6. Challenges of multiple myeloma treatment

The last step in the management of multiple myeloma is the therapeutic intervention. The current standard treatment for MM is palliative care. This is a holistic treatment that offers supportive, definitive, and psychosocial care for people living with MM [24]. There is a gross inadequacy in the palliative care of MM in developing countries, hence the call to scale-up the care of people living with MM. This is because of the life-threatening nature and the suffering associated with the disease. A recent study has shown that inadequate palliative care accounts significantly for the low survival interval of MM patients [3]. The overall survival interval of MM patients in various studies in a developing country such as Nigeria showed a range of 3 months to 39.7 months [3, 15–17]. In one of the studies, it was found that only about 7.6% of MM patients survive up to 5 years postdiagnosis. This was far below the estimated 5-year period survival of 32 and 44.9% recorded by Ries et al. [25] and Altekruse et al. [26] in Surveillance, Epidemiology, and End Results (SEER) cancer statistics review of 1975–2002 and 1975–2007, respectively, in the USA. The implication is that many LMICs are more than 40 years backward in terms of management of MM compared to high-income countries such as the USA. The two major challenges in the treatment of MM in developing countries are anchored on the supportive and definitive treatment of MM.

#### 6.1. Challenges in supportive treatment of MM

cytogenetic (FISH) test and this happened to be a high risk category (t(4,14) immunoglobulin A)multiple myeloma [3, 20]. In the study, only four subjects could afford immunofixation test, which showed IgA:IgG-type myeloma ratio of 1:3 and this was in keeping with previous study

5. Challenges due to skeletal related events (SREs) and other complications

MM poses a diagnostic dilemma for the orthopedic surgeons because of the frequent skeletal manifestations." It is usually misdiagnosed as an orthopedic disease when in the real sense it is a hematologic disease with orthopedic complications. At advanced stage, it causes multiple lytic bone lesions with severe osteoporosis and pathological fracture. A recent observational study in Nigeria [14] found that about 84.6% of newly diagnosed multiple myeloma patients in Nigeria presented with multiple bone lesions. Pathological fracture constitutes about 42.3% of SREs in the MM patients in the region. It is surprising to note that 84.6% of all newly diagnosed MM are referrals from orthopedic wards [3, 14]. The key players of the bone lesions in multiple myeloma are cytokines namely IL-6 (Interleukin-6), TNF-alpha (tumor necrosis factor), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and insulin-like growth factor (IGF). These cytokines, especially VEGF and PDGF, have angiogenic effect on the bone marrow microenvironment and this effect favors the growth of myeloma cells in the bone. IL-6, an important osteoclast-activating cytokine, plays an important role in the pathogenesis of osteoporosis in MM [21]. Annibali et al. [22], in their pilot study, described the roles of these cytokines in bone tissue destruction and the effect of zoledronic acid (a bisphosphonate) on their chemical behaviors in MM patients. Other complications such as anemia, hemiplegia, nephropathy, and constipation accounted for 61.5%, 35%, 23%, and 19% of newly diagnosed MM patients in same study. Anemia in MM results from bone marrow invasion by abnormal plasma cells that secret erythropoiesis-suppressive cytokines, and this anemia is usually anemia of chronic disorder [23].

The last step in the management of multiple myeloma is the therapeutic intervention. The current standard treatment for MM is palliative care. This is a holistic treatment that offers supportive, definitive, and psychosocial care for people living with MM [24]. There is a gross inadequacy in the palliative care of MM in developing countries, hence the call to scale-up the care of people living with MM. This is because of the life-threatening nature and the suffering associated with the disease. A recent study has shown that inadequate palliative care accounts significantly for the low survival interval of MM patients [3]. The overall survival interval of MM patients in various studies in a developing country such as Nigeria showed a range of 3 months to 39.7 months [3, 15–17]. In one of the studies, it was found that only about 7.6% of MM patients survive up to 5 years postdiagnosis. This was far below the estimated 5-year period survival of 32 and 44.9% recorded by Ries et al. [25] and Altekruse et al. [26] in

by Salawu and Durosimi [16].

