EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Multiple myeloma (MM) is a hematological malig-nancy characterized by uncontrolled proliferation of malignant plasma cells and production of monoc-lonal immunoglobulin (Ig).¹ The most common clinical symptoms of MM include hypercalcemia, renal failure, anemia, and bone lesions (CRAB features).² About 3 of every 4 patients with MM have anemia, most of whom experience mild to moderate intensity. Over the past 3 decades, with the availability of new novel agents such as immuno-modulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies, autologous stem cell transplant (ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed MM.³

Thalassemia is the most common monogenic disorder worldwide, with a high incidence in the Asian subcontinent.⁴ There are 2 major groups, α-thalassemia and β-thalassemia, which have the main features of thalassemia and include an unba-lanced ratio of α/β globin chain, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.⁵ These pathological features result in iron overload, which is also caused by an increased absorption of iron in the gastrointestinal tract and repeated blood transfusions.^6-8 Thalassemia displays a wide range of clinical severity, which has been utilized for clinical classification into non-transfusion-dependent thalas-semia and transfusion-dependent thalassemia, based on the requirement of those patients to receive regular blood transfusions to survive, whereas patients with thalassemia minor may rarely require transfusions.⁹ However, in certain cases such as MM with thalassemia genes, the symptoms of anemia may be exacerbated. In clinical practice, few cases of MM in thalassemia have been reported.

In an early report from 1977, Fabris and colle-agues¹⁰ reported a case of MM with a β-thalassemia trait. In 1986, Dash and colleagues¹¹reported an elderly man with smoldering MM and β-thalassemia who received melphalan and prednisolone therapy in addition to red blood cell (RBC) transfusions. However, he subsequently developed unstable angina, congestive heart failure, and pulmonary infraction, and he ultimately died from heart failure. Thalassemia patients exhibit a high incidence of thromboembolic events, particularly in β-thalassemia intermedia.^12-15 This hypercoagulable state is the result of a multifactorial mechanism involving pathological alterations to RBC, platelet activation, endothelial cell dysfunction, peripheral blood activation and the other factors.¹⁶ Furthermore, thalassemia-induced iron overload and oxidative stress result in dyslipoproteinemia, which has been confirmed to increase the incidence of cardiovascular disease in β-thalassemia patients.^17,18

For α-thalassemia, a previously published case study reported the diagnosis of light-chain MM with refractory MM disease and coexistent α-thalassemia, which resulted in the development of hyperviscosity syndrome.¹⁹ Although the mechanism by which light-chain MM and thalassemia contribute to hyperviscosity remains elusive, it is speculated that complex erythrocyte abnormalities may interact with κ-light-chain polymer, resulting in increased serum viscosity.¹⁹ In another case, a 66-year-old woman was diagnosed with MM and coexistent α-thalassemia received 6 cycles of melphalan and prednisone, and was maintained on thalidomide; over time, the anemia was only slightly improved.²⁰

To the best of our knowledge, no previous studies have reported an ASCT recipient with MM coexistent with the heterozygous thalassemia gene variant; similarly, we found no reports of the possible effects that this gene variant may have on outcomes of patients with MM who receive ASCT. Here, we investigated 4 ASCT recipients with MM (mean age, 56 years; range, 51-64 years; 75% female patients) who were heterozygous for the thalassemia gene variant. Both patients were diagnosed with MM and received chemotherapy and ASCT in the Department of Hematology at the Second Affiliated Hospital of Chongqing Medical University in 2022. Serum electrophoresis of 2 patients revealed IgG-kappa monoclonal gammopathy, and the other 2 patients had IgA monoclonal gammopathy. The percentage of media bone marrow-derived plasma cells was 32% (range, 25%-34%). Cytogenetic abnormalities were found in all patients, with adverse karyotype in 3 of 4 patients. Genetic testing for thalassemia revealed 3 patients with the β-thalassemia heterozygous gene variant and 1 patient with the β-thalassemia heterozygous gene variant. Three patients were diagnosed with thalassemia minor; 1 of these 3 patients received minimal RBC transfusion, and another was diagnosed with non-transfusion-dependent thalassemia and received occasional transfusions. Ferritin levels for all patients were within the reference range.

In terms of the treatment process, all patients received several courses of IMiDs, PI, and monoclonal antibody chemotherapy, and they all achieved complete remission. Details of patient characteristics at the time of treatment initiation, response, and subsequent treatments are provided in (Table 1).

All patients underwent ASCT following stem cell mobilization with cyclophosphamide (2 g/m²) and recombinant human granulocyte colony-stimulating factor. Stem cells were successfully collected in 3 patients after first mobilization; in 1 patient the first collection failed but was successful upon second mobilization. The conditioning regimen for ASCT consisted of 150 to 200 mg/m² of melphalan, and the mean CD34+ count was 4.97 × 10⁶ cells/kg (range, 3.9 to 7.28 × 10⁶ cells/kg), with a mean total nucleated cell count of 3.70 × × 10⁸ cells/kg (range, 1.78 to 6.80 × 10⁸ cells/kg). The day of white blood cell (WBC) engraftment was day 12 for patient 1, day 13 for patient 2, day 11 for patient 3, and day 12 for patient 4 (Figure 1). The day of platelet engraftment was day 13 for patient 1, day 17 for patient 2, day 11 for patient 3, and day 26 for patient 4. (The day of WBC engraftment was defined as the first of 3 consecutive days on which the granulocyte count exceeded 0.5 × 10⁹ cells/L. The day of platelet engraftment was defined as the first of 3 consecutive days on which the platelet count exceeded 20 × 10⁹ cells/L without platelet infusion.) With the engraftment of WBC, hemoglobin did not change significantly (Figure 1). The ASCT procedure did not result in any significant extramedullary toxicities, such as thromboembolic events or gastrointestinal and mucosal toxicity.

During maintenance therapy after ASCT, 3 patients received lenalidomide and 1 patient received daratumumab. At follow-up after ASCT, all patients had complete remission status; the routine blood test showed mild to moderate anemia with mean corpuscular volume <70 fL. The genetic detection of thalassemia showed that all patients were still heterozygous for the gene variant of thalassemia.

To conclude, we reported 4 patients with MM coexistent with the heterozygous thalassemia gene variant who received IMiDs, PI, and monoclonal antibody chemotherapy and fulfilled ASCT. These cases are remarkable for microcytic hypochromic anemia, and final diagnosis revealed a coexistence of MM and heterozygous thalassemia gene variant. However, it is worth noting that the presence of the thalassemia gene variant did not have any effect on stem cell mobilization or engraftment, and we did not observe any significant extramedullary toxicities such as thromboembolic events, gastrointestinal or mucosal toxicity, or hyperviscosity. Furthermore, ASCT does not affect the clinical severity of thalassemia in patients with MM. The ASCT did not aggravated anemia of thalassemia, and all patients achieved complete remission for MM.

Volume: 22 Issue: 1 January 2024

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