Second Primary Malignancies and Disease Transformation in Newly Diagnosed Symptomatic Patients with Waldenstrom's Macroglobulinemia: An Analysis from the Greek Myeloma Study Group
Authors: Gavriatopoulou Maria , Kastritis Efstathios , Ntanasis-Stathopoulos Ioannis , Kyrtsonis Marie-Christine , Symeonidis Argiris , Hatjiharissi Evdoxia , Repousis Panagiotis , Giannakoulas Nikolaos , Spanoudakis Emmanouil G , Delibasi Sossana , Michali Evridiki , Michael Michalis D , Vassou Amalia , Giannouli Stavroula , Iskas Michail , Kaiafa Georgia , Tsirigotis Panagiotis , Pouli Anastasia , Vervessou Elina , Christoulas Dimitrios , Katodritou Eirini , Terpos Evangelos , Dimopoulos Meletios A 
Published: October 2019

Abstract
Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous clinical presentation and prolonged course. In this context, determining the overall disease and therapy burden in terms of complications and associated comorbidities is necessary. Of special interest is the occurrence of a second malignancy and transformation to high grade lymphoma, due to their impact on survival and quality of life but also on health resource use and follow up strategies. Several factors including immune dysfunction, genetic predisposition, environmental factors and treatment effects have been suggested as possible underlying pathophysiologic mechanisms for development of second primary malignancies or transformation in patients with WM. While there have been data published from various series, it is crucial to have data after prolonged follow up, as the time for development of such complications may be long.
The current study included all patients with symptomatic WM that have been registered in the prospectively maintained database of the Greek Myeloma Study Group, in which the development of a second malignancy and disease transformation is being recorded, including type of second cancer and date of diagnosis. All patients fulfilled criteria for symptomatic WM diagnosis and for treatment initiation according to the Consensus Recommendations.
The analysis included 598 symptomatic newly diagnosed patients with WM with a median follow up of 114 months. The median age was 69 years and 284 (47%) have died. Primary therapy was rituximab-based in 65%, contained alkylating agents in 78%, a nucleoside analogue in 2% and an anthracycline in 4%. In 46 patients (7.7%) the diagnosis of a second tumor was made after the initiation of treatment for symptomatic WM. The most common malignancies were cancer of the prostate (18%), stomach (6%), colon (6%), lung (6%), pancreas (3%), non-melanoma skin (3%) and central nervous system (6%) and AML/MDS (6%). In addition, in 12 (2%) patients, a diagnosis of another malignancy preceded the diagnosis of WM. The median time from treatment initiation for symptomatic WM to the diagnosis of a second primary malignancy was 51 months [interquartile range (IQR): 16-79]. The incidence ratio (IR) of a second primary malignancy was 0.0095 per person-years and the cumulative incidence of a second primary malignancy, accounting for death due to WM or other causes as a competing event, at 5 and 10 years was 3.6% and 6.6%, while, the risk of death from WM or other causes was 22.5% and 46%, respectively (Figure). The IR of a second malignancy was higher in men [IR ratio (IRR): 0.5, 95% CI 0.2-1.1, p=0.067] while it was similar for younger vs older patients (>75 years) (IRR: 1.57, 95% CI 0.61-3.5, p=0.27). Importantly, the use of rituximab as primary treatment was not associated with any increased risk of a second malignancy (IRR: 0.99, 95%CI 0.5-2.1, p=0.97). The incidence of second malignancies has not changed significantly in the era before vs after 2000.
Overall, 19 (3.1%) transformation events were identified; the median time from treatment initiation to transformation was 51 months (IQR: 28-106). The IR for transformation was 0.005 per person-years and the cumulative risk for transformation, accounting for death of any cause as a competing event, was 2.2% and 3.6% at 5 and 10 years respectively. The presence of anemia (hemoglobin <11.5 gr/dl) at diagnosis was associated with increased risk of transformation (IRR: 6.75, 95% CI 1.06-50, p=0.02), while the use of rituximab in first line therapy decreased transformation risk (IRR: 0.36, 95% CI 0.11-1, p=0.041). Interestingly the incidence of transformation decreased after 2000 (IRR: 0.23, 95% 0.07-0.69, p=0.0035). We found no increased risk of transformation among patients that received alkylating agents in their primary therapy; the numbers of patients that received primary therapy with nucleoside analogues was small, however no increased risk was identified.
We conclude that the incidence of a second malignancy among patients with symptomatic WM is 7.7%, corresponding to an incidence rate of about 1 case per 100 patients per year. Transformation occurred in 3.1% corresponding to an incidence rate of 0.5 cases per 100 patients per year; this risk was higher among patients presenting with anemia and has been reduced after 2000. This may be related to the extensive use of rituximab and less frequent use of alkylating agents and nucleoside analogues.
Figure. Figure.

Disclosures
Kastritis: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Novartis: Consultancy; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding. Dimopoulos:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria.