Incidence of skin hyperpigmentation in Black patients receiving treatment with immunomodulatory drugs

TO THE EDITOR:

Immunomodulatory drugs (IMiDs) are a cornerstone of multiple myeloma treatment. IMiDs, particularly lenalidomide, are associated with adverse skin reactions. These reactions are most commonly rash, xeroderma, and pruritus.^1-3  Although multiple myeloma disproportionately affects Black patients, <2% of patients were Black in a pivotal clinical trial used for registration of these medications.^4,5  The incidence and severity of skin pigment changes in Black patients are not well described. This retrospective study seeks to describe the incidence and natural history of skin changes observed in Black patients receiving IMiD therapy.

Boston Medical Center is a large safety-net hospital in New England. More than 70% of patients treated at this institution are underserved minorities. This retrospective study evaluated all patients treated at Boston Medical Center with thalidomide, lenalidomide, or pomalidomide from January 2013 to March 2020. An internally developed survey consisting of 14 questions was mailed to all patients identified through prescriptions written in the electronic medical record. The survey questions included ethnicity and race identification and whether skin changes occurred during treatment. For those patients with skin changes, follow-up questions asked about the nature of the skin change, including pattern, location, and duration. Distress related to skin changes was reported on a scale of 1 to 10, with 1 being minimal distress and 10 being maximal distress. The distress score used was an original internally developed survey that had not been previously validated. Photographs were obtained of the skin changes after IMiD therapy. The research team reviewed all surveys received. Patients who did not return a survey were called at their primary phone number, and the survey answers were verbally obtained. This study was approved by the institutional review board at Boston University Medical Center.

Over the period of interest, there were a total of 214 patients prescribed thalidomide (n = 4; 1.9%), lenalidomide (n = 204; 95.3%), or pomalidomide (n = 81; 37.9%). Completed surveys were received from 106 (49.5%) of these patients. Of the 108 patients (50.5%) who did not respond to the survey, 57 did not answer after 2 attempts, 21 had died, 16 declined to participate, 6 had phone numbers that were not in service, 5 did not recall IMiD therapy, 1 was hospitalized, 1 was unable to consent to participate in the survey, and 1 returned the survey blank.

In the completed surveys, 49 patients (46.2%) identified as Black and 57 (53.8%) identified as non-Black (Asian, Hispanic or Latino, American Indian/Alaskan Native, White, Native Hawaiian/Other Pacific Islander, or other). Skin changes were reported by 27 patients (25.5%) who completed surveys.

Hyperpigmentation (skin darkening) was reported by 20 Black patients (40.8%) and 2 non-Black patients (3.5%). The most commonly reported locations of hyperpigmentation were on the palms and soles (n = 15; 68.2%), forearms (n = 7; 31.8%), and face (n = 6; 27.3%). Onset began within 3 months of starting therapy in 10 (45.5%) of these patients. Using the distress score, the changes were very bothersome (7-10 of 10) in 7 patients (31.8%) and less bothersome (1-6 of 10) in 15 patients (68.2%). Of the 11 patients who were no longer receiving IMiD therapy, 4 (36.6%) had full resolution of skin changes, 5 (45.5%) noted partial resolution, and 2 (18.2%) had no improvement. Description of the skin changes and associated distress can be found in Table 1. Photographs of typical skin hyperpigmentation are included in Figure 1. All responses are included in the supplemental Data, available on the Blood Web site.

The mechanism for hyperpigmentation resulting from IMiD therapy is not clear. Potential mechanisms for IMiD hyperpigmentation include melanocyte stimulation, impaired degradation of melanin, or direct pigmentation from the drug itself. Further research is required to elucidate the mechanisms responsible for the pigment changes.

The limitations of this research include the subjective nature of distress and recall bias. A prospective study using a validated distress instrument should be considered for future research.

This is the first study to describe skin hyperpigmentation resulting from IMiDs, an adverse effect that disproportionately affects Black patients. Specifically, hyperpigmentation is common in Black patients and is 11.6 times more likely to occur in Black patients than in patients of all other races. In these patients, hyperpigmentation is most noticeable on the palms, face, and soles of the feet. These changes typically occur early in the course of therapy and do not completely reverse, even long after drug cessation. It is important for providers to counsel patients about the risk of potentially irreversible skin changes when using IMiDs in this patient population.