Introduction: MM has envisioned numerous innovations, resulting in prolonged overall survival (OS), nevertheless, long-term complications may comprise the occurrence of different neoplasms (DNs). Recently, DNs after novel agent first-line- and maintenance-treatment have been reported, questioning whether specific risk factors (RFs) predispose to DNs. SEER and Swedish registry data on DNs have observed overall cumulative incidences of 5.1-5.5% in MM, and Mailankody et al. (Blood 2011) standardized incidence ratios in MM- and MGUS-patients for AML/MDS of 11.51- and 8.01-fold, respectively. In a previous registry analysis, we demonstrated an impaired prognosis in MM with subsequent DNs (HR 2.5; 95% CI 1.4-4.4) and that age >60 years was a confounding variable (HR 2.021; 95% CI 1.6-2.6; Hasskarl et al. 2011). Albeit previous analyses have focussed on subsequent DNs, rather than prior and synchronous (p/s) DNs (since the latter needs to live long enough to acquire MM), we assessed both, since p/s DNs is even more pertinent, both phenomenon need to be known to MM experts and should allow to define host-, MM- and/or therapy-related risks.
Methods: We assessed 681 consecutive MM patients treated at our institution between 1997 and 2011 and analyzed 1. patient characteristics (age, gender, familiar risks, smoking-, immune status), 2. frequency of DNs, 3. potential MM-specific RFs (stage, albumin, ß2-microgloblin (ß2-MG), bone marrow (BM) infiltration, cytogenetics), and 4. possible treatment-related RFs (novel agents, autologous stem cell transplantation [single vs. tandem (t)-ASCT], allogeneic (allo-) SCT, frequency of alkylating agents, cycles/lines of therapy and ionizing radiation).
Results: Of 681 MM patients, 91 (13%) showed DNs: ¾ (76%) had solid tumors (ST) and ¼ (24%) hematological neoplasms (HM). p/s DN were observed in 2/3 (n=63; 69%) and subsequent DNs in 1/3 (n=28; 31%). The median age of MM patients with additional DNs was 68 (range 39-89), which was older than our tertiary/referral center's usual MM age (Kleber et al. 2009, Hasskarl et al. 2011). DNs occurred in preferentially males (69%), predominantly in IgG- or IgA-MM and in advanced (II/III) Durie & Salmon [D&S] stages (80%). The comparative analysis of MM with subsequent DN vs. those with p/s DN revealed a younger age with 62 vs. 68 years, respectively; subsequent vs. p/s DNs had an IgG MM-subtype in 75% vs. 66%, and HM occurred in 32% vs. 21%, respectively. Subsequent DNs showed most prominently AML/MDS in 7 patients; lymphoma and CML were observed in one patient each. ST-entities were lung-, colorectal- and urothelial-cancer in each 4 patients, breast-, oropharyngeal- and skin-cancer in each 2 patients and prostate cancer in one patient. Single or t-ASCT had been performed more frequently in MM patients with subsequent DNs as opposed to those with p/s DNs, but bortezomib- and thalidomide were less often applied and allo-SCT, alkylators and lenalidomide comparable. Subsequent DN and p/s DNs patients did not reveal substantial differences in terms of D&S or ISS stage, BM-infiltration rate, gender- or smoking-status, albeit the family risk for cancer was different with 3% and 21%, respectively. Comparison of subsequent-HM vs. -STs in MM patients showed a more advanced age with 71 vs. 60 years. Males were less prominent in MM patients with HM than ST (33% vs. 89%, respectively). Alkylators had been used in 89% of HM compared to 68% with subsequent ST, albeit median therapy lines were comparable. MM patients with subsequent HM had received less single (22%), t-ASCT (22%), allo-SCTs (0%) and radiation (22%) compared to MM with ST (42%, 32%, 11%, 47%, respectively). Lenalidomide, bortezomib or thalidomide had been used less frequently in MM patients with subsequent HM (n=1) than with ST (n=5). No differences were evident in MM-specific RFs (stage, albumin, ß2-MG, BM-infiltration).
Conclusions: Our current data highlight the substantial risk for developing DNs in MM patients. We propose specific host- (age, gender, smoking) and treatment- (alkylators, ASCT/allo-SCT) related susceptibilities that may predispose to MM and subsequent DNs. Further analyses are underway to evaluate these and other potential RFs (cytogenetics, immunologic alterations) in comparison to MM patients without DNs and in relation to the German general population and SEER-data.