|Year : 2023 | Volume
| Issue : 2 | Page : 71-77
Approaches to multiple myeloma management in gulf countries: A narrative review insights from the Kingdom of Saudi Arabia and gulf multiple myeloma experts
Fahad Z Al Sharif1, Ahmad Alhuraiji2, Arif Alam3, Ayman Alhejazi4, Hani Osman3, Hesham El Sabah5, Faraz Khan6, Majed Alahmadi7, Musa Alzahrani8, Mustaqeem A Siddiqi9, Omar Zeid Abdeljalil10, Ahmed Hesham11, Magdy Rabea11, Waleed Hannout11, Mahmoud Marashi12
1 Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Hematology, Kuwait Cancer Control Center, Kuwait City, Kuwait
3 Department of Oncology, Tawam Hospital, Dubai, Saudi Arabia
4 Department of Oncology, King Abdulaziz Medical City, Dubai, Saudi Arabia
5 Hamad Medical Corporation, National Center for Cancer Care and Research, Dubai, Saudi Arabia
6 Department of Oncology, American Hospital, Dubai, Saudi Arabia
7 Department of Adult Hematology and HSCT, King AbdulAziz Medical City, King Saud bin Abdul Aziz University for Health Sciences, Riyadh, Saudi Arabia
8 Department of Medicine and Oncology Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
9 Division of Oncology and Hematology, Sheikh Shakhbout Medical City, Abu Dhabi, Saudi Arabia
10 Department of Oncology, King Fahd Specialist Hospital in Dammam, Dammam, Saudi Arabia
11 Department of Medical Affairs, Sanofi, GCC, Dubai, UAE
12 Department of Hematology, Dubai Health Authority, Mediclinic City Hospital, Dubai, UAE
|Date of Submission||07-Dec-2022|
|Date of Decision||12-Feb-2023|
|Date of Acceptance||02-Mar-2023|
|Date of Web Publication||27-Jul-2023|
Dr. Mahmoud Marashi
Department of Hematology, Dubai Health Authority, Mediclinic City Hospital, Dubai
Source of Support: None, Conflict of Interest: None
Multiple myeloma (MM) is neoplasm of the plasma cells derived from the postgerminal B-cell lineage and it ranges from premalignant conditions like monoclonal gammopathy of unknown significance and smoldering MM (SMM) to malignant diseases such as overt MM. With advances in science and technology, the understanding of the disease has increased paving the way for advanced therapeutic options and better patient outcomes. Thus, this article is a narrative review summarizing the recent advances in the epidemiology, clinical presentation, risk stratification, and MM patient populations treatment and to provide insights by the authors who are experts in the field of MM management who are considered as Gulf Myeloma Working Group and who were the members of 'Approaches to MM Management' Advisory Board meeting held on October 29, 2021. The expert panel provided several recommendations and drawn consensus statements pertaining to MM management in the Gulf countries.
Keywords: Gulf countries, multiple myeloma, plasma cells, relapse, Saudi Arabia, treatment
|How to cite this article:|
Al Sharif FZ, Alhuraiji A, Alam A, Alhejazi A, Osman H, El Sabah H, Khan F, Alahmadi M, Alzahrani M, Siddiqi MA, Abdeljalil OZ, Hesham A, Rabea M, Hannout W, Marashi M. Approaches to multiple myeloma management in gulf countries: A narrative review insights from the Kingdom of Saudi Arabia and gulf multiple myeloma experts. J Appl Hematol 2023;14:71-7
|How to cite this URL:|
Al Sharif FZ, Alhuraiji A, Alam A, Alhejazi A, Osman H, El Sabah H, Khan F, Alahmadi M, Alzahrani M, Siddiqi MA, Abdeljalil OZ, Hesham A, Rabea M, Hannout W, Marashi M. Approaches to multiple myeloma management in gulf countries: A narrative review insights from the Kingdom of Saudi Arabia and gulf multiple myeloma experts. J Appl Hematol [serial online] 2023 [cited 2023 Oct 2];14:71-7. Available from: https://www.jahjournal.org/text.asp?2023/14/2/71/382409
| Introduction|| |
Multiple myeloma (MM) is a neoplasm derived from the plasma cells of the postgerminal lymphoid B-cell lineage. Plasma cell dyscrasias are a spectrum of disease, which ranges from premalignant conditions such as monoclonal gammopathy of unknown significance (MGUS) and asymptomatic MM called smoldering MM (SMM) to malignant diseases such as overt MM and plasma cell leukemia that may be associated with end-organ damage and significant morbidity. Although almost all cases of MM evolve from MGUS, MGUS cases have only a 5% absolute risk of MM progression. MGUS may also develop into other associated disorders such as the Waldenstrom's macroglobulinemia, primary AL amyloidosis, or a lymphoproliferative disorder. Over the last few years, the understanding regarding the disease process of MM and the pharmacotherapeutic armamentarium for the treatment of MM has tremendously increased.
