Autologous stem cell transplantation in adult multiple myeloma patients at Chris Hani Baragwanath Academic hospital

Abstract

Multiple myeloma (MM) is a haematological malignancy that results from the unchecked proliferation of a clone of antibody-producing plasma cells. The disease is characterised by the appearance of the myeloma protein (M protein), which is seen in up to 97% of MM patients, and the clinical features are a consequence of end-organ involvement, especially bone and kidneys, by the M protein. Males are afflicted by the disease slightly more commonly, with a male: female ratio of 1.6:1 and black individuals have a two-fold increased prevalence compared to their white counterparts. The median age of patients at diagnosis is 65 years in the USA and 72 years in Europe. A local study done in sub-Saharan Africa showed that the mean age at diagnosis was 61.4 years and that 7.1% of newly diagnosed MM patients were less than 40 years of age. At Chris Hani Baragwanath Academic Hospital (CHBAH), the survival of newly diagnosed MM patients was shown to be < 50% within the first year after diagnosis, highlighting the dismal prognosis of this disease in our setting. For the past 40 years, high-dose chemotherapy with melphalan followed by autologous stem cell transplantation (ASCT) has been the standard of care globally for eligible patients < 65 years old and improves survival outcomes significantly. At CHBAH, high-dose chemotherapy with ASCT for MM patients has been used since 2003. This consolidation therapy is preceded by induction chemotherapy with a combination of different drugs to decrease the tumour burden and achieve a satisfactory response of the disease. The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) about 25 years ago has not superseded but, instead, further strengthened the role of ASCT as a central treatment modality (consolidation) in MM patients. Early upfront ASCT is associated with better survival outcomes than a delayed approach and is the standard of care in most centres across the world. This study was undertaken to analyse the demographic, clinical, laboratory and radiological findings as well as the complications, treatment outcome and survival of adult MM patients who underwent an ASCT at our treatment facility. b. Patients and methods This was a retrospective study of all adult patients with a confirmed diagnosis of MM who had an ASCT at the Clinical Haematology Unit, Department of Medicine, CHBAH over a 19-year period (01/01/2003 to 31/12/2021). Demographic, clinical, radiological and therapeutic data was retrieved from the patient files and laboratory data from the NHLS database. Data was captured on a spreadsheet using Microsoft Excel and was then statistically analysed using SAS Enterprise Guide 7.1. Categorical data was analysed and presented as frequencies and percentages for the overall study. Continuous measures were assessed using medians and inter-quartile ranges (IQR) as well as means and standard deviations and compared non- parametrically and parametrically using the Kruskal-Wallis test and student t-test, respectively. c. Results and discussion During the study period, a total of 691 patients were diagnosed with MM. 51 (7.4%) of these patients received an ASCT at our facility. There were three patients who received an ASCT at another centre and were therefore not included in the study. 30 (58.8%) females and 21 (41.2%) males received an ASCT. The male:female ratio was 1:1.43. The median age at presentation was 54 years (range 32-62 years). Black patients (86.3%) represented the major ethnicity to receive an ASCT. 76.5% of the transplanted patients had an ECOG performance status less than two. The key findings in our review were as follows: 1. The mean number of patients who received an ASCT per year was 2.68, with a median of three. The highest number of ASCT in a year was seven in the year 2019. The mean number of transplants in the second half of the study period (July 2012 to December 2021) was higher at 3.3 compared to the first half of the study, which was two. 2. The most common co-morbidity was hypertension (64.7%), followed by diabetes (19.6%). 29.4% had more than one co-morbidity. 7.8% had some degree of renal impairment at diagnosis (none required dialysis). Three patients had concomitant HIV infection, which was virologically supressed before their ASCT. 3. The most common presenting symptom was bone pain (86.3%); Anaemia (haemoglobin concentration of ≤ 12 g/dl) was seen in 83.3%. 