Low Frequency of Treatment-Related Myelodysplastic Syndromes (t-MDS) after Autotransplants (AT) for Multiple Myeloma (MM), Especially If AT Is Applied Early during Treatment.
Authors: Tricot Guido , Reiner Maureen , Sawyer Jeffrey , Anaissie Elias , van Rhee Frits , Zangari Maurizio , Hollmig Klaus , Dewald Gordon , Fox Michele , Barlogie Bart 
Published: April 2020

Background: AT’s have become the standard of care in the management of patients with MM, effecting 10-year survival rates of more than 30%. Long-term sequelae are uncommon, so that even 3rd and 4th AT have been applied. MDS is a well recognized complication of cancer therapy and has been reported in the context of both standard and AT-supported high-dose therapies for lymphoma and MM. It remains unclear whether t-MDS development is caused by prolonged “low” dose chemotherapy or by pre-transplant regimens. The purpose of this study was to survey a cytogenetic (CG) data base (DB) of &gt; 30.000 samples submitted with each bone marrow examination involving 2152 patients receiving at least 1 AT.

Patients and Methods: 1886 patients were identified with all relevant information as well as pre- and post-AT CG data available receiving at least 1 AT prior to January 2004. Common criteria for MDS-CA were employed. Routine CG follow-up studies were performed at 3–6 month intervals. MDS-CA development was examined in relationship to age, duration and type of therapy prior to transplant preparative treatment, blood counts, PBSC collection, AT regimen and number, post-transplant platelet and granulocyte recovery, as well as in the context of MM parameters. Interphase FISH analysis for MDS was also performed on PBSC in 42 patients (to detect early MDS cytogenetic changes caused by standard-doses therapies preceding AT) and correlated with MDS-metaphase CA post-AT in 7 patients.

Results: Eighty-five patients developed MDS-CA at a median of 33 months after AT (range, 5 to 126 mo); the 10-year incidence estimate was 7%. MDS-metaphase CA development was independently associated with older age (&gt; 55yr), lower CD 34 yield with first collection (&lt; 18 million/kg) and lower platelet recovery 3 mo post-AT. The 10-year probability of MDS-metaphase CA was 1% among 315 patients with 0 risk factor, 6% among 1367 patients with 1 or 2 and 13% among the 199 patients with 3 risk factors (p&lt;.0001). Univariately, &gt;12 mo of pre-AT standard therapy increased the cumulative incidence of MDS-metaphase CA (p=0.04). The median time to MDS-metaphase CA development was shorter (24 mo) in the 55 patients with 2 or 3 risk factors compared to the 28 patients with 0 or 1 risk factors (41 mo; p=0.01).

Conclusion: This report is the largest ever on the detection of MDS by metaphase CG, obtained in the context of AT for MM. Results confirm earlier findings that MDS-metaphase CA is infrequent when PBSC are procured early after the start of chemotherapies, in those with robust stem cell collection and prompt platelet recovery post-transplantation (evidence of non-damaged hematopoiesis) and among the younger age group. Thus, t-MDS after AT-supported high-dose therapy can be traced to stem cell damage likely inflicted by and not completely repaired after prolonged pre-AT therapies and accentuated by the post-AT replicative stress, especially in older patients. MDS- FISH data of PBSC will be presented at the meeting.