Abstract
Objective
This study aimed to evaluate treatment patterns and clinical outcomes among patients with multiple myeloma treated at a major cancer center in Kazakhstan over a 10-year period.
Methods
This retrospective observational study analyzed data from 261 patients with multiple myeloma treated at the National Research Oncology Center, Astana, between 2010 and 2021. Sociodemographic and clinical characteristics, treatment regimens, and survival outcomes were assessed using data from electronic medical records.
Results
Most patients were diagnosed with stage II of multiple myeloma, based on the Durie–Salmon staging system, and the majority received bortezomib plus dexamethasone as first-line treatment. Hematopoietic stem cell transplantation was performed in 117 (45%) patients, with a 5-year overall survival rate of 63.6%, compared with 46.2% in patients who received chemotherapy alone.
Conclusions
The mean age of this cohort was 54 years, suggesting an earlier onset of multiple myeloma in the Kazakh population. Treatment regimens, stem cell yield, and post-transplant complications significantly influenced survival outcomes, underscoring the need to optimize transplant strategies and supportive care in Kazakhstan.
Keywords
Introduction
Multiple myeloma (MM) is a malignant lymphoproliferative disease characterized by the proliferation of plasma cells within the bone marrow. MM typically evolves from monoclonal gammopathy of underestimated significance or smoldering MM and is characterized by the presence of monoclonal immunoglobulins in the blood serum and/or urine, and osteolytic bone lesions.1,2 According to the World Health Organization classification, MM is categorized as a peripheral B-cell lymphoid tumor.1,3
According to data from the International Agency for Research on Cancer, the estimated worldwide incidence of MM in 2018 was 160 per 100,000 population, with an age-standardized rate of 1.7 per 100,000 population.4,5 MM accounts for approximately 1% of all malignant tumors and up to 10%–15% of all hematopoietic and lymphoid tissue malignancies. 6 Age is considered a risk factor for the occurrence of MM. The median age of MM occurrence is approximately 66 years, and patients younger than 40 years account for less than 2% of MM cases.1,4
The increasing incidence of MM has been attributed to improvements in quality of life and longer life expectancy in recent years. 7 The global mortality from MM was estimated as 106 people per 100,000 population in 2018, with higher mortality observed in males than in females (58.8 and 47.3 people per 100,000 population, respectively). 4
Significant advances in the treatment of MM have been achieved with the development and introduction of high-dose chemotherapy supported by autologous hematopoietic stem cell transplantation (auto-HSCT) into clinical practice. Studies conducted since the mid-1980s have demonstrated high efficacy and safety of high-dose melphalan (200 mg/m2), followed by autologous stem cell transplant (SCT).8–10 Higher remission rates were obtained by increasing the melphalan dosages to levels requiring autologous stem cell rescue. 11 High-dose chemotherapy is recommended for patients younger than 60–65 years. 12
There is a lack of information regarding MM epidemiology, treatment approaches, and outcomes in Central Asia. The purpose of this study was to describe treatment approaches and outcomes of patients with MM at a single tertiary center in Astana, Kazakhstan, over an 11-year period.
Materials and methods
This study employed a retrospective observational design. Data on patient characteristics, treatment protocols, and clinical outcomes were retrieved from the hospital’s electronic medical record system and physical medical records. The dataset included all patients diagnosed with MM who received treatment at the National Research Oncology Center (NROC), Astana, Kazakhstan, between 2010 and 2021. All data were independently verified to ensure accuracy and completeness prior to analysis. To ensure patient confidentiality, all personal identifiers were removed, and records were completely deidentified before data extraction and statistical processing, preventing any possibility of individual identification. The study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 13
MM Staging
Patients with MM were staged according to the Durie–Salmon and Durie–Salmon PLUS staging systems proposed by the International Myeloma Working Group.14,15 The Durie–Salmon staging criteria sorts MM from stage I to stage III, and the Durie–Salmon PLUS staging system subclassifies each stage as either A or B. Stage A is defined as a serum creatinine level <177 µmol/L, while patients exceeding this threshold were classified as stage B. 16 Due to limited diagnostic resources at the time of data collection, cytogenetic analysis and serum β2-microglobulin testing required for International Staging System (ISS) and revised ISS (R-ISS) classification were not routinely available.
