Year : 2019 | Volume
: 10 | Issue : 2 | Page : 37--44
Multiple myeloma in Saudi Arabia: Consensus of the Saudi lymphoma/myeloma group
Ahmed Alaskar1, Ahmad Alsaeed2, Fahad Z Alsharif3, Hani Alhashmi4, Mubarak Alghamdi5,
1 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Ministry of National Guard Health Affairs; Saudi Society of Blood and Marrow Transplantation (SSBMT), Saudi Arabia
2 Saudi Society of Blood and Marrow Transplantation (SSBMT), Saudi Arabia; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Ministry of National Guard Health Affairs, Saudi Arabia
3 Saudi Society of Blood and Marrow Transplantation (SSBMT); King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
4 Saudi Society of Blood and Marrow Transplantation (SSBMT); King Fahad Specialist Hospital, Dammam, Saudi Arabia
5 Saudi Society of Blood and Marrow Transplantation (SSBMT); King Fahad Medical City, Riyadh, Saudi Arabia
Dr. Ahmed Alaskar
King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia. Ministry of National Guard Health Affairs, Riyadh
Multiple myeloma (MM) is a relatively uncommon cancer in Saudi Arabia. It is estimated that MM and lymphomas accounted for 9.6%–11% of cancer-related deaths in the Kingdom in 2014. However, published data on the characteristics and treatment patterns of, and outcomes for, MM patients in Saudi Arabia are scant. The Saudi Lymphoma/Myeloma held the “Scientific Gap Analysis Advisory Board” meeting in Riyadh on January 26, 2018, which represented six Saudi specialized institutions, in order to discuss different aspects of MM management in Saudi Arabia and to reach a consensus statement in each aspect of MM in Saudi Arabia. This consensus meeting brought together a panel of Saudi experts in MM to share their views on current trends and practice in Saudi Arabia and how these compare with the global picture.
|How to cite this article:|
Alaskar A, Alsaeed A, Alsharif FZ, Alhashmi H, Alghamdi M. Multiple myeloma in Saudi Arabia: Consensus of the Saudi lymphoma/myeloma group.J Appl Hematol 2019;10:37-44
|How to cite this URL:|
Alaskar A, Alsaeed A, Alsharif FZ, Alhashmi H, Alghamdi M. Multiple myeloma in Saudi Arabia: Consensus of the Saudi lymphoma/myeloma group. J Appl Hematol [serial online] 2019 [cited 2020 Feb 29 ];10:37-44
Available from: http://www.jahjournal.org/text.asp?2019/10/2/37/262542
Multiple myeloma (MM) is a malignant proliferation of monoclonal plasma cells, which usually produce monoclonal protein(s). According to the US Surveillance, Epidemiology, and End Results (SEER) program, about 30,770 new MM cases are expected to be diagnosed in the USA in 2018, while about 12,770 MM-related deaths are expected to occur. Although the incidence of MM increases steadily as a result of increased life expectancy of the general population, the major advances in our understanding of MM have led to dramatic changes in MM management and outcomes. The introduction of novel immunomodulatory agents and targeted proteasome inhibitors to MM treatment regimens has led to marked improvements in complete response rates and overall survival.,,
MM is a relatively uncommon cancer in Saudi Arabia. It is estimated that MM and lymphomas accounted for 9.6%–11% of cancer-related deaths in the Kingdom in 2014. A recent retrospective study by Abduljalil et al. observed that Saudi patients with MM are relatively younger and present with poorer performance status and higher International Staging System stage disease than western patients with MM. Interestingly, MM patients in Saudi Arabia are reported to have a higher response rate to treatment regimens compared with similar populations., However, published data on the characteristics and treatment patterns of, and outcomes for, MM patients in Saudi Arabia are scant.
This consensus meeting brought together a panel of Saudi experts in MM to share their views on current trends and practice in Saudi Arabia and how these compare with the global picture.