214 Update on Multiple Myeloma

6. Challenges of multiple myeloma treatment

The standard supportive care for MM patients at advanced stage of the disease, which include the use of analgesics, bisphosphonates (BPs), component blood therapy, antibiotics therapy, renal dialysis viz-a-viz renal transplant, radiotherapy, orthopedic care, is grossly inadequate. Chronic bone pain appears to be one of the commonest clinical features of MM, and analgesic drug is the first supportive therapy offered to patients with the disease. However, in the assessment and treatment of pain in MM patients in some low-income countries such as Nigeria, the WHO analgesic ladder for cancer pain control is not usually adhered to, as only few centers can access oral morphine and other opiate analgesics [27]. This leads to analgesic abuse (self-medication), most of which are nephrotoxic, hence, worsening the prognosis of the disease. A study showed that less than 40% of MM patients could afford BPs. BPs are useful in preventing, reducing, and delaying MM SREs such as bone pain, osteoporosis, and other lytic bone lesions. They can also help to control the growth of extramedullary tumors, hence the need to scale-up their usage in MM [22, 28].

There is a gross inadequate access to radiation therapy in LICs including Nigeria. Studies have shown that only about 3.8–20% (average 12%) of MM patients who need radiotherapy at one point or the other of the disease could access it [3, 17]. The major reason is that the megavoltage radiotherapy machine per population size is grossly inadequate (1-MV machine per 24 million population as against the International Atomic Energy Agency (IAEA) requirement of 1-MV machine per 250,000 population or per 350–400 new cancer patients in centers with excellent cancer registry) [29].

About 60% of MM patients seen in LICs such as Nigeria present with severe grade of anemia (hemoglobin <7 g/dL). The implication is that they will rely on blood transfusion therapy in order to improve the quality of their life. Unfortunately, many of the LICs do not practice safe blood transfusion. They depend majorly on commercial (paid) blood donation as against voluntary non-remunerated blood donation (VNRBD), thereby predisposing the patients to transfusion transmissible infectious diseases (TTIs) including HIV [30]. The facilities for component blood therapy (i.e., apheresis machines) are not available in most health centers. For instance, there was no documented beneficiary from component blood therapy in previous studies in Nigeria. All severely anemic patients that require blood transfusion benefited from either allogeneic whole blood transfusion (50%) or the use of erythroid growth factor such as human recombinant erythropoietin (38%) [3, 14].

Infection is one of the major killers in MM in LICs, especially when immune paresis has set in. About 11.1% of MM patients present with neutropenic sepsis in this region. Infection control is by the use of antibiotic therapy/prophylaxis and colony forming unit-granulocyte-monocyte agents (CFU-GM) such as filgrastim or neupogen. However, the later is usually expensive and only very few patients can afford it, hence worsening the survival outcome of the disease [3].

which is based not only on cytogenetic risk classification, but also on host factors, disease stage,

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According to the National Comprehensive Cancer Network (NCCN) guidelines, the consensus standard of care in newly diagnosed MM who have no intention for ASCT is RVD (lenalidomide, bortezomib, and dexamethasone) [36]. This is because RVD has improved median overall survival (OS) compared to conventional RD (75 months versus 64 months; HR 0.709; two-sided p = 0.025), improved overall response rate [ORR] (82 versus 72%), and improved progressive-free

This consensus standard of treatment of MM is yet to be achieved in many developing countries. Unlike in developed countries where treatment is beginning to be customized based on mapping of patient's genome, most low-income countries are yet to offer their patients such opportunities. In Nigeria, the major antimyeloma chemotherapy drug is the old conventional alkylating agent known as melphalan (M), which is usually combined with a steroid (i.e., prednisolone, P) as a double or triple-only combination regimen. MP is still the most accessible commonly used regimen for treating MM patients because of the cost and availability, long after it has been phased out for treating MM patients in developed countries. About 84% of newly diagnosed MM patients in some LICs still depend on MP doublet combination regimen [3].This is contrary to the standard RVD triplet regimen accepted worldwide as the current treatment of choice for MM. About 28% of MM patients from the group of patients already on MP could afford a "partial-standard" triplet regimen made up of either one PI (i.e., bortezomib-melphalan-prednisolone VMP (7.7%)) or one IMiD agent (i.e., thalidomidemelphalan-prednisolone TMP (19.7%). "Partial" in this context connotes combination of a target (novel) therapy with old conventional regimen (i.e., MP in this case). However, a recent study in Nigeria has shown that up to 16.7% of MM patients use bortezomib-thalidomide-dexamethasone (BTD) as their first-line regimen [39]. Although RVD has a better median overall survival (OS), progressive free survival (PFS) and overall response rate (ORR) compared to BTD, this is a move toward the right direction as the latter regimen is close to the standard regimen (RVD) in terms of the benefits derived from a PI and IMiD combination regimens [36]. But, again, this is a bad news for many developing countries as less than 20% of MM patients in the region could access close-to-standard (partial) antimyeloma regimen [40]. The remaining 16% constitute the MM patients who are either on unclassified (i.e., neither known old conventional nor new novel therapy) antimyeloma regimens (such as vincristine adriamycin dexamethasone VAD, CVP, and