Initial treatment
Clinical guidelines recommend one of three regimens for first-line therapy of patients with MM: bortezomib + dexamethasone (VD), bortezomib + doxorubicin + dexamethasone, or cyclophosphamide + bortezomib + dexamethasone (VCD). 14 Currently, VD and VCD are considered optimal regimens due to their demonstrated efficacy and favorable toxicity profiles compared with other chemotherapy regimens.6,17 At the time of treatment initiation, VCD was preferred over bortezomib–thalidomide–dexamethasone (VTd) or bortezomib–lenalidomide–dexamethasone (VRd) primarily due to limited access to thalidomide and lenalidomide, as well as cost constraints and availability within the local healthcare system. VCD represented a more feasible and cost-effective option while maintaining acceptable efficacy and safety profiles in routine clinical practice.
Therapy effectiveness assessment
During the study period, initial therapy consists of conventional protocols and regimens, including immunomodulator agents such as thalidomide and lenalidomide. 14 The introduction of novel agents significantly improved treatment outcomes. 17 In this study, we divided initial therapy into first and second lines. In cases of inadequate therapy response or disease progression, chemotherapy was either continued for an additional 2–4 cycles using the same regimen or switched to second-line chemotherapy in accordance with clinical guidelines. 14 Second-line therapy included regimens containing thalidomide or lenalidomide. An insufficient response to initial therapy was defined as the absence of disease progression without meeting the criteria for a partial or best response. After four treatment cycles, a follow-up examination was conducted to assess the disease status after treatment. Patients who were not eligible for auto-HSCT receive induction therapy for 8–12 cycles.
Therapeutic effectiveness was evaluated based on the patient’s response to treatment. According to the criteria of the International Myeloma Working Group, responses were categorized into complete response (CR), very good partial response (VGPR), or partial response (PR).2,18 Eligibility of auto-HSCT is dependent on the treatment response.
Indications/contraindications for auto-HSCT
Patients with adequate CD34+ cell counts who met all eligibility criteria for auto-HSCT, according to the clinical guidelines approved by the Republican Center of Health Development of Kazakhstan, underwent auto-HSCT. 14
Insufficient CD34+ cell counts and disease progression were considered the primary contraindications for auto-HSCT. In this study, an insufficient CD34+ count was defined as <2 × 106 CD34+ cells per kilogram of body weight. The primary criteria for transplant ineligibility included the following: (a) failure to mobilize the required number of CD34+ following standard mobilization regimens; (b) severe cardiovascular comorbidities such as congestive heart failure, clinically significant arrhythmias, or a history of myocardial infarction within the preceding 6 months; and (c) uncontrolled systemic infections, particularly bloodstream infections (BSI), accompanied by persistently elevated inflammatory markers (C-reactive protein and procalcitonin) despite antimicrobial therapy. 14
Statistical analysis
All statistical analyses were performed using statistical software STATA version 16.0. For bivariate analyses, parametric tests were conducted using Pearson’s chi-square and Student’s t-test. When assumptions for performing the chi-square test were not met, the nonparametric Fisher’s exact test was used. Cox regression was used to estimate the unadjusted hazard ratio (HR) for sociodemographic and clinical characteristics on the outcome. A two-sided p value <0.05 was considered statistically significant.
Ethical approval
This retrospective study was reviewed by the Local Bioethics Commission of the National Research Oncology Center and was granted an exemption from formal ethical approval. The study was conducted in accordance with the ethical standards of institutional and national research committees and the principles of the Declaration of Helsinki. The requirement for informed consent was waived because anonymized data from the hospital’s electronic medical records and physical records were used.
Results
Sociodemographic characteristics of patients
A total of 261 patients with MM were included in the study from NROC over an 11-year period (2010–2021). Sociodemographic and clinical data of all patients are summarized in Table 1. Among these patients, 117 underwent auto-HSCT, and 144 received chemotherapy alone. The cohort included 148 (57%) females and 113 (43%) males. There was no statistical difference in sex among patients with and without auto-HSCT (p = 0.505). Patients who underwent auto-HSCT were younger than those with chemotherapy treatment (median age: 52 and 55, respectively; p = 0.003). The median age of the cohort was 54 years (range: 24–76 years). Regarding survival outcomes, 107 of 261 patients died during follow-up: 37 (35%) among patients who underwent auto-HSCT and 70 (65%) among patients treated with chemotherapy only. The primary causes of death among patients with MM in this cohort were disease refractoriness or progression and severe infectious complications during therapy. There is a strong association between mortality and treatment group (p = 0.006), indicating that auto-HSCT was associated with improved survival outcomes.
