Response and Survival Estimates of Patients With Plasma Cell Myeloma in a Resource-Constrained Setting Using Protocols From High-Income Countries: A Single-Center Experience From Sri Lanka.

INTRODUCTION

Although global cancer death rate has declined, there are socioeconomic inequalities and racial gap in cancer mortality. Poorer countries have a few folds higher mortality in some cancers compared with those of affluent countries. 1 However, data related to geographical differences and clinicopathologic and global survival variability are not well-documented, with a correlation between poverty and lack of accessibility to health care and vice versa in low-income countries. 2

CONTEXT

Key Objective

Plasma cell myeloma (PCM) is a common type of blood cancer. The incidence of PCM has increased over time, but the death rate has fallen because of development of new treatment modalities and protocols. However, the availability of agents and applicability of protocols in low- and middle-income countries are debatable.

Knowledge Generated

To our knowledge, this is the only well-characterized study on long-term survival of patients with PCM in Sri Lanka. It provides data on response and long-term survival of patients with PCM treated with common treatment protocols used in high-income countries.

Relevance

These findings show the successful application of treatment and supportive care protocols from high-income countries in the setting of limited resources. These published data will help to benchmark and improve the treatment and develop blood cancer care in the local setting.

Plasma cell myeloma (PCM) is the second commonest hematologic malignancy, which accounts for 15%-20% of cases. 3 Incidence of PCM has increased over time, but the death rate has fallen because of improvement in polychemotherapy and radiotherapy. 4

Sri Lanka is a developing country with a diverse health care structure with no dedicated hemato-oncology/clinical hematology centers and transplant facilities or access to novel anticancer agents at the time this study was started. There are no published data on characteristics or survival of PCM in Sri Lanka. We established the Lanka Hospital Blood Cancer Centre (LHBCC) in 2013 as a self-funded hospital in Colombo, Sri Lanka, in collaboration with colleagues in government-subsidized hospitals. Previously, we have published data related to acute myeloid leukemia and Hodgkin lymphoma. 5 , 6 In addition, LHBCC was used for training purposes of first set of hemato-oncology trainees from government-subsidized hospitals.

The aim of the study was to analyze patient and disease characteristics and evaluate response and survival parameters in patients with newly diagnosed PCM. In the absence of published local data, we used studies from other Asian countries and high-income countries for comparison.

MATERIALS AND METHODS

Treatment Site and Patients

LHBCC is a dedicated unit for treatment of hematologic malignancies with trained staff. Treatment and supportive care protocols from the United Kingdom 7 were used with 2 decades of experience of the first author at tertiary care centers in the United Kingdom. All nursing staff had yearly training on administration of chemotherapy and supportive care methods. Medical aspects of hemato-oncology services were provided by full-time British-trained clinical hematologists, visiting general oncologists, and other supportive care specialists.

All patients with a diagnosis of PCM who presented to the LHBCC and completed the first-line therapy between May 1, 2013, and September 30, 2021, were included in the analysis. The diagnosis was based on a WHO classification of hematologic malignancies. 8

Clinical Management and Outcome Measurement

Patients were treated with combination chemotherapy after obtaining written informed consent with 28-day cycles of cyclophosphamide 500 mg once per week, thalidomide 50 mg once per day increased to 100 mg once per day if tolerated, dexamethasone 40 mg once per day on days 1-4 and 8-11 (cyclophosphamide, thalidomide, and dexamethasone [CTD]); or 28-day cycles of bortezomib 1.3 mg/m 2 once on days 1, 4, 8, and 11; thalidomide 50 mg once per day increased to 100 mg once per day if tolerated, and dexamethasone 40 mg once per day on days 1-4 and 8-11 (bortezomib, thalidomide, dexamethasone [BTD]). A maximum of four cycles if tolerated. In addition, all patients received acetylsalicylic acid 75 mg once per day as prophylaxis for deep venous thrombosis, 9 acyclovir 400 mg twice a day as antiviral prophylaxis, and zoledronic acid (4 mg once every 28 days) until progression International Myeloma Working Group uniform response and survival criteria were used for response assessment. 10

Statistical Analysis

Response to therapy and the survival status at the last follow-up were recorded, and analyses were performed using various survival analysis techniques through RStudio (RStudio Team, 2020). The median length of follow-up was computed using the reverse Kaplan-Meier estimator. 11 Kruskal-Wallis test was used to compare median age, calcium level, creatinine, and hemoglobin (HgB) level at presentation among patients who underwent different treatments. 12 To evaluate the difference in survival between different groups, the log-rank test was used and various proportion comparisons among treatment groups were made using chi-square test for independence. 13 Verbal consent was taken from patients for storage and analysis of data, and written approval was granted by the Lanka Hospital ethical committee for analysis and publication of anonymized data.