Stem cell transplantation (i.e., ASCT) is not a common option of treatment of MM in most developing countries. The only patient (3.8%) who benefited from this intervention from a previous study was outside Nigeria and the patient died two years posttransplantation. There is paucity of data regarding stem cell transplantation in most LICs especially those from Sub-Saharan African region. For instance, no center offers ASCT in Nigeria presently. Although few successful attempts on allogeneic stem-cell transplantation have been made in a center in Southern Nigeria (on sickle cell disease), but it has not been sustainable due to technological inequalities, brain drain of health workers, lack of funding, and political-will from the government. The public health system does not guarantee health insurance coverage

survival (PFS) (43 months versus 30 months, HR 0.712; one-sided p = 0.0018) [37, 38].

and a variety of other prognostic factors.

CVAP) or not on any cytotoxic chemotherapy [3].

There is an increase in the incidence of nephropathy in MM in LICs. A range of 16–36% was recorded in previous studies in Nigeria [3, 17, 31] as against 20% in the USA [32]. A striking finding about the nephropathies in MM patients in LICs is their severity at presentation, which qualifies most of them for renal dialysis (or renal transplant). However, this is an expensive palliative intervention as only very few patients can comply with the courses of dialysis, which may not be available in some centers.

In African continent, the major complications that bring MM patients to the hospital for the first time are operable (surgical) complications. A recent study revealed that 56.7% of patients diagnosed with MM received different forms of surgery ranging from craniotomy (plasmacytoma of the skull), partial cystectomy (solitary plasmacytoma of bladder), to internal fixation of orthopedic pins due to SREs complications arising from myeloma cells. Surprisingly, these complications have set in long before diagnoses were made. The presence of extramedullary plasmacytoma indicates poor prognosis, and this is worsened further in the absence of involved field radiotherapy (IFR) [33].

#### 6.2. Challenges in definitive treatment of MM

The standard definitive interventions for people living with MM are antimyeloma chemotherapy regimens and stem cell transplantation (autologous stem-cell transplantation (ASCT)). The antimyeloma chemotherapeutic regimens have undergone series of transformation and evolution over the years. The current antimyeloma therapeutic agents have changed the paradigm in the management of the disease. These agents have the best effect in improving the quality of life and overall survival intervals of MM patients. They have positively changed the course of the disease especially in high-income countries where they are relatively more available. This has been due in large part to a better understanding of the biology of the disease and the development of several highly effective therapies. They include proteasome inhibitors [PI] (bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib), immunomodulatory [IMiD] agents (thalidomide, lenalidomide, and pomalidomide), monoclonal antibody therapies (elotuzumab, daratumumab, and siltuximab), Bcl inhibitor (navitoclax), FGFR3 inhibitor (dovitinib), and histone deacetylase (HDAC) inhibitors (panobinostat, romidepsin, vorinostat, and rocilinostat). These agents include those that target the myeloma itself, some that target the bone marrow microenvironment, and those that target both [34].Unfortunately, these agents are not readily available in low- and some middle-income countries (LMICs) including Nigeria. The huge disparity in income, health-care infrastructure, and access to novel drugs in LMICs hinders the delivery of optimum care to every patient with MM in the region [35] due to limitation in purchasing power.

