Risk of Skin Cancer in Multiple Myeloma Patients

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. Berenson^2,3,5.
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.

Introduction

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

Results

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

(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).

Discussion

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.

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.

References

1. Siegel RL, Miller KD, Jamal A. Cancer statistics. CA Cancer J Clin 2015;65:5–29.
2. Raje N, Anderson KC. Multiple Myeloma. Curr Treat Options Oncol 2000;1:73–82.
3. Kristinsson SY, Landgren O, Dickman PW, Derolf
AR, Bj€orkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol 2007;25:1993–9.
4. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–20.
5. Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia 2009;23:1152–7.
6. Vij R, Wang M, Kaufman JL, et al. An open-label, singlearm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012;119:5661–70.
7. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120:2817–25.
8. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801–9.
9. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008;111:2521–6.
10. Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with multiple myeloma in 2006–2010. Haematologica 2009;94:270–5.
11. Thomas A, Mailankody S, Korde N, et al. Second malignancies after multiple myeloma: from 1960s to 2010s. Blood 2012;119:2731–7.
12. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770–81.
13. Mailankody S, Pfeiffer RM, Kristinsson SY, et al. Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS). Blood 2011;118:4086–92.
14. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol 1994;30:774– 8.
15. Chang ET, Canchola AJ, Cockburn M, et al. Adulthood residential ultraviolet radiation, sun sensitivity, dietary vitamin D, and risk of lymphoid malignancies in the California Teachers Study. Blood 2011;118:1591–9.
16. Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst 2013;105:350–60.
17. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681–91.
18. Usmani SZ, Sawyer J, Rosenthal A, et al. Risk factors for MDS and acute leukemia following total therapy 2 and 3 for multiple myeloma. Blood 2013;121:4753–7.
19. Dilworth D, Liu L, Stewart AK, et al. Germline CDKN2A mutation implicated in predisposition to multiple myeloma. Blood 2000;95:1869–71.
20. Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071–6.
21. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003;101:2377–80.
22. Li Z-W, Chen H, Campbell RA, Bonavida B, Berenson JR. NF-kappa B in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 2008;15:391–9.
23. van Hogerlinden M, Rozell BL, €Ahrlund-Richter L, Toftg
ard R. Squamous cell carcinomas and increased apoptosis in skin with inhibited rel/nuclear factor-jB signaling. Cancer Res 1999;59:3299–303.
24. Dajee M, Lazarov M, Zhang JY, et al. NF-jb blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 2003;421:639–43.
25. Zhang JY, Green CL, Tao S, Khavari PA. NF-jb RelA opposes epidermal proliferation driven by TNFR1 and JNK. Genes Dev 2004;18:17–22.
26. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782–91.
27. Wang Y, Yang F, Shen Y, et al. Maintenance therapy with immunomodulatory drugs in multiple myeloma: a meta-analysis and systematic review. J Natl Cancer Inst 2015;108. doi:10.1093/jnci/djv342.
28. Mills KHG, Cawley JC. Abnormal monoclonal antibodydefined helper/suppressor T-cell subpopulations in multiple myeloma: relationship to treatment and clinical stage. Br J Haematol 1983;53:271–5.
29. Brown RD, Pope B, Murray A, et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-b1 and interleukin-10. Blood 2001;98:2992–8.
30. Sanchez E, Li M, Kitto A, et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol 2012;158:727–38.
31. Kumar S, Zhang M-J, Li P, et al. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. Blood 2011;118:1979–88.
32. McCarthy PL, Hahn T, Hassebroek A, et al. Trends in utilization and survival after autologous hematopoietic cell transplantation in North America from 1995 to 2005: Significant
improvement in survival for lymphoma and myeloma during a period of increasing recipient age. Biol Blood Marrow Transplant 2013;19:1116–23.
33. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant 2008;8:2192–8.
34. Etzkom JR, Parikh RP, Marzban SS, et al. Identifying risk factors using a skin cancer screening program. Cancer Control 2013;20:248–54.