The present consensus was developed as a part of the Saudi Lymphoma/Myeloma Group's (SLMG) efforts to address the current practice in the field of hematological malignancies in Saudi Arabia. In order to address the current challenges and to reach a national consensus in the management of MM, the “Scientific Gap Analysis Advisory Board” was held in Riyadh on January 26, 2018; six consultant hematologists/oncologists participated in the meeting and represented six Saudi specialized institutions: national guard hospital in Riyadh, King Faisal Specialist Hospital in Riyadh, King Fahad Medical City in Riyadh, King Fahad Specialist Hospital in Dammam, National Guard in Jeddah, and King Faisal Specialist Hospital in Jeddah. The consultants discussed different aspects of MM management in Saudi Arabia and a consensus statement in each aspect was reached by the agreement of all attendants.
Incidence of Multiple Myeloma in Saudi Arabia
On the other hand, according to the most recent cancer facts and statistics from the USA, the annual age-adjusted incidence rate for MM is 6.5 new cases per 100,000 US general population (1.6% of total cancer cases), with a male-to-female ratio of 1.2; the lifetime risk of developing MM in the USA is only 0.7%. Globally, more than 114,000 new MM cases were diagnosed worldwide in 2012 (0.8% of total cancer cases). In Saudi Arabia, the exact incidence of MM is largely underreported. According to the WHO country profile, MM and lymphomas accounted for 9.6%–11% of cancer-related death in the Kingdom in 2014. According to the 2014 Saudi cancer registry, MM accounts for 1% of total cancer cases, with an age-standardized incidence of 1% in males and 0.7% in females.
The panel noted that the incidence of MM in Saudi Arabia is similar to, but relatively lower than, the global incidence. Although the 2014 Saudi registry shows that the male-to-female ratio of MM in Saudi Arabia is 2, it was suggested that this does not reflect the real pattern because a considerable proportion of cases are underreported. In line with this, a number of retrospective studies show the male-to-female ratio of MM in Saudi Arabia to be about 1.5. In addition, the panel agreed that 135 new MM cases would be expected every year.
It was proposed that the lower incidence rates of MM reported in Saudi Arabia compared with the global rates can be partly attributed to: the lack of serum-free light chain (FLC) testing in many hospitals; the high incidence of MM among elderly individuals, who tend to receive palliative care rather than a referral to a specialized hospital; underreporting of known cases as a result of low MM awareness among healthcare professionals and patients, leading to symptomatic treatment of the patient till death; high rates of misdiagnosis and misclassification; and under-resourcing of the National Cancer Registry.
With regard to age at diagnosis, MM is considered a cancer of elderly patients; current evidence suggests that the average age at diagnosis is about 71 years, with only 1% of patients diagnosed before the age of 40 years., Younger MM patients are reported to present with poorer performance status and have worse outcomes than elderly patients. The panel agreed that the average age of MM diagnosis in Saudi Arabia is similar to the global figures; however, the need for valid and reliable data regarding the age of diagnosis was highlighted. We noted that a considerable proportion of MM patients in Saudi Arabia are diagnosed before the age of 50 years, in contrast to the global picture.
MM patients with high-risk cytogenetics are those who show several cytogenetic abnormalities, such as t (4;14) del (17/17p), t (14;16), and t (14;20), which carry poor prognosis. Cytogenetic abnormalities may dramatically affect the clinical presentation and response to treatment. Previous reports show that cytogenetic abnormalities may be detected in up to 60% of MM patients., There was a discrepancy, in our view, between global reports and the prevalence of cytogenetic abnormalities in Saudi Arabia. The prevalence differed from one hospital to another, and ranged from 10% to 30%. However, the panel agreed that almost one-third of individuals with MM presenting to the Saudi health care system have cytogenetic abnormalities. The difference between the global figures and situation in Saudi Arabia was attributed to the low level of awareness of, and training in, cytogenetic abnormality testing, particularly among nonhematologists. The panel highlighted the importance of the availability of cytogenetic service, including FISH, in large healthcare facilities in the different regions of the Kingdom and the need for greater awareness of the importance of cytogenetic abnormalities among non-hematologists.
There are many reasons for the underreporting of MM cases in Saudi Arabia which may lead to the false notion of lower incidence of MM in the Kingdom than other parts of the world. Therefore, there is a need for a central unified and updated national registry in order to reflect the current trends of MM patients in Saudi Arabia. The panel highlights the importance of outreach campaigns, primary care hospitals support groups, and controlled social media support groups as well.
