a retrospective cohort study
Austin A. Robinson1, James Wang2, Suzie Vardanyan3, Erik K. Madden4, Frank Hebroni4, Kyle A. Udd2, Tanya M. Spektor5, Jason D. Nosrati3, Alex Z. Kitto3, Michael Zahab3, Simrin Cheema6, Darron H. Fors4, Adam Norberg4, Joseph Diehl4, Gabriel N. Waterman7, Regina A. Swift2, John Crowley8, James R. Berenson2,3,5.
1Yale University School of Medicine, New Haven, CT; 2James R. Berenson, MD, Inc., West Hollywood, CA; 3Institute for Myeloma and Bone Cancer Research, West Hollywood, CA; 4David Geffen School of Medicine, University of California, Los Angeles, CA; 5Oncotherapeutics, West Hollywood, CA; 6Fielding School of Public Health, University of California, Los Angeles, CA; 7Keck School of Medicine, University of Southern California, Los Angeles, CA; 8Cancer Research and Biostatistics, Seattle, WA, USA.
Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma (MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age-, race-, and gender-matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma (SCC) was higher than controls (P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC.
Key words multiple myeloma; skin cancer; secondary primary malignancy; squamous cell carcinoma
Accepted for publication 10 February 2016
Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow with an expected 26,850 new cases and 11,240 deaths in the United States in 2015 (1). At the turn of the century, the median overall survival (OS) of these patients was only approximately 3 years (2). However, with the advent of new MM therapies such as high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) and treatment with newer agents such as the immunomodulatory compounds (IMiDs) thalidomide, lenalidomide, and pomalidomide, and proteasome inhibitors such as bortezomib and carﬁlzomib (3–8), the OS of patients with MM has markedly improved (9,10).
With patients living longer, however, there has been observed an increase in the incidence of hematologic and non-hematologic secondary primary malignancies (SPMs) such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as higher rates of solid tumors which may be at least, in part, related to the use of specific drugs such as lenalidomide (11,12). In addition to MDS and AML, a recent study employing population-based ﬁgures from the Swedish Cancer Registry showed an increased incidence of non-melanomatous skin cancer (NMSC) among patients with MM (13).
The association between MM and NMSC may have not been previously recognized because of the short survival of patients with MM and these forms of cancer were often excluded from major cancer registries, such as the National Cancer Institute SEER database (14). Furthermore, this association is somewhat surprising given the known inverse correlation between MM and exposure to ultraviolet radiation (15). However, it is not surprising to ﬁnd an increased incidence of skin cancer among patients with immunosuppressed disease states such as MM. Specifically, skin cancer risk has been found to be increased among patients in states of immunosuppression including those undergoing solid organ transplantation and those with active HIV infection (16). Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) have been directly linked with immunosuppression in solid organ transplant recipients, with 65- to 250-fold and 10-fold increased risks, respectively (17).
In MM, SPM risk is often regarded as multifactorial, with much of the documented risk being linked to treatment with melphalan, an alkylating agent that is used not only for induction chemotherapy, but also as part of the myeloablative therapy prior to ASCT (18). Moreover, mutations predisposing patients to MM may also predispose patients to a higher risk of developing other malignancies (19). We have performed a retrospective cohort study of patients with multiple myeloma from a large clinic that specializes in MM and compared them to an age-, race-, and gender-matched control group to explore the occurrence of skin cancer among patients with MM and determined the types of skin cancer and possible relationships with specific drug treatments.
Patients and methods
Enrollment Approval for this study was obtained from the Western Institutional Review Board (WIRB). Following informed consent, consecutive patients with MM at a single clinic in West Hollywood, CA, James R. Berenson, M.D., were enrolled and surveyed for baseline demographics, clinical characteristics, and prior skin cancer history. When a potential skin cancer was identified, information on cancer type, date of diagnosis, and myeloma treatment regimens were collected and conﬁrmed with medical records from the diagnosing institution (s) or ofﬁce(s). When multiple skin cancer diagnoses were recorded for one individual, these were only included when verified as distinct primary cancers, rather than recurrences of a prior skin cancer at the same anatomic location. As for control subjects, we characterized skin cancer frequencies among a group of non-MM control subjects with similar baseline demographic and clinical characteristics, and used them to estimate expected cancer numbers from our patient cohort. Control subjects were recruited by inviting participation from spouses, unrelated companions, or friends accompanying patients to the clinic.