Ethical Committee Approval

This study was considered as a quality-improvement activity, and approval was obtained from the Lanka Hospitals medical research and the ethics committee for the collection and analysis of anonymized data. Informed consent was obtained from all patients.

RESULTS

Demographic and Clinical Characteristics and Treatment

Demographic and clinical characteristics of patients with PCM who received first-line therapy in LHBCC are summarized in Table 1 and Figure 1 . A total of 79 patients with PCM received first-line therapy during the study period. The median age was 64 years, and approximately one third (33%) of patients were older than 70 years. There were 42 (53%) males and 37 females; 36.7%, 38%, 72.1%, and 81% had hypercalcemia, renal impairment, anemia, and bone disease, respectively. Thirty-nine, 34, and six patients received a combination of CTD, BTD, and other treatments, respectively. Demographic and clinical characteristics of patients with PCM who received first-line therapy in LHBCC according to treatment type are summarized in Table 2 .

Response and Survival

The overall response (OR) rate (≥ partial response) was approximately 97% for both CTD and BTD groups. Response to therapy of patients with PCM who received first-line therapy in LHBCC according to treatment type is summarized in Table 3 . Twenty-three (29%) of these patients died during the study period, but only 14 (18%) died due to PCM or associated sepsis (Table 4 ). Cause of death in 14 (61%) patients was sepsis (five in BTD and seven in CTD group).

After a median follow-up of 40.63 months (95% CI, 35.2 to 59.07), the median overall survival (OS) was 84.2 months (95% CI, 60.87 to not available) and the estimated 5-year OS was 65%. The median OS for the CTD group was 84.2 (95% CI, 60.9 to not available; restricted mean [SE] of OS 69.88 [5.29]), and the median OS for the BTD group was not reached (restricted mean [SE] of OS 49.9 [3.4]), as illustrated in Table 5 and Figure 2 .

According to the log-rank test, there was no significant difference in OS according to age, sex, hypercalcemia, renal impairment, anemia, or bone disease at presentation (Table 5 and Fig 2 ). In addition, there was no significant difference in survival curves between the two treatment groups (Table 5 and Fig 3 A) or according to depth of response (achieving complete response [CR], VGPR, or partial response; Table 5 , Fig 3 B).

Safety

Two patients (2.5%) in our study had deep venous thrombosis while on treatment and aspirin prophylaxis. Seventy-two (98.6%) patients in this group treated with CTD and bortezomib, thalidomide, and dexamethasone completed intended four cycles of therapy. Only one patient discontinued treatment because of grade 3 peripheral neuropathy.

Twenty-three (29%) patients died during the study period, but only 14 (18%) died due to PCM or associated sepsis. Seven patients (9%) died within one year of diagnosis.

DISCUSSION

Curing most blood cancers is challenging in low-income countries, especially in a country without free and easy access to the specialty of blood cancer care, transplant facilities, or newer treatment options. Studies from low-income countries comparing clinicopathologic features and survival parameters with data from high-income countries have shown early-onset and late-stage presentation with reduced survival. 14 There is a paucity of trained clinical hematologists, hematopathologists, proper patient referral system, facilities for immunohistochemistry, and centralized review process in low- and middle-income countries.

Incidence of PCM varies among countries but has increased over the past few decades. The largest increase is in low- and middle-income countries. 15 It is known that African American populations show higher incidence, whereas Asian populations show lower incidence of PCM compared with White populations. 16 - 18 Waxman et al 19 showed higher incidence and younger age of onset in African Americans. Accurate and up-to-date cancer incidence data are required for health planning and to afford effective medication for every patient and to understand the underlying etiological factors for the heterogeneity of PCM incidence. 15 Cowan et al 15 reported age-standardized incidence rate per 100,000 of 0.4-0.9 in Sri Lanka in the Global Burden of Multiple Myeloma study. There is a paucity of up-to-date statistics related to the incidence of PCM in Sri Lanka.