Sociodemographic characteristics of all patients in cohort (n = 261).
SCT: stem cell transplant.
Clinical characteristics of patients
Characteristics of patients who underwent auto-HSCT were analyzed separately according to survival outcomes (Table 2). Prior to transplantation, 29 patients (25%) achieved CR, 50 patients (43%) achieved PR, 27 patients (23%) achieved VGPR, and 10 patients (9%) had stable disease.
Demographic and medical characteristics of patients, who had SCT (n = 117).
SD: standard deviation; SCT: stem cell transplant.
Melphalan 140 mg/m2 was utilized as a conditioning agent in 41 (35%) patients, and melphalan 200 mg/m2 was administered in the remaining procedures. Patients who received high doses of melphalan 200 mg/m2 had significantly better outcomes compared with those who received melphalan 140 mg/m2 (p = 0.003) (Table 2). Dose reduction to melphalan 140 mg/m2 was applied in patients with impaired renal function or significant comorbidities, including cardiac dysfunction or poor performance status. These dose adjustments were implemented to reduce the risk of treatment-related toxicity while maintaining transplant eligibility. There was no significant difference related to the number of transplanted cells (p = 0.083). The median time of engraftment was 17 days, which was approximately similar in both groups (p = 0.501). Engraftment was defined as the day of “neutrophil” engraftment.
The most common post-transplant complications included BSI, mucositis, and aspergillosis. In total, infectious complications occurred in 78 (67%) patients, including bacterial sepsis confirmed by positive blood cultures. Mucositis occurred in 35 (30%) patients, of whom 14 cases (40%) were classified as grade 3–4. Aspergillosis was diagnosed in nine (8%) patients. Cardiac toxicities were rare, occurring in less than 1% of patients. The occurrence of BSI and mucositis was significantly associated with unfavorable treatment outcomes (p = 0.024 and p = 0.028, respectively; Table 2). It should be noted that categories were not mutually exclusive, as some patients experienced multiple complications simultaneously.
Therapy line and treatment response
In the cohort, 43 (37%) patients required two lines of therapy prior to transplantation. Fifty patients achieved PR, and outcomes were not statistically associated with the number of therapy lines (p = 0.073) (Table 3). Twenty-two (81%) of 27 patients with VGPR received only the first-line therapy, which was statistically different from those who required the second-line therapy (p = 0.025). Nine (90%) of 10 patients who achieved “stabilization” required two lines of therapy (p < 0.001). Among patients who underwent auto-HSCT, the pretransplant treatment response was as follows: CR in 30 patients (25%), VGPR in 27 patients (23%), PR in 50 patients (43%), and stabilization in 10 patients (9%). The median number of induction therapy cycles from diagnosis to auto-HSCT was five.
Association between therapy line and treatment response.
Patients who underwent auto-HSCT and achieved at least a PR by day +100 received maintenance therapy with lenalidomide or thalidomide, continued until disease progression or for a maximum duration of 2 years. Patients who were not eligible for transplantation also received maintenance therapy following the completion of induction therapy, provided there were no signs of progression. Evaluation of treatment response after auto-HSCT (day +100, n = 117): CR in 35 (30%), VGPR in 28 (24%), PR in 28 (24%), stable disease in 14 (12%), and progression in 12 (10%).
Survival of patients
There was a significant statistical difference in overall survival (OS) between patients who received auto-HSCT and those who received chemotherapy alone (log-rank test: p < 0.001). The 1-, 3-, and 5-year OS was 94.8%, 75.9%, and 63.6%, respectively, for patients who underwent auto-HSCT compared with 80.7%, 58.3%, and 46.2% for the chemotherapy only group. The Kaplan–Meier survival curves are shown in Figure 1.
Survival probabilities of patients with and without SCT (n = 261). SCT: stem cell transplant.