Data analysis To ensure uniformity of the patient and control groups, unpaired t-tests and chi-squared tests were performed as appropriate on demographic data with a P-value of
Subjects and treatments We enrolled 205 patients with MM and 193 control subjects. Demographic information is shown in Table 1. The patient cohort was 55.6% male and 85.4% Caucasian with a median age of 61 years at the time of MM diagnosis. Both groups had similar baseline demographic characteristics, including smoking and alcohol intake histories (Table 1). Regarding the proportion of patients with MM receiving specific drugs, 156 (76.0%), 143 (69.8%), 110 (53.7%), 72 (35.1%), and 73 (35.6%) of patients received at least one dose of glucocorticosteroids, bortezomib, IMiDs, anthracyclines, and alkylating agents, respectively. A total of 25 (12.2%) patients with MM underwent ASCT. A detailed list of the distribution of agents used among the patients with MM is shown in Table 2.
Skin cancers of specific types Overall, patients with MM reported 110 separate skin cancers and controls reported 60 skin cancers. Specifically, there were 52 and 37 BCCs, 44 and 17 SCCs, and 9 and 5 melanomas among the patients with MM and control subjects, respectively. The SIRs for patients with MM were as follows: skin cancer: 1.72 (95% CI 1.43–2.07), and speciﬁc types of skin cancer were as follows: BCC: 1.32 (95% CI 1.00–1.72), SCC: 2.44 (95% CI 1.78–3.24), NMSC: 1.67
Baseline demographic and clinical characteristics of the patients and control subjects
Percent of patients with multiple myeloma receiving at least one treatment of each therapy
(95% CI 1.36–2.03), and melanoma: 1.69 (95% CI 0.83– 3.11) (Table 3). When comparing the incidences of specific types of skin cancers in patients post-MM diagnosis with pre-MM diagnosis, the SIRs were as follows: SCC: 2.27 (95% CI 1.50– 3.31), BCC: 0.86 (95% CI 0.53–1.32), NMSC: 1.33 (95% CI 0.98–1.77). All known dates of diagnosis for melanoma were pre-MM diagnosis and were not analyzable for SIR. Fifty-ﬁve patients with MM (26.8%) reported the occurrence of at least one type of skin CA, compared to only 31 (16.1%) of control individuals (P = 0.009). Among those diagnosed with BCC, 33 were patients with MM and 24 were controls (P = 0.297). SCC occurred in 26 patients with MM and only 11 controls (P = 0.016). Melanoma was identified in nine patients with MM and ﬁve controls (P = 0.330).
Predicting skin cancers among all subjects A logistic regression analysis was conducted to predict the presence of skin cancer of any type using the following predictors: MM diagnosis, age, gender, race, tobacco use, and alcohol use. When predicting the presence of skin cancer, it was found that MM diagnosis (P = 0.0498), age (P = 0.006), and Caucasian ethnicity (P < 0.001) were significant predictors, displaying no notable multicollinearity. In contrast, gender, tobacco use, and alcohol use were not significant predictors of skin cancer development (P > 0.05). To assess the contributors to SCC, another logistic regression analysis was conducted to predict the presence of SCC utilizing the same predictors as the ﬁrst analysis. When predicting the presence of SCC, it was found that MM diagnosis (P = 0.038) and age (P = 0.003) were significant predictors, displaying no notable multicollinearity. Ethnicity, gender, tobacco use, and alcohol use were not significant predictors (P > 0.05).
Predictors of skin cancers among patients with MM Additional analyses were completed to delineate which characteristics of the MM disease state contributed to its association with skin cancers. The following predictors were analyzed: treatment with at least one dose of glucocorticosteroids, bortezomib, IMiDs, anthracyclines, or alkylating agents. We also examined age, male gender, Caucasian ethnicity, tobacco use, and alcohol use. Only Caucasian ethnicity was found to be a significant predictor (P = 0.005) and age was a borderline significant predictor (P = 0.057). All other factors examined were not significant (P > 0.05).
The results of the present study suggest a higher risk of NMSC among patients with MM. The strongest evidence exists for a correlation with SCC lifetime, SIR 2.44 (95% CI 1.78–3.24), and after the diagnosis of MM with an SIR of 2.27 (95% CI 1.50–3.31). While the SIRs of both SCC and BCC were higher among patients with MM, only the proportion of patients diagnosed with SCC is significantly increased over controls, suggesting it is only those patients with MM who would already develop BCC which seem to be at higher risk for developing new primary BCCs. The absolute numbers of melanoma cases in our cohort were overall too small for a detailed analysis. These data indicate that it is primarily SCC driving the higher risk of skin cancer in patients with MM.