Diagnosis of Multiple Myeloma
It is reported that one-third of MM patients are asymptomatic at the time of presentation, with incidental abnormalities in renal or blood analysis found during routine examination., Symptomatic patients commonly present with nonspecific symptoms, such as fatigue, anemia, bony pain, and osteolytic skeletal lesions. Approximately 1%–2% of patients with MM have the extramedullary disease at the time of initial diagnosis. The panel agreed with this picture; the commonly encountered presentations described at the meeting were bone pain and Calcium, Renal failure, Anemia and Bone lesions (CRAB)-related symptoms (i.e., elevated CRAB), such as renal failure, unexplained anemia, and pathological fractures.
With regard to the initial diagnostic approaches, the current National Comprehensive Cancer Network (NCCN) clinical practice guidelines on MM recommend the inclusion of serum lactate dehydrogenase (LDH) and beta-2 microglobulin, serum quantitative immunoglobulins, serum protein electrophoresis, serum immunofixation electrophoresis, 24-h urine for total protein, urine protein electrophoresis, urine immunofixation electrophoresis (UIFE), FLC assay, and plasma cell fluorescence in situ hybridization (FISH) in the initial diagnostic workup. However, the diagnostic tests performed routinely for MM patients in Saudi Arabia are CBCD, RP, HP, IgQ, SPEF, serum FLC assay, 24-h urine serum for total protein, UIFE, protein electrophoresis, beta-2 macroglobulin, serum LDH, BMA, and Bx + FISH panel for MM, and imaging studies with either a skeletal survey or whole-body magnetic resonance imaging (MRI).
In 2014, the International Myeloma Working Group (IMWG) updated their criteria for the diagnosis of MM. According to recent updates, the individual is considered to have MM when the following two criteria are met: (1) clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma; and (2) myeloma-defining events, which comprise established CRAB features as well as three specific biomarkers. The updated IMWG criteria presumably allow for early diagnosis and management of MM patients before end-organ damage. The panel agreed to follow the IMWG criteria for MM diagnosis in their institutions. The panel also emphasized the importance of monoclonal plasma cells and FLC assays for establishing the diagnosis.
There are several techniques for diagnosing cytogenetic abnormalities, with widely varying accuracy. Conventional karyotyping was reported to detect cytogenetic abnormalities in 20%–30% of patients, mainly the numerical abnormalities. Though FISH is considered the standard technique for cytogenetic analysis, it does not detect single-nucleotide variants. Single-nucleotide-polymorphism-based mapping arrays and comparative genomic hybridization exhibit high sensitivity for numerical aberrations. Although gene expression profiling is a significant prognostic tool that can identify a high-risk profile, it cannot be performed in Saudi Arabia.
Till date, conventional skeletal survey (CSS) is still the standard imaging modality for the evaluation of myeloma bone disease. However, previous reports showed a low sensitivity of CCS for the detection of myeloma lesions; Therefore, the updated IMWG have implemented cross-sectional imaging modalities such as computed tomography (CT) and MRI. While positive CCS is usually sufficient to indicate major bone damage with no further needs for confirmatory imaging, almost 25% of the patients with negative CSS will show significant bone damage in CT scan. The panel members had different views on the standard imaging technique for detecting cytogenetic abnormalities in MM patients. Low-dose CT or whole-body MRI was suggested, as was low-dose CT plus positron emission tomography (PET) for response assessment. Whole-spine MRI was proposed as the best modality for assessing suspected MM. In one of the institutions represented, PET is routinely performed for all patients and also for follow-up. Another opinion was that whole-body CT or skeletal survey remains the standard, with PET and MRI useful in certain cases and mandatory for suspected solitary plasmacytoma and smoldering myelomas. In general, the panel agreed that whole-body MRI and low-dose CT scan are the imaging modalities of choice. For risk stratification, the panel agreed with the IMWG recommendations.