There may be no "standard therapy" forMM treatment, based on the many novel therapies, which have emerged for the treatment of the disease. The treatment approaches that are often referred to as standard are usually those with strong evidence of clinical efficacy. Although a recent clinical trial has shown that a combination of PI and IMiD will make for a standard regimen when added with dexamethasone [36], the current opinion is in favor of individualized treatment options, which is based not only on cytogenetic risk classification, but also on host factors, disease stage, and a variety of other prognostic factors.

agents (CFU-GM) such as filgrastim or neupogen. However, the later is usually expensive and only very few patients can afford it, hence worsening the survival outcome of the disease [3]. There is an increase in the incidence of nephropathy in MM in LICs. A range of 16–36% was recorded in previous studies in Nigeria [3, 17, 31] as against 20% in the USA [32]. A striking finding about the nephropathies in MM patients in LICs is their severity at presentation, which qualifies most of them for renal dialysis (or renal transplant). However, this is an expensive palliative intervention as only very few patients can comply with the courses of dialysis, which

In African continent, the major complications that bring MM patients to the hospital for the first time are operable (surgical) complications. A recent study revealed that 56.7% of patients diagnosed with MM received different forms of surgery ranging from craniotomy (plasmacytoma of the skull), partial cystectomy (solitary plasmacytoma of bladder), to internal fixation of orthopedic pins due to SREs complications arising from myeloma cells. Surprisingly, these complications have set in long before diagnoses were made. The presence of extramedullary plasmacytoma indicates poor prognosis, and this is worsened further in the absence of involved field radiother-

The standard definitive interventions for people living with MM are antimyeloma chemotherapy regimens and stem cell transplantation (autologous stem-cell transplantation (ASCT)). The antimyeloma chemotherapeutic regimens have undergone series of transformation and evolution over the years. The current antimyeloma therapeutic agents have changed the paradigm in the management of the disease. These agents have the best effect in improving the quality of life and overall survival intervals of MM patients. They have positively changed the course of the disease especially in high-income countries where they are relatively more available. This has been due in large part to a better understanding of the biology of the disease and the development of several highly effective therapies. They include proteasome inhibitors [PI] (bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib), immunomodulatory [IMiD] agents (thalidomide, lenalidomide, and pomalidomide), monoclonal antibody therapies (elotuzumab, daratumumab, and siltuximab), Bcl inhibitor (navitoclax), FGFR3 inhibitor (dovitinib), and histone deacetylase (HDAC) inhibitors (panobinostat, romidepsin, vorinostat, and rocilinostat). These agents include those that target the myeloma itself, some that target the bone marrow microenvironment, and those that target both [34].Unfortunately, these agents are not readily available in low- and some middle-income countries (LMICs) including Nigeria. The huge disparity in income, health-care infrastructure, and access to novel drugs in LMICs hinders the delivery of optimum care to every

There may be no "standard therapy" forMM treatment, based on the many novel therapies, which have emerged for the treatment of the disease. The treatment approaches that are often referred to as standard are usually those with strong evidence of clinical efficacy. Although a recent clinical trial has shown that a combination of PI and IMiD will make for a standard regimen when added with dexamethasone [36], the current opinion is in favor of individualized treatment options,

patient with MM in the region [35] due to limitation in purchasing power.

may not be available in some centers.

6.2. Challenges in definitive treatment of MM

apy (IFR) [33].

216 Update on Multiple Myeloma

According to the National Comprehensive Cancer Network (NCCN) guidelines, the consensus standard of care in newly diagnosed MM who have no intention for ASCT is RVD (lenalidomide, bortezomib, and dexamethasone) [36]. This is because RVD has improved median overall survival (OS) compared to conventional RD (75 months versus 64 months; HR 0.709; two-sided p = 0.025), improved overall response rate [ORR] (82 versus 72%), and improved progressive-free survival (PFS) (43 months versus 30 months, HR 0.712; one-sided p = 0.0018) [37, 38].

