guided biopsy of a 9-mm nodule in the right lower lung confirming
metastatic cSCC. PET-CT at this time also found new hypermetabolic preauricular lymphadenopathy
(Fig 1, B).
Although the effects of cemiplimab are not known in cSCC patients with MM, multidisciplinary
consultation including medical oncology and hematology suggested no clear contraindication.
Of note, the patient's medical history from 3 years prior included 2 brief mild elevations
of aspartate aminotransferase (AST) (with the highest to 76 U/L) and alanine aminotransferase
(ALT) (to 128 U/L), which were felt to not be clinically significant as they had spontaneously
resolved before cemiplimab initiation. However, at the time of cemiplimab initiation,
the patient did have persistent mild elevation of alkaline phosphatase (ALP) (with
highest value to 272 U/L), thought to be caused by his MM.
The patient was started on cemiplimab, 350 mg intravenously every 3 weeks. A PET-CT
3 months, 6 months, and 12 months after cemiplimab initiation found clinical complete
resolution of both the lung nodules and the preauricular lymphadenopathy (Fig 1, C).
He reported no side effects from the cemiplimab.
However, 3 months after cemiplimab initiation, moderate elevations of AST (to peak
126 U/L), and ALT (to peak 69 U/L) became more persistent, and ALP levels increased
(to peak 1,003 U/L), with γ-glutamyl transpeptidase elevation confirming the liver
source of the ALP. During this time, concomitant medications that could contribute
to hepatotoxicity including fluconazole and ampicillin were discontinued, with partial
improvements in the liver function tests. Liver ultrasound scan found cirrhosis; esophagogastroduodenoscopy
with portal hypertensive gastropathy supported this diagnosis. The hepatologist felt
the cirrhosis was chronic and caused by alcoholic steatohepatitis (from a 20-year
history of alcohol usage) and nonalcoholic steatohepatitis (from MM and mitral stenosis).
Cemiplimab was discontinued 1 year after initiation with normalization of his AST
and ALT, suggesting a mild component of immune-related hepatitis. ALP improved to
368 U/L.
Eleven months after starting cemiplimab, the patient had an increasing M spike and
worsening anemia, and carfilzomib was added to daratumumab and dexamethasone for his
MM, with improvement in laboratory parameters. Unfortunately, the patient died about
15 months after starting cemiplimab from multiorgan failure in the setting of liver
cirrhosis, which contributed to anasarca with pleural effusions and hepatorenal syndrome
with kidney failure.
Discussion
This case is instructive in that the MM patient's duration of response for metastatic
cSCC exceeded the meaningful duration of response (105 days) as defined in previous
trials for cemiplimab.
1
To date, there is a paucity of systematic studies on the effectiveness of PD-1 inhibition
in cSCC patients with altered immune systems, and it is unclear which patients with
immunodeficiency can respond to PD-1 inhibition. Our case indicates that a durable
response is possible in MM.
Despite the effectiveness of PD-1 inhibitors against several types of solid cancers,
including cSCC, the utility of this drug class against hematologic neoplasms is less
clear (except for treatment of classic Hodgkin lymphoma).4, 5, 6, 7, 8, 9 Although
our patient had a clinical response of cSCC to cemiplimab, he did experience eventual
progression of his MM with increase in M spike 11 months after starting PD-1 inhibition,
necessitating addition of carfilzomib to his MM treatment regimen.
It is unclear whether the PD-1 inhibition played a significant role in accelerating
his hepatic cirrhosis or progression of his MM. Hepatitis is a well-known immune-related
adverse event from PD-1 inhibitors, and the presence of MM can make the detection
of PD-1 inhibitor–related hepatitis more challenging, as both can lead to abnormalities
in liver function tests. Although our case showed therapeutic benefit of PD-1 inhibition
against cSCC, additional systematic studies are needed to assess the risks and benefits
of treating advanced cSCC with PD-1 inhibition in MM patients, and the effect of PD-1
inhibition on the course of MM.