The incidence of second malignancies was shown to be increased in patients with multiple myeloma. Although a shared genetic predisposition or common environmental carcinogens may account for the occurrence of both myeloma and additional cancers, multiple immune defects encountered in myeloma might play an important role in this regard. This review explores the impairments in both cellular and humoral mediated immunity in multiple myeloma, linking them with increased susceptibility to infections and additional cancers. In addition, the recent therapeutic advances transformed myeloma into a chronic entity, with multiple relapses and salvage therapies, which may result in cumulative immunosuppression. Although recent reports have suggested an increased rate of second cancers in myeloma patients treated with lenalidomide, the true impact of this agent and other novel anti-myeloma therapies on the incidence of additional malignancies remains to be clarified.
VarkonyiJKovalszkyINemethA. Increased risk for cancer in multiple myeloma patients and their first-degree relatives. Haematologia (Budap)2001; 31: 45–50.
2.
Todolí ParraJACampo LópezCSegura HuertaA. Association of multiple myeloma and solid neoplasms: analysis of 13 cases. Rev Clin Esp1999; 199: 725–728.
3.
RajkumarSVKyleRABuadiFK. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc2010; 85: 945–948.
4.
DörffelWVReitzigPDörffelY. Secondary malignant neoplasms in patients with breast cancer. Zentralbl Gynakol2000; 122: 419–427.
5.
PrattGGoodyearOMossP. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol2007; 138: 563–579.
6.
SchüttPBrandhorstDStellbergW. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma2006; 47: 1570–1582.
7.
MillsKHCawleyJC. Abnormal monoclonal antibody defined helper/suppressor T-cell subpopulations in multiple myeloma: relationship to treatment and clinical stage. Br J Haematol1983; 53: 271–275.
8.
OgawaraHHandaHYamazakiT. High Th1/Th2 ratio in patients with multiple myeloma. Leuk Res2005; 29: 135–140.
9.
MurakamiHOgawaraHHiroshiH. Th1/Th2 cells in patients with multiple myeloma. Hematology2004; 9: 41–45.
10.
MossPGillespieGFrodshamP. Clonal populations of CD4+ and CD8+ T cells in patients with multiple myeloma and paraproteinemia. Blood1996; 87: 3297–3306.
11.
JoshuaDEBrownRDHoPJ. Regulatory T cells and multiple myeloma. Clin Lymph Myeloma2008; 8: 283–286.
12.
FrassanitoMACusmaiADammaccoF. Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Experim Immunol2001; 125: 190–197.
13.
BrownRDPopeBMurrayA. 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 factorbeta1and interleukin-10. Blood2001; 98: 2992–2998.
14.
CampbellJDCookGRobertsonSE. Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15. J Immunol2001; 167: 553–561.
15.
UrashimaMOgataAChauhanD. Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood1996; 87: 1928–1938.
16.
NucciMAnaissieE. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis2009; 49: 1211–1225.
17.
PilarskiLMAndrewsEJMantMJ. Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function. J Clin Immunol1986; 6: 491–501.
18.
BorsonNDLacyMQWettsteinPJ. Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma. Blood2002; 100: 4629–4639.
19.
NagyMChapuisBMatthesT. Expression of transcription factors Pu.1, Spi-B, Blimp-1, BSAP and oct-2 in normal human plasma cells and in multiple myeloma cells. Br J Haematol2002; 116: 429–435.
20.
FauriatCMalletFOliveD. Impaired activating receptor expression pattern in natural killer cells from patients with multiple myeloma. Leukemia2006; 20: 732–733.
21.
JarahianMWatzlCIssaY. Blockade of natural killer cell-mediated lysis by NCAM140 expressed on tumor cells. Int J Cancer2007; 120: 2625–2634.
22.
RattaMFagnoniFCurtiA. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood2002; 100: 230–237.
23.
BrownRDPopeBMurrayA. 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 factorbeta1 and interleukin-10. Blood2001; 98: 2992–2998.
24.
JacobsonDRZolla-PaznerS. Immunosuppression and infection in multiple myeloma. Semin Oncol1986; 13: 282–290.
25.
DasanuCARealeMABauerF. Mantle cell lymphoma arising in a multiple myeloma patient responding to lenalidomide. Leuk Res2010; 34: e178–e180.
26.
Van RaamsdonkCDGriewankKGCrosbyMB. Mutations in GNA11 in uveal melanoma. N Engl J Med2010; 363: 2191–2199.
27.
ScéloGBoffettaPAutierP. Associations between ocular melanoma and other primary cancers: an international population-based study. Int J Cancer2007; 120: 152–159.
28.
HaslettPACorralLGAlbertM. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production and cytotoxic responses in the CD8+ subset. J Exp Med1998; 187: 1885–1892.
29.
VerbonAJuffermansNPSpeelmanP. A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans. Antimicrob Agents Chemother2000; 44: 2286–2290.
30.
TaiYTLiXFCatleyL. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res2005; 65: 11712–11720.
31.
DasanuCAAlexandrescuDT. A case of severe aplastic anemia secondary to treatment with lenalidomide for multiple myeloma. Eur J Haematol2009; 82: 231–234.
32.
BartlettJBMichaelAClarkeIA. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer2004; 90: 955–961.
33.
NencioniAGrunebachFPatroneF. Proteasome inhibitors: antitumor effects and beyond. Leukemia2007; 21: 30–36.
34.
Chanan-KhanASonneveldPSchusterMW. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol2008; 26: 4784–4790.
