Second Primary Hematological Malignancy in Multiple Myeloma Patients Exposed to Lenalidomide and Autologous Stem Cell Transplantation
Authors: Jiang Justin , Galloway Joshua , Srisuwananukorn Andrew , Borate Uma , Sharma Nidhi , Bumma Naresh , Devarakonda Srinivas , Umyarova Elvira , Rosko Ashley , Khan Abdullah Mohammad , Benson Don , Cottini Francesca 
Published: December 2024

Introduction: Compared to age-matched individuals, patients with MM are at greater risk of developing a second primary hematological malignancy (SPHM). Clonal hematopoiesis (CH) is associated with greater risk of SPHM, especially myeloid neoplasms (MN; acute myeloid leukemia-AML, or myelodysplastic neoplasms-MDS), while its role in acute lymphoblastic leukemias (ALL), is less explored. Lenalidomide (LEN) exposure or autologous stem cell transplantation (ASCT) could potentially increase the risk of SPHM; however, it is unclear whether they can also exacerbate or induce CH. In this study, we characterized patients with MM who developed SPHM at our institution.

Methods: We performed a retrospective chart review of patients with MM who developed a SPHM, focusing on ALL or MN, between the years of 2001-2020. We collected information on patient demographics, initial myeloma characteristics, MM-directed therapies, with specific focus on exposure to LEN or ASCT, and SPHM characteristics.

Results: We identified 28 patients who developed SPHM after treatment for MM, including 14 patients with MN (9 AML, and 5 MDS), and 14 patients with B cell precursor ALL. The median age of MM diagnosis was 62 years; most patients were male (68%), White (89%), and had ISS stage I-II (71%). 26/28 patients underwent ASCT, and 27/28 patients received LEN maintenance after induction (median time on LEN = 39 months, range: 1.9-119 months). The median time to SPHM from MM was 75 months (range: 27-177 months), while median time to SPHM from first ASCT was 66.3 months (range: 22.6-131 months).

Median age of MN diagnosis was 69 years and median age of ALL diagnosis was 67 years. Median time to transformation from MM was 82.8 months for MN and 63 months for ALL (p = 0.25), while median time to transformation from ASCT was 77 months for MN and 55.7 for ALL (p = 0.047). Exposure to LEN was longer in patients with ALL, despite quicker transformation time (median ALL: 45.8 months, range: 30-119; AML: 32 months, range 1.84-80 months). Among the 14 patients with MN, 2 patients had MDS morphologically defined, 3 had MDS with defining genetic abnormalities (either TP53 biallelic or SF3B1 mutations); 4 patients were diagnosed with MDS with high/intermediate IPSS-R scoring and rapidly progressed to AML (median time from MDS to AML: 9 months, range: 7.3-15.9), and 5 patients developed AML with either TP53 mutations or myelodysplasia-associated changes.

Regarding patients with ALL, no cases of Ph-positive ALL were noted, one patient had Ph-like ALL, secondary to NRAS mutations, 3 patients had B-ALL with hypodiploidy (2 cases of Low-haploid-ALL, with biallelic TP53 mutations), and one patient had B-ALL with hyperdiploidy. Other poor prognostic features for ALL included age &gt;55 (13/14, 93%), CD20 positive disease (10/14, 71%), and WBC &gt;30,000 at presentation (2/14, 14%). Median overall survival was 0.5 years for AML and 2.8 years for ALL. At time of ALL or MN diagnosis, the most frequent CH-associated mutations were TP53 (47.4%), DNMT3A (26.3%), RUNX1 (21%), ASXL1/SF3B1/NRAS (10.5%), with some mutations being seen only in ALL patients (e.g. STAT6 or IRF8 genes) or AML patients (RUNX1). All patients except 2 had &gt;1 mutations.

Conclusion: We report our experience of patients with MM who developed SPHM after a median time from MM diagnosis of 6.2 years. Most of these patients were exposed to LEN and underwent ASCT. SPHMs was commonly associated with poor prognostic features including age, TP53 mutations, hypodiploidy, or complex karyotype. Median OS remained very poor for both patients with ALL and AML. We are currently investigating apheresis and bone marrow samples of 10 patients obtained before their AML/ALL diagnoses to evaluate when these mutations occurred. We acknowledge the support of the Mason Fisher grant for this project.