Cumulative incidence and SIRs of types of skin cancers
We also determined which MM-related factors were predictive of skin cancer and/or SCC. Indeed, regression analyses identified MM, age, and Caucasian ethnicity as independent predictors of skin cancer generally and MM and age as independent predictors of SCC specifically. However, it is difficult to distinguish whether MM drives this relationship to increased rates of skin cancer or if the factors that predisposed patients for MM also predisposed patients to skin cancer. In our study, no specific drug treatment increased the likelihood of developing skin cancer, which is in line with previous studies (20–27). It was also difficult to separate treatment from MM diagnosis as a factor for skin cancer since all except one patient in the study who developed skin cancer following the diagnosis of MM also had initiated MM treatment. Bortezomib has not been shown to increase SPMs to date, despite evidence of its oncogenic potential. Proteasome inhibitors such as bortezomib are postulated to exert much of their antitumor activity via inhibition of NFjB, a mechanism which is known to increase cell growth and oncogenesis, including spontaneous SCCs in murine epidermal cell lines and similar neoplasia in human cells (20– 25). We did not ﬁnd treatment with bortezomib as a risk factor for skin cancer (P = 0.44). Similarly, IMiD use as a driver of SPMs has been found in some studies, but a recently published meta-analysis from randomized trials suggests that the risk is conﬁned to hematologic malignancies (26). In addition, another recent large meta-analysis shows no higher risk of SPMs overall or of either solid or hematologic malignancies among patients treated with lenalidomide (27). However, two randomized, controlled trials of lenalidomide following ASCT demonstrated an increase in both hematologic malignancies and solid tumors among the patients in the arms randomized to receive this IMiD (12, 26). In our study, we did not ﬁnd IMiD use as a risk factor for skin cancer (P = 0.69). The Swedish Cancer Registry analysis found no signiﬁcant differences in the rate of AML/MDS among patients with MM before and after the year of introduction of HDM-ASCT, and it is not implausible that the increased occurrence of skin cancers among patients with MM also preceded the advent of newer therapies (13). Additionally, the present study did not include information on the clinical status and course of the patient’s MM, which could also potentially be an additional predictor for the development of skin cancers. Through complex and in many ways different from that of HIV infection or solid organ transplant recipients, MM disease itself is known to induce a state of relative immune suppression (28, 29).
Future studies may examine the specific effects of the patient’s MM as it relates to the development of skin cancers (30). Weaknesses of this study include the evaluation of patients from a single clinic specializing in MM and a somewhat lower percentage (12%) of transplanted patients, although a lower rate of ASCT would be, if anything, expected to underestimate the rate of SPMs including skin cancers in patients with MM (31, 32). Furthermore, the relatively short follow-up period of a median of 3.8 years between MM diagnosis and study enrollment may constitute a small window for observing the emergence of skin cancers, or any SPMs, in patients with MM. A longer surveillance period may demonstrate an even greater divergence in the occurrence of skin cancers between patients with MM and non-MM individuals. There are several unanswered questions in this analysis that may be addressed by future studies. Higher numbers are needed to determine whether patients with MM are also experiencing increased rates of melanoma given the trend observed in this study. In addition to the number of individual cancers, other characteristics of MM-related skin cancers should be addressed, including relative growth rate, local recurrence, and metastatic potential, all of which are known to be relatively more aggressive in immunosuppression related NMSC (33). Moreover, the appropriate skin cancer surveillance and treatment in patients with MM is certainly an important, but heretofore unanswered question for the clinical realm. Additionally, the different roles that genetics, MM disease process, and disease-speciﬁc treatments play in the development of skin cancers may be more thoroughly evaluated by comparing rates of these malignancies between patients with MM and those with MGUS. The current study demonstrates a significant association between MM and NMSC (SIR = 1.67). Mailankody et al. have also reported a correlation between MM and NMSC (SIR = 2.22) among MM patients with a median age of 72 (13). Our study has also demonstrated this correlation among patients with MM who have a median age of 65. Since age is a known risk factor for skin cancer development (34), the difference in standardized incidence rates is likely attributed to the difference in median age of patients with MM in each study. In addition, we examined whether different subcategories of NMSC correlate with MM incidence and have identified SCC as the specific NMSC occurring most frequently in patients with MM (SIR = 2.44). Further studies will elucidate the relative roles of intrinsic MM disease severity and burden, as well as the degree to which specific combination therapies and newer classes of agents such as histone acetylase inhibitors and monoclonal antibodies are causative agents in the development of skin cancers and other secondary malignancies in MM. Importantly, the results of this study suggest a role for increased skin cancer surveillance in this at-risk patient population. Here are some tips on how to treat hyperpigmentation.
Conﬂict of interest
All authors declare that they have no competing ﬁnancial interests.
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