The OS among patients who received auto-HSCT differed according to the number of stem cells transplanted. The 1-, 3-, and 5-year OS of patients who received more than 4 × 106 CD34+ cells/kg were 95.4%, 81.1%, and 66.5%, respectively (Figure 2). Although the log-rank test did not show statistical significance (p = 0.14), patients who received less than 4 × 106 CD34+ cells/kg were 92.6%, 56.9%, and 52.5%, respectively.
Survival probabilities of patients with SCT depending on number of stem cells transplanted.
The Cox regression hazards model did not show any significant association between survival and sociodemographic or clinical characteristics. Only the complication category labeled “other” was associated with a 2.17-fold increased risk of death, which was statistically significant (p = 0.026). Although the results were not significant, patients who achieved a VGPR demonstrated improved survival within the cohort. The risk of death was reduced by 23% in this group. The development of BSI after transplantation was associated with a higher risk of unfavorable outcomes in the cohort (HR = 2.27, p = 0.052); in contrast, other common complications, such as mucositis and aspergillosis, were found to be protective, although these findings were not statistically significant (p = 0.308 and p = 0.465, respectively).
Discussion
This study analyzed the incidence, mortality, and clinical characteristics of MM in Kazakhstan using electronic records collected over the past decade. These findings are particularly valuable given the scarcity of epidemiological and outcome data on MM in Central Asia. 19 Although MM is typically diagnosed at a median age of 65 years or older, 17 the mean age of our cohort was 55 years, and patients undergoing auto-HSCT were younger, with a mean age of 52 years. This finding reflects the strict eligibility criteria and selection bias favoring younger and fitter patients for transplantation.
Since the 1990s, high-dose chemotherapy followed by auto-HSCT has been established as the standard of care for eligible patients with MM. 7 In our cohort, auto-HSCT was associated with a significantly improved OS compared to chemotherapy alone. Similar outcomes were reported in the randomized trial conducted by Attal et al., 9 in which 5-year OS was higher in the transplant arm. The superior OS observed in our study may be partly explained by the careful selection of younger patients with fewer comorbidities.
Achievement of a VGPR or better after induction therapy has been recognized as a strong predictor of favorable survival.17,20 Consistent with these findings, our study demonstrated a positive association between pretransplant response depth and survival. No difference in OS was observed among patients with a poor pretransplant response, possibly due to the small sample size and selection bias. Survival outcomes were also influenced by the number of transplanted stem cells, with ≥4 × 106 CD34+ cells/kg serving as a favorable cutoff. Until 2014, melphalan conditioning was administered at a dose of 140 mg/m2, after which the 200 mg/m2 became the standard; the higher dose was associated with improved outcomes, aligning with international experience. 21
Adverse events were common, with BSI, mucositis, and aspergillosis representing the most frequent complications. Sepsis was associated with poorer outcomes, likely due to the predominance of gram-negative infections, which can be associated with mortality rates of up to 57% in hematologic patients. 22 Oral cryotherapy during melphalan infusion was routinely applied, potentially contributing to a reduced frequency and severity of mucositis, as reported in prior studies. 23
Compared with other Asian cohorts, the proportion of patients undergoing auto-HSCT in our study was higher than that typically reported from Indian centers, where socioeconomic and infrastructural barriers limit access to transplantation. In the North Indian experience reported by Malhotra et al., 24 the median patient age was 53 years, and the 6.5-year OS reached 76.7%, which is comparable to our findings. The incidence of grade 3 mucositis was 37.5%, which is similar to our 30% rate of grade 3–4 mucositis. The large 15-year Indian mobilization study by Mirgh et al. 25 further demonstrated that cyclophosphamide-based regimens, with or without bortezomib, achieve high CD34+ yields (median: 8–9 × 106/kg) and low mobilization failure rates (≤7%), consistent with our center’s defined threshold of 2 × 106/kg.
In Japan, Shibayama et al. 26 reported that 25% of newly diagnosed patients with MM received upfront auto-HSCT, achieving a 3-year OS of 90.3%, compared to 61.4% in nontransplant patients. Likewise, Yoon et al. 27 analyzed more than 8000 Korean patients with MM and reported a median OS of 7.0 years in the SCT group versus 2.5 years in the non-SCT group. Although our study lacked PFS data due to limited follow-up, the magnitude of OS improvement observed after transplantation is consistent with these regional outcomes, confirming the continued importance of auto-HSCT in improving long-term survival across Asia.