Thus, the aim of the current review was to summarize the current knowledge regarding the epidemiology, clinical presentation, risk stratification, and treatment of newly diagnosed MM including newer therapies to treat different MM patient special populations and to provide author's insights who are experts in the field of MM management. The insights from the working group for MM management were developed with an effort to address the current challenges of MM treatment in the Gulf Countries and to provide the recent local methodologies in the management of MM, especially in special populations of MM patients.
| Methods|| |
This review article is a narrative review based on available literature. This was done using Medical Subject headings (MeSH) terms or equivalent such as “Multiple Myeloma” and “Plasma cell dyscrasias” in PubMed Central, PubMed, Medline, and Google Scholar. In addition, the key discussions of the Gulf Myeloma work group and members of “Approaches to MM Management” Advisory Board meeting held on October 29, 2021, were incorporated as expert opinions on MM Management in the Gulf region. A total of 12 MM working group members from the Kingdom of Saudi Arabia (KSA), United Arab Emirates, Kuwait, and Qatar attended the meeting. The statements presented in this article represent the authors' opinion and the management recommendations that were formed by a panel of MM experts from Gulf Countries during the advisory board discussions, which was subsequently drafted and peer-reviewed by the authors.
Epidemiology of multiple myeloma in the Gulf region
MM accounts for approximately 1%–2% of all cancers and nearly 17% of all hematologic malignancies with an annual incidence of approximately seven per 100,000 people per year. It has a slight male preponderance (men: women = 1.4:1), and the median age at diagnosis is the seventh decade of life. Some of the well-known risk factors include African race, high body mass index, and exposure to agent orange. However, in the Gulf countries, a case series of 92 MM patients from the KSA, treated at a single center between 1975 and 1987 showed the mean age to be 56 years with a greater male preponderance (men: women = 2:1). The experts also agreed on the opinion that in their practice, roughly two-thirds of the patients they treated were men and the median age is approximately the 5th decade of life. With regard to the comorbidities, the experts opined that approximately 25% are expected to have renal impairment and 10%–15% to have cardiac diseases.
Clinical presentation of multiple myeloma
Patients with MM commonly present with anemia, musculoskeletal pain, elevated creatinine, fatigue, hypercalcemia, and weight loss. Some of the less common signs and symptoms include paresthesia, hepatosplenomegaly, lymphadenopathy, and fever.
The recommended assessments for the diagnosis of MM comprises of different investigative modalities including history/physical examination, routine testing (blood counts, routine biochemistry, lactate dehydrogenase [LDH], β2microglobulin, serum protein electrophoresis and immunofixation, immunoglobulin light changes, [kappa, lambda, and K/L ratio], quantitative immunoglobins level [Ig G, Ig A and Ig M], 24h urine proteinuria, quantification of both urine M-component and albuminuria), bone marrow testing (aspirate and trephine biopsy and cytogenetics, fluorescent in-situ hybridization [FISH] and immunophenotyping), Imaging (positron emission tomography [PET], low-dose computed tomography [LDCT], whole-body magnetic resonance imaging [MRI] for lytic lesions or spine), and assessment for other comorbidities using chest X-ray, electrocardiogram, electrocardiography etc. In the opinion of the Gulf myeloma working group members, MM Immunoglobulin G disease followed by the light chain and Immunoglobulin A disease are more frequently encountered and many of the patients get diagnosed at a late stage of the disease presenting with excessive disease or renal impairment. In general, bone disease problems were the single most common presentation observed and PET/CT is the most sensitive modality of diagnosis with skeletal survey or other biochemical abnormalities raises the clinical suspicion of MM. Although some centers reported to have begun using LDCT of late, most patients in the Gulf countries also undergo FISH but only a few centers in a few countries have cell sorting and CD-138 identification facilities, thereby resulting in frequent false negative FISH results. In general, the workup follows the IMWG criteria.