The median age of incidence of PCM in White people is in the seventh decade according to previously published data. 16 , 20 , 21 However, it has been shown that the median age of onset in African Americans was at least a decade younger. 4 , 19 The median age at presentation in our cohort was 64 years, and more than two third are younger than 70 years. However, the median age of onset in our study is higher than that reported by some Asian studies. An Iranian study has shown the median age of presentation to be 51 years, 22 and a Pakistani study has shown it to be 57 years. 20 In another study from Vasquez et al 23 from a middle-income country, the median age was 56 years and 59% were male. However, our data are similar to the data of an Asian Myeloma Network study, in which the median age of presentation was 62 years. 24 Larger and more extensive research studies may be needed to clarify the disparity in median age of presentation in PCM in middle- and low-income countries.

Our cohort has shown a slight male predominance (53.2%), which is in keeping with some other published data. 24 , 25 However, Sultan et al 20 reported a higher percentage (70%) of affected males in their study.

In an Asian study, the majority of patients presented with symptomatic anemia and backache (80%). 20 In our cohort, 81% presented with myeloma bone disease and 72% had a HgB of < 100 g/L. Although there is no information related to the cause of backache in the study by Sultan et al, it is likely they suffered from myeloma bone disease. These figures are significantly higher than those reported in trials from high-income countries. 26 The study by Rosiñol et al had only 32% of patients with HgB of < 100 g/L. It is likely less symptomatic patients present for treatment in high-income countries and with more symptomatic disease in low-income countries. This may be due to lack of knowledge related to early signs of cancer and proper infrastructure for early cancer detection as in high-income countries.

Conventional treatments for PCM include chemotherapy and radiation therapy. Addition of immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab) significantly improved the survival of patients with PCM. 27 , 28 Induction followed by high-dose therapy and lenalidomide maintenance is recommended as standard of care in certain settings in high-income countries. 29 - 31

Large international clinical trials from high-income countries have set the stage for evidence-based guidelines for treatment of PCM, but heterogeneous care of patients in low-income countries results in inferior outcomes. 32 However, access to effective care is limited in many low- and middle-income countries, causing huge disparity in cancer care. 15

In our study, 39 patients (49%) received CTD and 34 (43%) received BTD. In another Asian study by Hameed et al 22 in 2017, most of the patients (n = 59; 71.9%) were treated with the CTD regimen and 13 (15.8%) received bortezomib-based treatment. Our study showed a higher percentage of patients receiving bortezomib-based treatment probably as the study by Hameed et al, was from July 2012 to December 2015 and our study was from 2013 to 2021. Thalidomide was used as first-line therapy in 2013 in LHBCC, considering the efficacy of it in high-income countries. 33 , 34 Lenalidomide and bortezomib were approved in Asia in 2016. 15 We started using bortezomib in 2016 at the LHBCC. This explains a shorter follow-up in the BTD group. There is a long delay in new cancer medications reaching patients in low-income countries, causing unfavorable outcome.

A study by Vasquez et al 23 from a middle-income country showed a total response rate of 69.5% using CTD. Our study showed 15.3% CR rate and 97% OR rate in the group treated with CTD, which is higher than that reported by the study by Vasquez et al. The finding in our study is comparable with the results reported in the myeloma IX trial by Morgan et al. 7 The OR rate and CR rate with CTD in their study were 82.5% and 13.0%, respectively. 7 Although our study has a smaller number of patients, this showed better response rates compared with publications from other middle-income countries and comparable results with those of high-income countries.

The cohort of patients treated with BTD in our study showed an OR rate of 97% and a CR rate of 14.7%. Moreau et al had shown similar results in a high-income setting. In their study, after four cycles of treatment, the OR rate was 92.3% and the CR rate was 13% in the BTD arm. 35 In a study by Cavo et al, 36 CR or near-complete response was 31% in the group receiving BTD in a high-income setting. An Italian study by Rosiñol et al 26 reported a CR rate of 35%, but the study showed only 14.7% of CR. We had less number of patients with CR, probably because of not performing bone marrow assessment to define CR. They were classified into groups of lesser response.