For non–transplant-eligible patients, our results are consistent with reports from Japan and India. Suzuki et al. 28 demonstrated that the use of daratumumab–lenalidomide–dexamethasone as first-line therapy improved survival compared to its use in later lines of treatment, highlighting the benefits of early access to novel agents. Similarly, Tembhare et al. 29 showed that measurable residual disease (MRD) assessment in peripheral blood is a strong predictor of survival in patients not planned for upfront transplantation (OS HR = 3.97; p = 0.013). MRD testing, which remains unavailable at our center, could enhance prognostic stratification in future clinical practice.
Recent studies have also emphasized long-term survivorship issues. Mirgh et al. 30 reported second primary malignancies in 3.3% of auto-HSCT recipients after a median follow-up of 8.7 years, while Yadav et al. 31 demonstrated that a second auto-HSCT for relapsed or refractory MM achieved a 3-year PFS of 37% and OS of 63%, with no transplant-related mortality. These findings support the feasibility and safety of repeat transplantation and highlight the importance of long-term follow-up and survivorship programs, which remain underdeveloped in Kazakhstan.
Over the past decade, treatment strategies for MM in Kazakhstan have evolved significantly. Early in the study period, first-line therapy primarily consisted of bortezomib-based triplets such as VCD or VD, reflecting limited access to novel drugs. However, following the approval of the revised national clinical protocol “Multiple Myeloma and Malignant Plasma Cell Neoplasms,” 32 new therapeutic options were introduced into clinical practice, including daratumumab (intravenous and subcutaneous forms), pomalidomide, and ixazomib. 32 These changes have broadened access to modern combination regimens, enabling the use of quadruple induction therapy (Dara-VRd) for high-risk patients and maintenance therapy with lenalidomide or thalidomide in transplant recipients. Consequently, a gradual improvement in OS has been observed over time, likely associated with increased availability of novel drugs, improved infection control, and optimization of supportive care.
Limitations of this study include its retrospective design, single-center setting, and incomplete long-term follow-up data, particularly regarding progression-free survival. The limited number of transplants performed nationwide also reflects the presence of only one active transplant center in Kazakhstan, with six available beds, resulting in prolonged waiting times and potential selection bias toward younger, fitter patients. Additionally, cytogenetic and MRD data were not available for most patients, precluding detailed molecular risk stratification. Nevertheless, this study provides valuable real-world data from a national referral center and establishes a foundation for future prospective, multicenter studies in Kazakhstan and Central Asia.
Conclusion
In this study, we report the experience of the National Research Oncology Center in the management of MM treatment outcomes between 2010 and 2021. Less than half of the patients underwent stem cell transplantation, and the crude survival of the cohort was low. Over the past decade, the treatment landscape in Kazakhstan has shifted toward the integration of novel agents, the adoption of quadruple induction regimens, and the implementation of structured maintenance therapy. These changes, supported by the 2023 national protocol, are expected to further improve survival outcomes and align national practice more closely with regional and international standards. Future research should focus on expanding access to transplantation, improving national registry data, and incorporating cytogenetic and MRD assessment into routine care to enable precision-based stratification and optimize treatment outcomes for patients with MM in Kazakhstan.
Footnotes
Acknowledgments
The authors express their sincere gratitude to the transplant team of the National Research Oncology Center for their dedicated work and invaluable contribution to patient care and data collection over the past ten years.
Author contributions
Conceptualization Vadim Kemaykin and Azat Karabekov; methodology, Azat Karabekov, Olga Kolesnikova, Jamilya Saparbay, Ruzal Vildanova, Aigerim Idrisova, Dinara Zharlyganova; formal analysis, Gulnur Zhakhina; writing – original draft preparation, all; writing – review and editing, all; supervision, Azat Karabekov and Vadim Kemaykin, Zhandos Burkitbayev; project administration Zhuldyz Kuanysh. All authors have read and agreed to the published version of the manuscript.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declaration of conflicting interests
The authors declare no conflict of interest.
Funding
No funding was received for conducting this study.