Definitions of multiple myeloma special populations
Progressive disease after a response has been obtained to prior therapy, currently requiring salvage therapy, but does not meet the criteria for “primary refractory” or “relapsed and refractory” MM categories, based on laboratory and radiologic evidence such as:
- ≥25% increase from the lowest confirmed response of the monoclonal protein (M-protein) in the serum (absolute increase ≥0.5 g/dL) or in the urine (absolute increase, ≥200 mg/day) or
- ≥25% increase from the lowest confirmed response between uninvolved and involved serum-free light chains (absolute increase >10 mg/dL) or
- >10% increase of the absolute percentage plasma cells in the bone marrow or
- Development of new soft tissue (extramedullary) plasmacytomas or bone lesions.
It is defined as MM progression identified based on an increase in M-protein alone with no associated symptoms or MM-associated organ dysfunction.
It is defined as the presence of direct indicators of increasing disease such as new soft-tissue plasmacytomas or bone lesions and/or end organ dysfunction (CRAB features – Hypercalcemia, renal failure, anemia and bone lesions) due to the to the underlying plasma-cell dyscrasia. The features of end organ dysfunction are defined as follows:
- Hypercalcemia (serum calcium concentration >11.5 mg/dL)
- Renal failure (rise in serum creatinine level ≥2 mg/dL from the start of the therapy and attributable to myeloma)
- Anemia (fall in hemoglobin level by ≥2 g/dL unrelated to therapy or other nonmyeloma-related conditions) and
- Hyper viscosity related to serum paraprotein level.
Relapsed and refractory
It is an MM disease that is either nonresponsive when undergoing salvage therapy or becomes progressive within 60 days of last therapy in patients who had achieved a minor response (MR) or better on previous therapy.
This refers to refractory MM disease in patients who have never achieved an MR with any of the therapies. These include patients in whom there is no stark change in the concentration of M-protein, no evidence of clinical progression, and who never achieve an MR or better.
These patients are defined by the presence of any of the following:,,
- Aggressiveness at relapse (extramedullary disease, high LDH, high β2M, high plasma cell count that does not fulfill criteria for the diagnosis of plasma cell leukemia (plasma cell count of >20% of the total white blood cell count in the peripheral blood smear) a high plasma cell proliferative index at post-autologous stem-cell transplantation, short duration of response or progression while on therapy, rapid-onset of symptoms, disease-associated organ impairment, and isotype transformation such as light chain escape or hyposecretory disease)
- Adverse cytogenetic abnormalities [del (17p), t,(4;14) t (14;16), t (14:20), del (1p) and Gain 1q].
Lenalidomide refractory multiple myeloma
It is defined as any progressive disease during therapy or within 60 days of discontinuation from lenalidomide-containing regimens or no response (less than partial response) to prior lenalidomide-containing therapy.
Risk Stratification in multiple myeloma
Since the disease heterogeneity influences outcomes, the prognosis and treatment choices are stratified based on the following:,
- Disease burden (MM International staging system 2 stage/MM Revised ISS stage, Mayo Stratification of Myeloma and Risk-Adapted Therapy [mSMART] stage and presence or absence of extramedullary disease)
- Host factors (Age, Eastern Cooperative Oncology Group Performance Status, renal function)
- Disease Biology (cytogenetic risk, gene expression profile, plasma cell proliferation, presence of circulating plasma cells, plasmablastic morphology and LDH).
The R-ISS stages comprises three stages, stages I–III. Stage I incudes all of the following namely, serum β2-macroglobulin <3.5 mg/L, serum albumin ≥3.5 g/dL, standard risk chromosomal abnormalities by interphase FISH (iFISH), and normal LDH. On the other hand, stage III includes serum β2-macroglobulin ≥5.5 mg/L with high risk chromosomal abnormalities by iFISH or high LDH and stage II includes MM that do not fulfill criteria for stages I and III. The mSMART staging on the other hand, defines the presence of any two high-risk factors as double-hit myeloma and the presence of three or more high-risk factors as triple-hit myeloma. These high-risk factors include high-risk genetic abnormalities [t(4;14), t(14:16), t(14:20), Del 17p, p53 mutation and Gain 1q)], R-ISS Stage 3, and Gene Expression Profiling high risk signatures.
