Early Mortality in Patients with Multiple Myeloma Treated with Novel Agents - Analysis from Polish Myeloma Study Group
Authors: Charlinski Grzegorz , Tyczyńska Agata , Zaucha Jan M , Czyz Adriana , Czyż Jarosław , Dytfeld Dominik , Malecki Bartosz , Gil Lidia , Fornagiel Szymon , Grosicki Sebastian , Barchnicka Agnieszka , Holojda Jadwiga , Kolkowska Agnieszka , Hus Iwona , Helbig Grzegorz , Kopinska Anna , Masternak Anna , Woszczyk Dariusz , Markiewicz Miroslaw , Piszcz Jaroslaw , Kloczko Janusz , Usnarska-Zubkiewicz Lidia , Wrobel Tomasz , Robak Pawel J. , Robak Tadeusz , Waszczuk-Gajda Anna , Basak Grzegorz , Jurczyszyn Artur 
Published: November 2020

Background
Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients.
Aims
In this study we investigated risk factors associated with EM in MM patients initially treated with novel-agent containing regimen.
Methods
We conducted a multicenter (15 Polish sites) retrospective study a cohort of symptomatic MM pts diagnosed between October 2006 and November 2019 and living &lt; 365 days (d) after diagnosis. All pts were dead at the time of the analysis. Data were collected from medical registries and databases. Mortality rate and cause at 2, 6, and 12 months following diagnosis was evaluated. Clinical staging was performed using the International Staging System (ISS). Response to treatment was evaluated according to the International Myeloma Working Group (IMWG) consensus criteria (2016). Statistical analysis was performed using R-studio v.1.3.959. and significant levels were set at p&lt;0.05.
Results
Of the 197 pts were included in the study, 112 (57%) male and the median age at diagnosis was 69 y (41-91). The MM type of 100 patients (52%) was Immunoglobulin (Ig) G, 24% of patients was IgA, 15% of patients had light chain disease, and 3% of patients IgM or IgD. At diagnosis, renal impairment (RI) was present in 43%, extramedullary disease (EMD) in 15% of the pts; 15% were in stage I, 10% in stage II, 60% in stage III (ISS) and 15% not done. Fluorescent in situ hybridization analysis was performed in 59 pts, 69% presenting high-risk cytogenetic abnormalities (HRC) [t(4;14), t(14;16), t(14;20) or del17p]. 54% pts were &gt;2 comorbidities at diagnosis. Heart disease was presented at diagnosis in 57% pts and diabetes in 22% pts. First-line treatment (1stL), 41% of the pts patients were bortezomib-based (Bor) regimens, 25% Bor with thalidomide (VT)-based, 22% IMiD-based and 13% others.
Response evaluation showed an overall response rate (ORR) of 44% (3% CR; 14% VGPR; 27% PR). 46% pts survived &lt; 2 months, 29%; 2-6 months and 25%: 6-12 month. Median time until death was 2.5 month; 31% of pts died directly from progression disease (PD), and 69% from other causes [infection in 66%, cardiovascular complications in 27%, RI in 8%]. In our study, age &gt; 65 y (HR 1.67; 95% CI 1.24-2.26; p=0.0007), and &gt;75 y (HR 1.5; 95% CI 1.10-2.03; p=0.0087), &gt;2 comorbidities (p=0.002), heart disease (HR 2.12; 95% CI 1.57-2.85; p &lt; 0.0001), RI (HR 0.7; 95% CI 0.53-0.95; p=0.029), dependence of dialysis (HR 1.50; 95% CI 1.05-2.14; p=0.029) were associated with increased risk of death. Mortality predictive value showed HRC (p=0.05), lactate dehydrogenase levels (HR 0.65; 95% CI 0.38-1.1; p=0.002), and &gt;PR (HR 0.30; 95% CI 0.21-0.43; p&lt;0.0001). Moreover, sex, hypertension, diabetes, type of MM, extramedullary disease, ISS stage, hemoglobin level, count of platelets didn't show a mortality predictive value.
Conclusions
IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. Infections and refractory disease were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM.

Disclosures
Wrobel: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Research Funding; Janssen: Honoraria. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, F. Hoffmann-La Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Robak:Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy; GSK: Research Funding; UTX-TGR: Research Funding; Acerta: Research Funding; BioGene: Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; UCB: Honoraria, Research Funding; Pfizer: Research Funding; Momenta: Consultancy; Sandoz: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.