The time between symptom onset and diagnosis can be excessive for hematological malignancies; multiple primary care consultations before referral to secondary care may significantly contribute to the delay. Existing SEER-based studies suggest that the average time to diagnosis of MM is between 3 and 5.5 months. Another large retrospective study showed that the delay in the diagnosis of MM may extend past 12 months. To the best of our knowledge, there are no existing reliable data from which to estimate the average time from initial presentation to diagnosis in Saudi Arabia. Strikingly, a Saudi individual may not see a specialist hematologist/oncologist for 6 months, or sometimes 1 year, after initially noticing MM symptoms. This delay was attributed to initial misdiagnosis and the complicated referral system. In the USA, the initiation of chemotherapy and the assessment of eligibility for autologous stem cell transplantation (ASCT) require referral to a specialized hematologist/oncologist. The assessment of infection, adverse treatment effects, and renal and thrombotic complications may require long-term follow-up by family physicians. The referral system in Saudi Arabia was acknowledged as being unclear and complicated, with many barriers, such as long distances between the patient's home and the hospital location and long waiting lists (although patients are usually seen very quickly in the hospital, some wait for a month).
The panel emphasizes on the importance of monoclonal plasma cells and FLC assays for establishing the diagnosis of MM. In addition, the panel agreed that whole-body MRI and low-dose CT scan are the imaging modalities of choice. For risk stratification, the panel agreed with the IMWG recommendations.
Treatment paradigms for MM have changed dramatically since 2000, from alkylators/corticosteroids/high-dose chemotherapy to proteasome inhibitors and immunomodulatory drugs., Previous systematic reviews and meta-analyses demonstrated that therapy based on bortezomib, the most commonly used proteasome inhibitor, significantly improved the response rate and overall survival in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients.,, In addition, ixazomib and carfilzomib were effective and well tolerated in RRMM patients., With regard to immunomodulatory drugs, lenalidomide effectively improved the response rate, progression-free survival, and overall survival of MM patients in a large number of randomized controlled trials, either alone or in combination with dexamethasone.,, In contrast, regimens including thalidomide, doxorubicin, vincristine, or melphalan have been removed from many guidelines because of their toxicity or the availability of more effective treatment.,
Newly diagnosed multiple myeloma
In NDMM patients with active disease, the treatment approach depends on whether the patient is eligible for stem cell transplantation or not. Transplant-eligible patients are those with adequate organ function. ASCT is considered the standard of care. With the introduction of novel agents, the response rate to ASCT has improved dramatically in recent years. At the meeting, the panel noted that they usually follow the NCCN guidelines for the treatment of NDMM patients in their institutions. These recommend the three-drug regimens for transplant-eligible patients. A local guideline has been developed in one of the institutions, based on the drugs available.
Bortezomib/cyclophosphamide/dexamethasone (VCD), bortezomib/doxorubicin/dexamethasone and bortezomib/lenalidomide/dexamethasone (VRD) were the regimens preferred by the NCCN for induction therapy. Two members of the expert panel stated that they use the VCD regimen, while the remaining panel members said they use the VRD regimen. However, in one of the institutions represented, the carfilzomib/lenalidomide/dexamethasone (KRD) regimen is considered for certain patients.
The NCCN recommends harvesting peripheral blood early in the course of primary treatment, preferably after three to four cycles of initial therapy. In Saudi Arabia, the number of pretransplant cycles varies, ranging from four to eight cycles, with some institutions usually giving three or four pretransplant cycles and an additional two cycles if the patient has not achieved complete remission before transplantation. It was also emphasized that the decision to perform ASCT depends on disease progression status and induction outcome.
For maintenance therapy, lenalidomide was considered category 1 by the NCCN. However, there are several reports of a higher incidence of secondary malignancies when lenalidomide is used as maintenance therapy posttransplantation. Bortezomib is another option suggested by the NCCN. The panel agreed that lenalidomide is normally used as maintenance therapy; however, bortezomib plus dexamethasone may be considered for high-risk patients. Different views were expressed on the duration of maintenance therapy. The majority supported 1–2 years of maintenance therapy, while others supported the concept of “treat till disease progression.” Although the IMWG recommends continuing lenalidomide maintenance treatment until disease progression or untoward toxicity, it is not clear whether shorter-duration therapy is similarly effective. In general, maintenance therapy has a beneficial effect on survival compared with no maintenance therapy, though it is associated with a higher degree of grade 3/4 toxicities.,
Supportive care is an important aspect of management of both NDMM and relapsed patients. Previous studies report that 80% of MM patients have bone complications and up to 33% have renal complications. Randomized controlled trials report that intravenous pamidronate and zoledronic acid significantly reduce the rate of skeletal-related events and improve the quality of life in MM patients., However, bisphosphonates are largely contraindicated in patients with severe renal impairment.
