Case Presentation: We present a case series of three patients who developed secondary B-cell acute lymphoblastic leukemia (B-ALL) after multiple myeloma (MM) treatment. Case 1: A 71-year-old male with a four-year history of standard-risk kappa MM presented with weakness, fever, cough, and pancytopenia. His MM had initially been treated with six cycles of lenalidomide (R), bortezomib (V), and dexamethasone (d) followed by an additional cycle of Rd, to which he achieved a stringent complete response (sCR). He subsequently underwent a consolidative melphalan-based autologous stem cell transplant (MEL-ASCT) and began maintenance lenalidomide therapy for the next 33 months. On current presentation, bone marrow biopsy revealed Philadelphia chromosome negative (Ph-) B-ALL. Fluorescent in-situ hybridization (FISH) showed hyperdiploidy. Next generation sequencing (NGS) yielded a TP53 mutation, TP53 deletion, and IKZF1 deletion. He was treated with doxorubicin/vincristine followed by inotuzumab, but ultimately passed away from meningitis secondary to his immunocompromised status.Case 2: A 59-year-old female with a five-year history of IgG MM (unknown risk stratification) presented with persistent neutropenia despite discontinuation of lenalidomide. Her MM had been initially treated with four cycles of RVd, to which she achieved a very good partial response. She then underwent MEL-ASCT before starting lenalidomide maintenance for the next 54 months. While working up her neutropenia on current presentation, a bone marrow biopsy revealed Ph- B-ALL (with +14q on FISH). She began treatment with hyperCVAD, which was complicated by septic shock, and she switched to blinatumomab. After one cycle of blinatumomab, a repeat bone marrow biopsy showed no evidence of leukemia, and she has since undergone allogeneic SCT.Case 3: A 78-year-old female with a six-year history of standard-risk IgA kappa MM presented with a white blood cell count of 59,000 on CBC with a large percentage of blasts. Her MM had initially been treated with four cycles of RVd, to which she achieved a sCR, before undergoing consolidative MEL-ASCT. She then started lenalidomide maintenance for the next 57 months before switching to ixazomib for 5 months. On current presentation, flow cytometry confirmed a new diagnosis of B-ALL (Ph- on FISH with a CDKN2A homozygous deletion on NGS). She received two weekly cycles of vincristine/dexamethasone followed by one cycle of inotuzumab (with an interim repeat bone marrow biopsy showing no evidence of B-ALL).

Discussion: While conventional MM therapies, including lenalidomide and MEL-ASCT, are associated with various secondary primary malignancies (SPMs), < 50 cases of MM therapy-related B-ALL have been reported in the literature [1]. In this case series, all three patients developed B-ALL after receiving consolidative MEL-ASCT and an extended duration of lenalidomide (ranging from 33-57 months). Furthermore, while the t(9;22) translocation is observed in up to 30% of patients with de novo B-ALL, all our patients had Ph- disease, which is consistent with other published case series [2,3]. Additional research is thus needed to understand how both immunomodulatory and alkylating agents may contribute to the pathogenesis of MM treatment-related Ph- B-ALL [1,2].

Conclusions: Patients with MM who are found to have new onset constitutional symptoms and/or abnormalities on routine laboratory/bone marrow biopsy follow-up should be appropriately evaluated for SPMs, including the rare possibility of B-ALL.