Pharmacotherapy of multiple myeloma
Of late, there has been an increase in the number of treatment options that are available for the treatment of MM. The following are the classes of drugs that are approved by the United States Food and Drug Administration:
- Alkylating agents: Cyclophosphamide (C), melphalan (M)
- Topoisomerase II inhibitors: Doxorubicin
- Vinca Alkaloids: Vincristine
- Proteosome inhibitors: Bortezomib (V), Carfilzomib (K), Ixazomib (Ixa)
- Histone deacetylase inhibitors: Panabinostat
- Corticosteroids: Dexamethasone (d), Prednisone (P)
- Anti-CD-38 Monoclonal Antibody (MAb): Daratumumab (D), Isatuximab (Isa)
- Anti-SLAMF7 MAb: Elotuzumab (Elo)
- Immunomodulators: Thalidomide (T), Lenalidomide (R), Pomalidomide (Pom)
- Selective inhibitor of nuclear export (SINE): Selinexor (S)
- Selective inhibitor of BCL-2: Ventoclax (Ven)
- Anti B-cell maturation antigen with microtubule-disrupting agent, monomethyl auristatin F (MMAF): Belantamab Mafadotin
- Chimeric antigen receptor T cells (CAR-T): Idecabtagene vicleucel, ciltacabtagene autoleucel.
- Bispecific T-cell Engagers.
| Multiple Myeloma Treatment Approach and Guidance|| |
The following are excerpts from the European Hematology Association (EHA) and European Society for Medical Oncology (ESMO) guidelines approved in 2020 for the diagnosis and management of MM.
Newly diagnosed multiple myeloma
Patients who are less than 70 years of age and without comorbidities, the treatment of choice is induction therapy followed by high dose Melphalan (200 mg/m2) conditioning and autologous stem cell transplantation (ASCT). For induction, 4–6 cycles of VRd or DVTd is the treatment of choice. If these are not available, the second choice of induction agents may be VTD or VCD. Post-ASCT maintenance with lenalidomide or in high-risk disease, bortezomib may be considered. Although consolidation therapy post-ASCT is not an established standard of care, patients who receive VCd induction may be given 2 cycles of VCd consolidation. In case of genetically defined high-risk disease tandem ASCT is recommended. In patients who are not eligible for ASCT, the options for standard of care include, VRd, DVMP and DRd. If none of the three regimens are available, the second choice includes Rd or VMP while Vd could be a good option in some frail patients.
Multiple myeloma patients at 2nd line of treatment
Based on the first-line treatment, there are three different scenarios that would exist and the resultant second-line options, which are summarized in [Table 1].
In patients who received ASCT followed by lenalidomide maintenance as their primary therapy and duration of the initial remission is ≥36 months, then second-line ASCT may be considered. Also, in patients with t(11; 14) who have failed lenalidomide and are sensitive to proteosome inhibitors, VenVd may be considered.
- MM patients at 3rd line of treatment and above: For those who are lenalidomide and bortezomib refractory, the recommended regimens include DKd, IsaPd, EloPd, IsaKd, DPd. While for those who are lenalidomide refractory but proteosome inhibitor sensitive, in addition to the previously mentioned regimens, DVd, SVd and VenVd are suitable. The alternative and less preferred regimens include PomCd and Daratumumab as a single agent. For patients who are triple class refractory the recommended treatment includes Sd or belantamab mafodotin monotherapy.
| Challenges in Multiple Myeloma Management in the Gulf Countries|| |
The experts summarized the challenges that hinder the medical management of MM patients in the Gulf Countries under two broad categories of clinical challenges and patient-perspective challenges. Some of the clinical challenges include the lack of LDCT scan, lack of consistent availability of PET scan for staging, lack of minimal residual disease (MRD) testing facilities, Lack of CD138 selected FISH, late diagnosis and referrals, inaccessibility of medications to expats, turn-around time for completion of tests and cytogenetics infrastructure, and busy chemotherapy room. Patient perspective challenges include a tendency to delay the initiation of treatment waiting for second or third opinion, expat status and wishes to travel home, affordability issues especially for the expats, insurance refusals, patient treatment spread over many countries, and drug going suddenly out of stock. Given these challenges, the experts suggested several solutions to overcome such challenges.