4. The baseline median haemoglobin level was 9.65 g/dl, albumin 35 g/l, creatinine. 82 mmol/l, calcium 2.4 mmol/l, beta 2 microglobulin 4.9 mg/l and LDH 256 U/l. 5. The following improvements in mean laboratory indices were seen one year after ASCT: i. Haemoglobin: 9.65 g/dl to 12.3 g/dl. ii. Total serum protein: 93 g/l to 77 g/l. iii. Serum albumin: 35 g/l to 42 g/l. iv. Serum paraprotein level: 38 g/l to 9 g/l. 6. Thirty-two % of the patients were classified ISS I, 32 % ISS II and 36 % ISS III; 94 % had Durie-Salmon stage III disease. 7. CVAD was the most commonly used induction regimen (85.1%); a median of eight induction chemotherapy cycles was given before ASCT; the median time between completing induction chemotherapy and receiving ASCT was six months, with a mean of 10.5 months for the entire cohort. 8. Etoposide was used as mobilisation agent in all of our patients; the median CD34+ yield obtained for ASCT was 9.83 x 106/kg (range 2-36 x 106/kg). 9. Melphalan 200 mg/m2 was used in 80% of the patients as conditioning regimen prior to ASCT. 10. Neutrophil engraftment occurred after a median of 11 days; platelet engraftment occurred after a median of 10 days. 11. Forty-one patients received a single ASCT; 10 patients received a second ASCT as salvage therapy following disease relapse. The majority of the patients (74.5%) received a delayed ASCT (>12 months from the date of diagnosis). 12. The most common complication following HDT was neutropenia. Three patients died as a result of transplant-related complications. 13. Thalidomide was the main maintenance chemotherapy agent in our patients. Most patients benefited from thalidomide in the second half of the study (26 versus 3). 14. The median OS was 57 months from the time of diagnosis (range 12-209 months). The median OS in the early ASCT group was 32 months compared to 58.5 months for the delayed ASCT group. In terms of disease response status, 54.5% and 55.5% were in PR or better status in the early and delayed ASCT groups, respectively. 15. Twenty-two patients (43.1%) were alive at the conclusion of the study, out of which 17 (77.2%) were in PR or better disease response status. 56.9% had demised or presumed to be dead as per their last visit notes. 16. Twenty-three patients relapsed at some point after ASCT. The median time for relapse after the first ASCT was 30 months. d. Conclusions and future recommendations: Autologous stem cell transplantation remains the standard of care for patients with newly diagnosed MM. Despite the advent of novel agents, ASCT remains a very common treatment modality as consolidation that has consistently shown to improve survival outcomes. It is clear from this study that ASCT improves the outcome of our patient population and its continued use is relevant given the fact that we are still using outdated induction agents and that novel agents are not widely accessible in the South African public sector. In the South African public sector, only a limited number of health facilities offer ASCT to MM patients. A recommendation at our treatment facility would be to consider offering ASCT to patients > 65 years of age with a good performance status and minimal co- morbidities as these patients represent a significant proportion of newly diagnosed MM patients, keeping in mind that the life expectancy of the South African population is increasing. Earlier diagnosis and referral to our treatment facility will ensure that these patients stand a better chance of receiving earlier therapy, including ASCT. With regards to this, continued education and training of medical personnel, especially at peripheral hospitals, is of paramount importance. ASCT has been consistently shown to be of more benefit to MM patients with high- risk cytogenetics. Hence, FISH analysis and cytogenetics on BMAT samples should be offered more widely by the NHLS laboratories across the country. This will require recruitment and training of more personnel to help with this service. Finally, a concerted effort is needed by the Department of Health and the South African private health sector to make the novel induction agents more accessible to patients at public health sector facilities, as these agents will change the landscape of MM care and significantly improve outcomes by improving the quality of the initial induction response, by allowing us a wider selection of maintenance therapy agents, by allowing a greater access to therapies in the relapsed setting and ultimately with the goal of improving overall survival in patients with MM