This consensus standard of treatment of MM is yet to be achieved in many developing countries. Unlike in developed countries where treatment is beginning to be customized based on mapping of patient's genome, most low-income countries are yet to offer their patients such opportunities. In Nigeria, the major antimyeloma chemotherapy drug is the old conventional alkylating agent known as melphalan (M), which is usually combined with a steroid (i.e., prednisolone, P) as a double or triple-only combination regimen. MP is still the most accessible commonly used regimen for treating MM patients because of the cost and availability, long after it has been phased out for treating MM patients in developed countries. About 84% of newly diagnosed MM patients in some LICs still depend on MP doublet combination regimen [3].This is contrary to the standard RVD triplet regimen accepted worldwide as the current treatment of choice for MM. About 28% of MM patients from the group of patients already on MP could afford a "partial-standard" triplet regimen made up of either one PI (i.e., bortezomib-melphalan-prednisolone VMP (7.7%)) or one IMiD agent (i.e., thalidomidemelphalan-prednisolone TMP (19.7%). "Partial" in this context connotes combination of a target (novel) therapy with old conventional regimen (i.e., MP in this case). However, a recent study in Nigeria has shown that up to 16.7% of MM patients use bortezomib-thalidomide-dexamethasone (BTD) as their first-line regimen [39]. Although RVD has a better median overall survival (OS), progressive free survival (PFS) and overall response rate (ORR) compared to BTD, this is a move toward the right direction as the latter regimen is close to the standard regimen (RVD) in terms of the benefits derived from a PI and IMiD combination regimens [36]. But, again, this is a bad news for many developing countries as less than 20% of MM patients in the region could access close-to-standard (partial) antimyeloma regimen [40]. The remaining 16% constitute the MM patients who are either on unclassified (i.e., neither known old conventional nor new novel therapy) antimyeloma regimens (such as vincristine adriamycin dexamethasone VAD, CVP, and CVAP) or not on any cytotoxic chemotherapy [3].

Stem cell transplantation (i.e., ASCT) is not a common option of treatment of MM in most developing countries. The only patient (3.8%) who benefited from this intervention from a previous study was outside Nigeria and the patient died two years posttransplantation. There is paucity of data regarding stem cell transplantation in most LICs especially those from Sub-Saharan African region. For instance, no center offers ASCT in Nigeria presently. Although few successful attempts on allogeneic stem-cell transplantation have been made in a center in Southern Nigeria (on sickle cell disease), but it has not been sustainable due to technological inequalities, brain drain of health workers, lack of funding, and political-will from the government. The public health system does not guarantee health insurance coverage for oncology treatment and stem-cell transplantation. Transplant-eligible patients who require stem-cell transplantation usually pay out from their pockets, and this could add to another burden to the patients [41–43]. However, in high-income countries, the reverse is the case and the survival outcome is usually better.

developing countries. The public health system should as a matter of urgency provide health insurance coverage for the management of MM patients especially in LICs such as Nigeria where the over 62% of population lives on extreme poverty of less than two dollars per day [41].

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There is also a need to build special centers designated for the treatment of MM where all relevant modern health-care facilities/equipments for diagnosis, risk assessments, and treatment of MM should be available, while taking into cognizance international best practices for

Adequate access to radiation therapy is a crucial component of modern multidisciplinary cancer care including MM. There must be a strict adherence to the IAEA recommendation of one megavoltage machine per 400 new cancer patients in areas with excellent cancer registry or one per 250,000 population size in areas without excellent cancer registry. The implication is that in countries like Nigeria where there are barely five functioning radiotherapy machine, the number has to be scaled up between 260 and 840 megavoltage units taking into cognizance a population size of 210 million people (based on 2006 population census and average annual

Supportive care of people living with MM must take into cognizance psychosocial health of the individuals and their families. This is the only way forward in ensuring a holistic care and improved quality of life of these patients. Every component of palliative workforce including

There is a need to scale-up definitive treatment of MM in developing countries using stemcell transplantation. Autologous non-cryopreserved stem-cell transplantation avoids the cost of establishing and maintaining a cryopreservation facility, and this can be feasible in transplant centers in economic-constrained regions [45, 46]. Studies have shown that high-dose melphalan with autologous stem-cell support improves the survival rate for patients with myeloma. Also, when they are carefully selected for treatment with ASCT, they can be managed with a brief initial hospitalization and outpatient follow-up, with low morbidity

Also, efforts should be intensified to set up excellent cancer (MM) registries in developing countries so as to improve on the statistics and epidemiology of MM and other cancer diseases. Each country is expected to formulate its own consensus guidelines that will best serve the

1 Department of Hematology, Federal Medical Center, Umuahia, Abia State, Nigeria 2 Department of Hematology, College of Health Sciences, Abia State University, Aba,

the management of the disease.

growth rate of 3.1%) [29].

and mortality [47–50].

Author details

Abia State, Nigeria

Ogbonna Collins Nwabuko1,2\*

patients using international best practices.

\*Address all correspondence to: ogbollins2002@yahoo.com

the social workers must be involved in realizing this goal.