| Gulf Myeloma Working Group insights for Multiple Myeloma Management|| |
For newly diagnosed multiple myeloma patients
- In Transplant eligible patients VRd, DVTd, VTd, VCd are induction options mentioned in the ESMO guidelines. However, VTd has not been commonly used for the past few years
- Triplet therapy with VCd in patients with impaired renal function is the preferred induction treatment. While quadruplet of Anti-CD38 plus VRd is the experimental treatment with a potential in future to become the standard of care for both transplant-eligible and transplant ineligible newly diagnosed multiple myeloma
- In transplant ineligible patients, DRd and VRd are the preferred options as first-line. D-VMP has not been used quite often in the region.
For RRMM after 1st relapse based on refractory status
- In case of Len-refractory patients, the most appropriate regimens would Anti CD38-Pd or Anti CD38-Kd. In those who have already received an Anti CD38 therapy upfront, K-based therapy such as PomKd may be the preferred choice of therapy. Alternate option but rarely used is KCd
- Anti-CD38 therapy may be used again in such patients preferably after a significant time of almost 6 months has passed since last Anti-CD38 dose
- Those who are eligible for SCT, transplant option shall be explored. Second transplant may be considered only after they complete 36 months of first transplant remission
- In patients who are Bortezomib refractory and Lenalidomide sensitive DRd, KCd, or PomKd may be preferred
- In case of double refractory patients, DKd, IsaKd, IsaPd, PomKd, or KCd, may be considered. For those in whom anti-CD38 was used upfront, PomKd or KCd may be considered
- In frail patients, IxaRd may be considered in lenalidomide sensitive and PomCd may be considered in lenalidomide refractory patients.
For RRMM after 2nd relapse and lenalidomide refractoriness
- Depending on the drugs used in previous line therapies, Pomalidomide based regions such as Isa-Pom-d or Pom-d etc., are preferred. Other therapies include Antibody Drug Conjugate Balantumumab or Selinexor or Elotuzumab based regimens
- Venetoclax is preferred in patients with t (11, 14) or those with plasma cell leukemia or extramedullary disease with refractoriness to multiple drugs requiring high-dose chemotherapy
- CAR-T cell therapy is approved for triple refractory MM. However, access to the same is still an issue to many patients and many treating centers in the Gulf countries.
- It was recommended to enroll patients in clinical trials post 2nd relapse
- There is no consensus on the treatment regimen for 3rd or 4th relapse and it depends purely on the history of previous drugs uses and their refractoriness status.
- Providing general supportive care such as vaccinations, antimicrobial prophylaxis, and bone directed therapy, and in few cases, the need to administer radiotherapy must be borne in mind by the treating physician.
Treatment sequencing in multiple myeloma management
With the introduction of new treatment strategies and novel drugs, the landscape of management of MM is completely evolved and continues to do so. In order to achieve a better depth of response that is ascertained by MRD negativity which in turn translates to superior overall survival and progression free survival, highly efficacious drugs are used upfront rather than saving it for use in subsequent relapses as transplant eligible patients have the possibility of an operational cure while transplant ineligible patients have a probability of death following treatment complications or disease progression., Both transplant eligible and transplant ineligible patients would be on Lenalidomide, and refractoriness to Lenalidomide is quite common along with previous exposure to a proteasome inhibitor, more commonly Bortezomib. Despite Lenalidomide refractoriness, there is good scientific evidence that confirms the use of Pomalidomide based triplet regimens during relapse. However, with changing treatment landscape, the anti-CD-38 MAbs which were once used in heavily pre-treated individuals are now being increasingly used as first-line agents. Since there are two biologics in the class of anti-CD-38 MAbs – Dara and Isa, sequencing amongst the two becomes important as well. Both these agents slightly differ in the mechanism of action wherein Isa has more antibody-dependent action rather than complement-mediated cytotoxicity and it relatively relies less on Fc receptor-mediated crosslinking to induce apoptosis. In addition, Isa also inhibits the enzymatic activity of CD38 in a unique manner by allosteric inhibition unlike Dara and thus Isa may retain its efficacy even after Dara refractoriness., Although more research is needed to confirm this, certain early reports for instance, in a multicenter study for among 59 heavily pre-treated RRMM patients from the USA the outcomes suggest that there is real world evidence of clinical evidence in use of Isa following Dara, although modest, if the sequencing is sufficiently spaced out i.e., at least 6 months.