The 5-year survival rate in PCM has improved significantly over the past few decades. However, only 10%-20% of patients achieved expected survival compared with matched general population. 37 There is a wide variation in reported survival parameters in different studies. Immunomodulatory drugs and proteasome inhibitors were shown to affect OS when used as first-line therapy. 24 The majority of patients in our study received these drugs and showed a median OS of 84.2 months and an estimated 5-year survival rate of 65%. To our knowledge, this is the only available Sri Lankan study with a long-term follow-up of patients up to a median follow-up of nearly 4 years.

Several Asian studies tried to assess the survival of patients with PCM. In an Iranian study performed from 2012 to 2015, the median OS was 48 months. 22 However, this study had a lower number of patients receiving bortezomib-based therapy. A study by Lu et al 21 reported an OS of 54 months and another study by Asian Myeloma Network (in which Sri Lanka is not a part of) reported an OS of 47 months. 24

According to a study by Chan and Milne, 38 the median OS was 50.7 months in a population from New Zealand. 38 This study was conducted from 2012 to 2017 after the availability of novel myeloma agents. The OS reported in our study is significantly better than that in the aforementioned studies. Patients treated at LHBCC showed better survival compared with other studies from middle- and low-income countries. However, Vasquez et al reported a median OS of 81 months and a 5-year OS rate of 57.5% in a study from a middle-income country. 23

Furthermore, we did not see a survival difference between patients treated with CTD and BTD. Similar results were reported by Rosiñol et al. The estimated OS rate at 4 years was 74% for patients treated with BTD, and there was no OS difference between BTD and other treatments groups. 26 Similarly, there was no significant OS difference in the CTD and BTD groups in a study published by Hameed et al. 22 Our data have a shorter follow-up in the BTD group compared with CTD because of late availability of bortezomib in Sri Lanka.

It has been shown that there are several disparities in PCM care depending on access to quality medical care and newer antimyeloma drugs. 32 There is a significant heterogeneity between different hospitals with regard to diagnostic and treatment facilities and access to trained personnel and supportive care in Sri Lanka. Superior results in our study may be due to selection bias. Patients treated at LHBCC, established in a self-funding hospital, may attract patients belonging to a higher socioeconomic and education level. Xu et al 39 have previously shown that high education levels may independently predict better survival outcome in patients with PCM in an Asian study. Furthermore, socioeconomic status is a global prognostic factor in PCM survival. 40 However, we recognize these results may not represent the survival of patients with PCM in Sri Lanka, and larger studies covering government-subsidized centers are needed for better evaluation.

Risk of thrombosis (VTE) is increased by 28-fold in patients with hematologic malignancies compared with 7- to 10-fold in patients with other cancers. 41 VTE thromboprophylaxis is recommended according to risk assessment: aspirin for low-risk patients and low-molecular-weight heparin for high-risk patients. 9 In a study from South America, the incidence of VTE was 6.8%. 23 However, there are no guidelines or publications related to VTE risk in Asian people, and maintenance of low-molecular-weight heparin is relatively expensive in the local setting. Furthermore, aspirin has been used in primary and secondary thromboprophylaxis. 42 This prompted us to the use of cheap alternative (aspirin) as VTE thromboprophylaxis. Further studies are needed to understand the best thromboprophylaxis policy for the local population.

Twenty-three patients died during the study: fifteen in the CTD, five in the BTD, and three in the other treatment group. Cause of death in 14 (61%) patients was sepsis (five in BTD and seven in CTD group). More patients died in the CTD group because of other causes, and it may be due to longer follow-up and the age range was 48-86 years. Nine percent of patients died within one year of diagnosis in our study (three in the BTD, two in CTD, and two in other treatment). Three of those patients were older than 70 years. The early mortality is exclusively related to sepsis. We used a similar type of antimicrobial prophylaxis. Cause of death may be multifactorial, but the numbers are too small to draw conclusions. In a study by Kumar et al, 43 13% of patients died during the first year, with age older than 70 years as a risk factor for early mortality. Although the number of patients in our study is too small to arrive at conclusions, it is likely sepsis is a major cause of mortality and further studies/interventions are needed to mitigate it.

We acknowledge that a limitation of this study was the small sample size, which may be due to selection bias toward better outcome. There were also no facilities for genetic risk classification and stem-cell transplants, and there were limitations on the available supportive care, including antibiotics, in Sri Lanka. In addition, it is not possible to compare with other general oncology centers or generalize these findings to the entire country. A larger study may be needed in the future with development of the specialty of blood cancer care in Sri Lanka.