Relapsed and refractory multiple myeloma
In US clinical practice, regimens based on bortezomib are the cornerstone of therapy for RRMM patients; bortezomib is used either as first-line therapy or for retreatment in patients who achieved a durable response before disease relapse. The panel's views on optimal regimens for RRMM patients varied considerably. Two members described their use of daratumumab/bortezomib/dexamethasone (DVD) and KRD regimens, with patients undergoing a second transplant in the case of late relapse. Another member reported using VRD and KRD regimens.
The panel attributed the difference in preferred treatment regimens among Saudi institutions to resource-related factors (cost of medications, availability of drugs and their efficacy, patient preference/convenience) and disease-related prognostic factors (renal failure, age, comorbidities, cytogenetic abnormalities, risk of the disease and other diseases, treatment-related toxicity, and local physician experience and practice). The panel agreed on the need for outreach and educational programs and unified local guidelines for better outcomes in RRMM.
Another important issue is the assessment of minimal residual disease (MRD) in response to therapy. The current body of evidence shows that MRD-negative patients achieve longer progression-free survival and overall survival compared with MRD-positive patients, reflecting the prognostic importance of MRD assessment. Previous studies have demonstrated the high sensitivity of next-generation flow and sequencing methods for the detection MRD, and these may be combined with functional imaging to detect MRD outside of bone marrow. The use of PET to detect MRD was agreed, as was the need for well-designed studies to address the optimal assessment of MRD. Despite this discussion, the panel noted that MRD is not usually assessed in Saudi institutions.
The role of healthcare professionals (nurses and hematopathologists) is pivotal to the management of MM patients. Nurses contribute to all aspects of MM management, particularly the prevention and management of complications of the disease and its treatments, and the provision of information and support. The hematopathologist plays critical role in the diagnosis and staging of MM, especially given the recent advances in biomarkers and genomic analysis that can predict the disease course and response to treatment. The panel emphasized the need for quality improvement projects, MM coordinators, and education for hematopathologists and molecular hematologists to improve patient outcomes and minimize the risk of miscommunication between different disciplines.
In conclusion, the clinical challenges highlighted in the management of MM were: high cost of medications; availability of drugs; patient compliance with follow-up; the severity of treatment-related adverse events; and the wide variation in treatment response. The panel highlighted the need for a multi-disciplinary approach that includes the technical staff who have experience in flow cytometer and other laboratory testings
Treatment of high-risk cytogenetic multiple myeloma patients
The IMWG recommends the use of high-dose therapy (HDT) plus double ASCT as the standard therapy for high-risk MM patients. Bortezomib/thalidomide combinations with HDT + ASCT partly improves the response rate and progression-free survival. In high-risk patients, the treatment differs in all phases. Induction by a triplet regimen followed by tandem ASCT is the best option, followed by maintenance with bortezomib-based treatment with or without lenalidomide.
The management of different phases of MM varies among Saudi institutions; however, the regimens usually follow the recommendations of the NCCN and IMWG guidelines. The panel highlighted the need for a multi-disciplinary approach that includes the technical staff who have experience in flow cytometer and other laboratory testings.
Follow-up and outcomes
The rise of novel treatment options for MM over the past 15 years has led to substantial survival gains. According to a real-world trial from the USA, individuals diagnosed in 2012 were 1.25 times more likely to survive for 2 years than patients diagnosed in 2006. MM patients also showed improved survival outcomes over the study period, with the 2-year survival gap between MM patients and their matched controls decreasing at a rate of 3% per year. However, patient adherence to treatment is a major concern. Patients with MM undergo continuous therapy for several years; therefore, adherence and persistence with MM treatment are critical to a better prognosis. Recent data from the USA suggest that non-adherence may be as high as 50%. In Saudi Arabia, a considerable proportion of patients do not attend their clinic appointment. Moreover, more staff are needed for optimal follow-up. Concerns were also expressed about physician adherence; some physicians do not schedule appointments according to treatment protocols. Patient-centered treatment is needed. Triplet oral regimens (ixazomib, lenalidomide and dexamethasone) would reduce the frequency of clinic visits to receive treatment and thus would be expected to achieve better treatment adherence.