Minimal residual disease testing recommendations
MRD refers to the small number of cells that survive even after treatment and is therefore considered to be an important prognostic factor and a significant predictor of relapse of MM. As per the International Myeloma Working Group (IMWG), 2016, MRD negativity is defined as the absence of cancer cells when tested in the background of at least 105 normal cells as assessed by multi-parameteric flow cytometry (MFC) or next-generation sequencing (NGS) technology in patients with MM who have achieved complete remission. IMWG recommends either intramedullary or extramedullary methods of assessment. Besides MFC and NGS techniques, the intramedullary assessment method alternative testing methods include methods such as allele-specific oligonucleotide quantitative polymerase chain reaction (ASOqPCR), and next generation flow cytometry (NGF). The extramedullary methods include imaging techniques such as F-deoxyglucose PET/CT or MRI scan. It is believed that from diagnosis to MRD, a lot of signaling pathways and gene expressions are modified within the tumor cells and that, clone evolution may occur at MRD which in turn is associated with poor long-term outcomes. However, more research is still needed to answer more unanswered queries in MRD of MM. The members of the Gulf Myeloma Working Group also echoed the same thoughts and further added that the facilities to test MRD are not widely and easily available in all centers and in all Gulf countries.
Future treatment options in the pipeline multiple myeloma
As endorsed by the experts, many times there is no better treatment option available rather than to enroll the patient as a participant in an ongoing clinical trial. A review of the clinical trial registries across the world shows a plethora of studies exploring new targets, new drugs of existing targets as well as different combination of drugs in multidrug treatment regimen. Some of these include, but limited to, the following experimental agents namely:
- Cereblon E3 ligase modulator (CELMoD): Iberdomide, CC92480,
- CAR-T cell therapy: Orvacabtagene autoleucel
- Anti-BCMA antibody–drug conjugates: AMG224, MEDI2228 and HDP-101
- Bispecific T cell engagers: Talquetamab, Cevastomab, Teclistamab, AMG 701, CC93269, AMG 420, REGN5458, PF-06863135
- Bruton's tyrosine kinase inhibitor: Ibrutinib
- Inhibition of MAPK pathway: Vemurafenib and trametinib
- Kinesin spindle protein inhibitor: Filanesib
- Cyclin dependent kinase inhibitor: Dinaciclib.
Besides new drugs, targets and regimens, clinical trial are ongoing to reverse refractoriness and restore drug sensitivity. For example, there is growing evidence that protease inhibitor nelfinavir may exhibit synergistic effect with Bortezomib by impairing proteasome activity. Yet another experimental approach is the use of oncolytic viruses such as the oncolytic Herpes simplex virus type 1.
| Conclusions|| |
We have summarized the current knowledge pertaining to the pharmacotherapy and management guidelines of MM with a special inclination towards MM special population. in this article. We have also drawn consensus statements and provided recommendations pertaining to the Gulf Countries based on the experience of the experts from the Gulf Myeloma work group who routinely manage MM patients and who were also the members of “Approaches to MM Management” Advisory Board meeting held on October 29, 2021. There are certain unique regional differences that pose unique hurdles with regard to availability and affordability of various treatment options. In the Middle East, it is the delayed diagnosis, lack of diagnostic infrastructure, and expat status who either lack medical insurance or to whom newer drugs are unaffordable. Therefore, it is important that the Gulf region also has recommendations curated to the needs of its people. Such region-specific recommendations would help the entire medical community serve the people of that region much better based on latest scientific evidence using available options which in turn would result in better patient outcomes.
Financial support and sponsorship
Sanofi Genzyme has provided advisory board honoraria for authors.
Conflicts of interest
The research upon which this manuscript is based was funded by Sanofi Genzyme. The meeting of the working group was organized and funded by Sanofi Genzyme. All authors were paid honoraria for attending the advisory board. No additional payment was provided for authorship. Magdy Rabea, Waleed Hannout and Ahmed Hesham are employees for Sanofi Genzyme.
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