To our knowledge, this is the only documented study related to outcome and applicability of Western treatment and supportive care protocols to Sri Lankan patients with PCM. We have previously shown that blood cancer care can be continued safely with higher success even during these testing times. 44 In this study, we have presented data to support the feasibility of establishing a successful and dedicated hemato-oncology/clinical hematology unit where not only patients were treated according to Western protocols but also participated in subspecialty training for hemato-oncology trainees from government-subsidized hospitals. These real-world data identify areas that need further attention and stress the importance of right treatment on the first presentation to improve outcome. We believe that these published data will help to benchmark and develop the specialty of blood cancer care in the local setting.

In conclusion, to our knowledge, this is the only well-characterized study on long-term survival of patients with PCM in Sri Lanka. We have shown that it is possible to successfully apply Western treatment and supportive care protocols to the local population. These published data will help to benchmark and improve the treatment and develop blood cancer care in the local setting.

ACKNOWLEDGMENT

The authors acknowledge all patients, management, and health care workers at Lanka Hospital and Lanka Hospital Diagnostics, Sri Lanka.

Chandana Wickramarathna

Employment: Lanka Hospitals Diagnostic Laboratory, Galle Sri Lanka, Ruhunu Hospitals Private Limited, Galle

Consulting or Advisory Role: Lanka Hospitals Diagnostic Laboratory, Galle Sri Lanka, Ruhunu Hospitals Private Limited, Galle Sri Lanka.

No other potential conflicts of interest were reported.

DATA SHARING STATEMENT

Data used in this study are available from the corresponding authors upon reasonable request.

AUTHOR CONTRIBUTIONS

Conception and design: Saman Hewamana, Prasanna Gunasena, Chathuri Jayasinghe, Thurairajah Skandarajah, Surjit Somiah, Ananda Wijewickrama, Sarath Paranawithane, Thet Thet Lin, Bandula Wijesiriwardena, Jayantha Balawardena

Financial support: Gnani Somasundaram, Natasha Peiris

Administrative support: Saman Hewamana, Thurairajah Skandarajah, Ashfaq Mowlana, Samadhi Deshapriya, Natasha Peiris, Jayantha Balawardena

Provision of study materials or patients: Saman Hewamana, Prasanna Gunasena, Sobitha Abeyaratne, Lalith Ekanayake, Gnani Somasundaram, Surjit Somiah, Vadivelu Srinivasan, Gehan Arseculeratne, Neomal Perera, Mazhar Faiz, Nihal Munasinghe, Chandana Wickramarathna, Ananda Wijewickrama, Priyankara Jayawardena, Eranga Perera, Natasha Peiris, Chitranganie Perera, Rohini Wadanamby, Geethani Galagoda, Bandula Wijesiriwardena

Collection and assembly of data: Saman Hewamana, Prasanna Gunasena, Thurairajah Skandarajah, Mahesh Harischandra, Sobitha Abeyaratne, Lalith Ekanayake, Gnani Somasundaram, Surjit Somiah, Vadivelu Srinivasan, Gehan Arseculeratne, Neomal Perera, Jayaindra Fernando, Mazhar Faiz, Nihal Munasinghe, Ashfaq Mowlana, Samadhi Deshapriya, Supun Mawathakubura, Chandana Wickramarathna, Ananda Wijewickrama, Priyankara Jayawardena, Eranga Perera, Chitranganie Perera, Sanjeewa Munasinghe, Chandu De Silva, Rohini Wadanamby, Geethani Galagoda, Thet Thet Lin, Jayantha Balawardena

Data analysis and interpretation: Saman Hewamana, Prasanna Gunasena, Chathuri Jayasinghe, Thurairajah Skandarajah, Surjit Somiah, Supun Mawathakubura, Ananda Wijewickrama, Priyankara Jayawardena, Natasha Peiris, Chitranga Kariyawasam

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center .

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians ( Open Payments ).

Chandana Wickramarathna

Employment: Lanka Hospitals Diagnostic Laboratory, Galle Sri Lanka, Ruhunu Hospitals Private Limited, Galle

Consulting or Advisory Role: Lanka Hospitals Diagnostic Laboratory, Galle Sri Lanka, Ruhunu Hospitals Private Limited, Galle Sri Lanka.

No other potential conflicts of interest were reported.

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