The rate of nonadherence can be attributed to the lack of insurance/cost of medication, disease-related morbidities, lack of social support, lack of proper knowledge about the importance of adhering to a treatment plan, treatment toxicity, and patients skipping doses.
Most attendees followed-up their patients closely following ASCT, i.e., twice weekly after discharge, then weekly, then once every 2 weeks until the patient becomes stable, and then every 1–3 months. Others said they usually followed up their patients every month. However, our group concluded that the follow-up should vary according to the stage of disease and disease progression.
Disease-related long-term complications and treatment-related toxicities are major concerns in MM, and impact prognosis– they include renal impairment, skeletal fractures, peripheral neuropathy, and hematologic complications. In a recent real-world study from the USA, a consistent increase across the majority of comorbid conditions and disease-related complications was observed as patients progressed through the lines of therapy for MM. The Charlson comorbidity index (CCI) increased for these patients as they progressed through the lines of therapy: the mean CCI was 0.77 at the start of the first line, 0.86 at the start of the second line, and 0.91 at the start of the third line. Among the 1707 patients, 22.7%, 25.4%, and 25.9% had CCI 2 at the start of first-, second-, and third-line therapy, respectively. During the 6 months before the start of first-, second-, and third-line therapies, the percentage of patients with comorbidities or disease-related complications increased as patients progressed to higher lines of therapy. The panel members stated that the most commonly encountered treatment-related adverse events in their institutions are: dental-related toxicities; peripheral neuropathies; and skin rashes.
Saudi Arabia is the largest country in the Arabian peninsula, with a population of more than 28 million. Despite healthcare being free to Saudi citizens, a number of potential barriers to healthcare access and individual healthcare seeking have been reported., While MM is a relatively uncommon cancer in Saudi Arabia, it has been reported that the characteristics of Saudi patients with MM differ from those of western MM patients, highlighting the need for a national study of the trends and outcomes of MM in Saudi Arabia.,, However, published literature on MM patient characteristics, treatment patterns, and outcomes in Saudi Arabia is scant.
The SLMG held a consensus meeting to gather views from a panel of Saudi experts on current trends and practice regarding MM in Saudi Arabia, and to compare their views with current global trends and practice. Panel members agreed that the clinical characteristics of MM patients in Saudi Arabia are similar to the characteristics described globally. However, they highlighted the need for a central, unified, and updated National Registry to monitor the current trends in MM.
Although serum FLC assay was considered an essential diagnostic tool by the panel members, as many Saudi healthcare facilities do not have access to serum FLC tests, the average time for MM diagnosis and referral from the first presentation may be as long as 1 year. Issues around the availability of drugs have led to the development of local management guidelines in some Saudi institutions. However, most institutions follow NCCN guidelines. Finally, the panel members recommended the development of educational and quality improvement programs to improve patient adherence and compliance rates.
Conclusions and Recommendations
There is a need for a central, unified, and updated National Registry to chart the current trends in MM patients in Saudi ArabiaOutreach campaigns, primary care hospitals support groups, and controlled social media support groups should be used to ensure a high level of awareness of physicians about the common presentation of MMPrompt access to tertiary health care is needed for MM patients to overcome current delays in diagnosis and managementThe healthcare authority needs to address the high cost of medication and availability of drugs to improve treatment outcomesWell-designed studies are needed to address the optimal assessment of MRD and to unify the management of MM through study protocols and local guidelinesPatient-centered treatment is needed to improve patient adherence and minimize the risk of severe adverse events.
The present consensus was sponsored by Takeda-KSA pharmaceuticals. Takeda-KSA played no role in gathering, analyzing, or interpreting the manuscript. Saudi Lymphoma/Myeloma Group would like to thank Takeda-KSA pharmaceuticals for providing the logistics for this meeting. Medical Writing was provided by Ahmed Elgebaly, MD, Reham ElGarhy, MD, and Fady Adel, MSc Pharm of RAY contract research organization, and was funded by Takeda-KSA.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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