Therapy-Related Myeloid Neoplasms Following Treatment for Multiple Myeloma : A Single-Center Analysis
Authors: Boquoi Amelie , Banahan Soraya Magdalena , Strapatsas Judith , Lopez y Niedenhoff David , Kobbe Guido , Gattermann Norbert , Germing Ulrich , Haas Rainer , Schroeder Thomas , Fenk Roland 
Published: November 2019

Introduction
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) comprise late complications following mutagenic treatment. Limited data is available on the outcome of patients (pts) developing therapy-related MDS and AML (tMDS, tAML) after treatment for multiple myeloma (MM).
Methods
From 1976 to 2011, 3814 pts were entered into the Düsseldorf MDS registry. We identified 200 pts with tMDS or tAML. Of those, 41 pts had also been diagnosed with multiple myeloma (mm-MDS/AML). We compared these 41 pts to pts with de novo MDS (n=3614) and to pts with tMDS with other underlying diseases (n=159, 55 pts with other hematological diseases (34.5%), 93 with solid tumors (58.5%) and 11 with other diseases (7%)).
Patient characteristics
Median time between MM diagnosis and the onset of MDS was 5.5 years (range 0-28.5 years). Median age at the time of diagnosis of mm-MDS/AML was 67.8 years (range 32.5-84.6 years). Of all 41 mm-MDS pts, 13 developed AML (32%). Median time to progression from MDS to AML was 5 months (range 0.5-68 months).
According to the WHO classification of 2016, there were 7 MDS-SLD, 10 MDS-MLD, 1 MDS-RS SLD, 13 MDS-RS MLD, 7 MDS-EB I, 2 EB-2, 1 MDS del(5q). 58% of mm-MDS pts had a complex karyotype, mostly affecting chromosomes 5 (22%) and 7 (17%), less often affected were chromosomes 17 (13%), 20 (13%) and 21 (13%).
At MDS diagnosis, 11 MM pts were in complete remission (22%), 29 pts showed partial remission (58%), and 10 pts a stable disease (20%).
84.4% of pts with mm-MDS/AML had received conventional chemotherapy, mostly anthracyclines and alkylating agents. 94.4% had received melphalan. 15% of pts had received novel agents including immunomodulatory drugs and proteasome inhibitors.
Results
Both mm-MDS pts and tMDS pts were significantly younger than de novo MDS pts, however, there was no age difference between mm-MDS and tMDS (mm-MDS: mean 67.8 years, range 32-85, tMDS: mean 64.3 years, range 21-85, p<0.05, de novo MDS: 71,9 years, range 18-105; p<0.05).
Both mm-MDS pts and de novo MDS pts showed significantly more males than females (mm-MDS 67% male versus 33% female, de novo MDS 57% versus 43%, p<0.05) while tMDS pts showed an equal ratio (48% versus 52%).
When we compared risk group distribution according to IPSS-R we found significantly fewer mm-MDS pts to be in the lower risk categories (p<0.05 for both mm-MDS versus t-MDS and mm-MDS versus de novo MDS). Both mm-MDS and tMDS pts had a significantly worse karyotype when compared to de novo MDS (p<0.05).
More cell lineages were affected in mm-MDS and tMDS pts than in de novo MDS (p<0.05). 50% of mm-MDS pts were pancytopenic versus 26% of de novo pts (p<0.05). Hemoglobin levels were significantly lower in mm-MDS and tMDS pts than de novo MDS pts (p<0.05). mm-MDS pts showed significantly higher blast counts in the bone marrow than all tMDS (p<0.05).
Progression to AML occurred significantly more often in mm-MDS pts. At 12 months we discovered 12% of de novo MDS pts to have transformed to AML, 19% of tMDS and 24% of mm-MDS. At 36 months, 20% of de novo MDS pts had transformed to AML, 34% of tMDS and 39% of mm-MDS (p<0.05).
When mm-MDS pts transformed to AML their survival was very poor, however, not significantly different compared to mm-MDS without AML transformation (7 months versus 11 months, p>0.05).
Median survival of de novo MDS pts was 32 months (CI 29.940 - 34.192, range 1-345 months). In contrast, median overall survival of both mm-MDS and all other t-MDS was significantly shorter with 13 months in both groups (p<0.05, mm-MDS: CI 5.262 - 20.692, range 1-99 months; tMDS: CI 10,016 - 15,939, range 0-160 months).
Myeloma remission status had no impact on survival: pts in complete remission showed a median survival of 6 months (95% CI, range 0 - 35 months), pts with partial remission 7 months (95% CI, range 5 - 9 months) (p>0.05).
Conclusion
Pts developing a myeloid neoplasm after treatment for multiple myeloma present with biological characteristics similar to those seen in pts with other tMDS.
However, both clinical and molecular features are more severe with higher bone marrow blast counts, worse karyotypes, a more unfavourable IPSS-R score, and a significantly higher rate of transformation to AML. Yet despite a more aggressive phenotype, prognosis is equally poor and independent of myeloma remission status in mm-MDS/AML pts suggesting secondary myeloid neoplasia to govern the stem cell niche independent of previous disease or treatment.

Disclosures
Boquoi: Celgene: Other: Travel, Accommodation, Expenses; Janssen: Other: Travel, Accommodations, Expenses; BMS: Honoraria; Amgen: Honoraria, Other: Travel, Accommodations, Expenses. Kobbe:Takeda: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Neovii: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support, Research Funding. Gattermann:Takeda: Research Funding; Novartis: Honoraria; Alexion: Research Funding. Germing:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenk:Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria, Other: Travel, Accomodation, Expenses; Amgen: Honoraria; Celgene: Honoraria, Research Funding.