To the editor.
Ixazomib is an orally available proteasome inhibitor, which leads to cell growth arrest
and apoptosis via interfering with protein degradation.1 An analysis of the safety
and tolerability of ixazomib, in combination with lenalidomide (Revlimid) and dexamethasone
(IRd) for multiple myeloma, illustrated that cutaneous and subcutaneous adverse events
were the most common cause of dose reduction.2 Furthermore, there have been case reports
of Ixazomib-induced cutaneous necrotizing vasculitis. Here, we report the case of
a 70-year-old male patient with IgM multiple myeloma who developed a rash after ixazomib
treatment and developed into skin exfoliation after adding lenalidomide.
He was diagnosed with IgM-κ MM in October 2020 with complaints of waist pain. The
initial workup revealed multiple bone destructions in the thoracolumbar vertebrae
and appendages, bilateral ribs, and shoulder blades. Peripheral blood showed hemoglobin
of 121 g/L, platelets of 131×109/L, white blood cell count of 5.49×109/L, serum creatinine
of 96 μmol/L, and serum calcium of 2.78 mmol/L. Serum protein electrophoresis and
immunofixation showed an IgM-kappa monoclonal protein (Figure 1A) with an M protein
of 70.6 g/L. Serum kappa-light chain levels were elevated (1261 mg/L), and the kappa/lambda
ratio was 157.3267. Urinary kappa light chains were 4225 mg/L, compared with lambda
light chains of 5.9 mg/L. A bone marrow aspirate confirmed the presence of 60% plasma
cells and a normal karyotype, 46, XY. Fluorescence in situ hybridization (FISH) analysis
of the specimen showed immunoglobulin heavy chain (IGH) translocations t(11;14), del(17p),
and 1q21 gain/amplification (Figure 1B, C, D). Finally, the patient was diagnosed
with multiple myeloma IgM+κ type (D-S stage III, ISS stage II, R-ISS stage III).
Considering the obvious symptoms of bone pain, the most common nonhematologic adverse
reaction of bortezomib was peripheral neuropathy, and neuralgia side effects may exacerbate
patient suffering. When the creatinine clearance rate was approximately 49 ml/(min*1.73
m2), bortezomib and lenalidomide were abandoned. Then, the patient started therapy
with ixazomib 4 mg on Days 1, 8, and 15 plus dexamethasone 20 mg on Days 1, 8, 15,
and 22. After some time on this regimen, he developed some rashes but did not pay
attention to them. After two cycles of chemotherapy were completed, the creatinine
clearance rate returned to normal, which allowed the use of lenalidomide. In pursuit
of more effective treatment, an IRd regimen (ixazomib 4 mg on Days 1, 8, and 15 plus
dexamethasone 15 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 with lenalidomide 25 mg/d)
was planned to be implemented. Unfortunately, erythema and desquamation symptoms were
further aggravated after four days of chemotherapy (Figure 2 A, B, C, D), which forced
us to stop the treatment. In addition, a skin biopsy could not be performed due to
severe skin lesions and exudation. After specialist symptomatic treatment, the skin
peeling and exudation recovered (Figure 2 E, F). Because we were unsure which drug
caused the skin peeling, we could no longer allow the patient to take ixazomib or
lenalidomide continuously. Therefore, the treatment regimen was changed to pomalidomide
and dexamethasone (PomDex) in the next cycle, with anti-platelet aggregation to prevent
thromboembolism. During these two cycles, he did not have other skin lesions. In May
2021, bone marrow aspiration confirmed that abnormal proliferation of plasma cells
increased to 35%. With a suboptimal response to PomDex, the addition of cyclophosphamide
was expected to improve the response and outcomes further. In January 2022, we tried
to add bortezomib from 1mg to 2mg, closely monitoring the skin reactions. The patient
did not experience rash or skin peeling again. The treatment and review results of
the patient are summarized in Figure 3.
According to the updated cytogenetic risk stratification criteria (including 2016
IMWG and 2018 mSMART 3.0), high-risk cytogenetic abnormalities (HRCAs) are defined
as 1q amplification, del (17p), t (4; 14), t (14; 16) and t (14; 20). Recently, several
foreign studies have proposed that a combination of various adverse prognostic factors
leads to a worse prognosis and survival.3 An unsatisfactory drug effect cannot exclude
the existence of poor prognostic markers.
The cutaneous side effect profile of ixazomib remains to be documented. Kumar et al.2
discussed the safety of ixazomib in patients with previously untreated myeloma. 17%
of patients had skin and subcutaneous tissue disorders, including rash maculopapular,
rash, rash pruritic, erythema, skin exfoliation, etc. In this case, the rash was considered
due to ixazomib, the only new medication before the patient’s skin manifestations.
However, exacerbation of the rash caused by lenalidomide cannot be ruled out. The
rash was observed with IRd, reflecting the overlapping character of the toxicity that
has been seen with ixazomib alone2 and with lenalidomide.4,5 The rash observed with
IRd typically ranges from limited erythematous, macular, and/or papular lesions that
could be pruritic over a few body areas to a more generalized eruption predominantly
on the trunk or extremities.6 Most lenalidomide-related rashes are of mild-to-moderate
severity and present as patchy, raised macular skin lesions, sometimes with localized
urticaria and/or pruritus.5 However, serious dermatological reactions, including Stevens-Johnson
syndrome (SJS)7,8 and toxic epidermal necrolysis (TEN),8,9 have been reported with
lenalidomide. For the aggravation of skin lesions that occurred 4 days after starting
IRd, the cutaneous adverse reactions of lenalidomide may have a certain boosting effect,
with ixazomib playing a leading role.
Both ixazomib and bortezomib are proteasome inhibitors, but cross-allergic reactions
may not necessarily occur, which has a clinical significance for drug use. Also, it
is important to monitor the skin response after treatment with IRd. Recognizing and
identifying cutaneous adverse events allows for early intervention and management
while achieving continuous and effective treatment.