Discussion

As described previously, concomitant CNL and MM have been described in the literature. This is probably one of the first reported cases depicting the development of CNL years after remission of MM following ASCT.

Dinçol et al. described a case of simultaneous CNL and MM in a 71-year-old male with hepatosplenomegaly, high neutrophil alkaline phosphatase score, monoclonal IgG kappa paraproteinemia, and the bone marrow demonstrating abundance of both myeloid and plasma cells. Their patient died of bronchopneumonia within 18 months of diagnosis [5]. Diéguez et al. described a case with concurrent diagnosis in a female, who was given melphalan and prednisone [6]. Cehreli et al. diagnosed a 60-year-old female presenting with weight loss and night sweats, with hepatosplenomegaly, with the same diagnosis [7]. Han et al. reported an 86-year-old male who was diagnosed with MM and CNL concomitantly, who died within four months of the diagnosis, without any treatment [8]. Standen et al. reviewed seven patients with the two diagnoses. They found that MM preceded the diagnosis of CNL in seven patients by three months to 14 years. They found that concomitant CNL did not impact the survival following the diagnosis of MM [9].

Many case reports have described neutrophilia in patients with MM. Kohmura et al. demonstrated that plasma cells can produce granulocyte colony-stimulating factor (G-CSF), resulting in neutrophilia [10]. Additionally, the myeloma cells and the immunoglobulins, as well as the cytokines produced by them, create a niche that favours the proliferation of the granulocytes [11]. Méhes et al. described two cases of acute erythroid leukemia following chemotherapy, radiotherapy, and ASCT in patients with MM. They attributed it to CH, which was exacerbated by the mutations resulting from the VCD protocol and melphalan [12].

Importantly, chemotherapy affects hematopoietic stem cells by inducing mutations, and alkylating agents, such as melphalan, which the patient likely received, are well known for this. Further, stem cells following chemotherapy produce clones with TP53 mutations, increasing the odds of leukemia [13,14]. Moreover, mutations in ASXL1, DNMT3A, and TET2 have been reported frequently [15]. It has been thought that often these stem cells are harvested before they can repair their DNA following the insults of the chemotherapy drugs. Mitochondrial dysfunction has also been reported in the stem cells. The mitochondrial dysfunction causes decreased scavenging of the free oxygen radicals, thereby promoting DNA mutations [16]. Genetic mutations, organelle dysfunction, defective repair, and aberrant signalling pathways ultimately lead to CH and neoplastic transformation. It has been seen that the incidence of CH increases with age, and those with CH are 12 times more likely to develop a hematological neoplasia compared to those without it [15].

Elghawy et al. reviewed 1,770 MM patients who underwent ASCT retrospectively and found that 1.01% of them developed treatment-related acute leukemia (t-AL) at a median interval of 60.0 ± 41.3 months from the ASCT. They deciphered that the median overall survival following the t-AL diagnosis was 19.5 months and concluded that those who achieved complete remission had better survival outcomes [17]. As per the study by Mahindra et al., male sex, older sage and obesity were associated with a higher incidence of new cancers in MM patients following ASCT [14].