Multiple myeloma: Management in resource-limited settings

INTRODUCTION — Multiple myeloma (MM) is a plasma cell neoplasm characterized by clonal plasma cells that produce a monoclonal immunoglobulin. These plasma cells proliferate in the bone marrow and can result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Additional disease-related complications include hypercalcemia, kidney impairment, anemia, and infections. Treatment directed at the underlying plasma cell clone is required to prevent complications and improve overall survival.

MM must be distinguished from the premalignant stages of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) (table 1 and algorithm 1). In contrast to MM, active treatment is not routinely indicated for patients with MGUS or SMM.

This topic discusses management of patients with MM in resource-limited settings largely defined as those areas with limited access to thalidomide analogs, proteasome inhibitors, monoclonal antibodies, and other novel agents that are commonly used in resource-abundant settings. Separate discussions are available regarding diagnosis and management in resource-abundant settings.

●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●(See "Multiple myeloma: Overview of management".)

COMMON CHALLENGES IN THE RESOURCE-LIMITED SETTING — While major advances in the field of MM have improved the diagnosis, risk stratification, and management of patients in resource-abundant settings, much of the world faces challenges in their broad application. Common themes of these challenges include [1-3]:

●Heterogeneous access to care and disparities between those with private insurance, government-based care, and self pay.

●Delays in diagnosis leading to more patients with advanced, highly symptomatic disease impacting eligibility for different therapies (eg, hematopoietic cell transplantation [HCT]).

●Limited access to advanced molecular studies to aid risk stratification and disease monitoring.

●Prohibitive costs of novel therapies.

●Limited staffing and logistical support.

●Limitations in epidemiologic data given the lack of consistent registries.

The disparities between public and private care were highlighted in a retrospective study of 148 patients with MM treated in Mexico [2]. Patients in the two groups had a similar age at presentation (mean 59 versus 61 years) and percentage eligible for HCT (62 versus 63 percent). When compared with those treated in private settings, patients treated at public hospitals were more likely to:

●Have advanced disease at diagnosis as illustrated by higher rates of International Staging System (ISS) stage III disease (51 versus 28 percent), kidney impairment (25 versus 13 percent), and hypercalcemia (28 versus 13 percent).

●Receive less effective initial treatment as illustrated by increased use of thalidomide-based regimens (91 versus 18 percent), less use of bortezomib-based regimens (4 versus 75 percent), and a lower percentage of transplant-eligible patients undergo transplant (38 versus 84 percent).

●Experience inferior outcomes as illustrated by worse progression-free survival (median 23 versus 41 months) and overall survival (median 51 versus 79 months), and higher rates of death within 12 months of diagnosis (13 versus 4 percent).

These challenges were further highlighted in a retrospective study of 1103 patients with newly diagnosed MM treated in seven Latin American countries between 2008 and 2015, which reported the following [4]:  

●High rate of end-organ involvement at diagnosis (bone disease 79 percent; anemia 73 percent; kidney disease 27 percent; hypercalcemia 17 percent).

●Limited access to cytogenetics for risk stratification (not available for 80 percent).

●Low percentage of patients undergoing HCT (34 percent) despite a median age of 61 years.

●Common regimens used were thalidomide based (55 percent), bortezomib based (29 percent), and chemotherapy (10 percent). Those treated in a non-private setting were more likely to receive thalidomide-based therapy (71 versus 34 percent) and less likely to receive bortezomib (15 versus 54 percent).  

CLINICAL PRESENTATION AND DIAGNOSIS — Patients in resource-limited settings are more likely to have diagnostic delays and more advanced disease at the time of diagnosis [2]. Most patients with MM present with signs or symptoms related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains:

●Common presentations include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia.

●Less common presentations that require urgent evaluation include spinal cord compression, acute kidney failure, severe hypercalcemia, and hyperviscosity.

Diagnosis is based on criteria from the International Myeloma Working Group (table 1) [5]. An approach to the evaluation of suspected cases may need to be modified based on available resources (algorithm 1). The clinical features, laboratory manifestations, diagnosis, and differential diagnosis are discussed in more detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Clinical presentation'.)

The main conditions to consider in the differential diagnosis for MM include monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, Waldenström macroglobulinemia, solitary plasmacytoma, AL amyloidosis, POEMS syndrome, and metastatic carcinoma (table 2 and table 3). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Differential diagnosis'.)

GENERAL MANAGEMENT PRINCIPLES

Goals of therapy — Patients with MM are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and decreases end-organ damage, and it is given with the overall goals of improving quality of life and prolonging overall survival (OS).

Prior to the development of effective therapies, median OS was less than one year among patients with symptomatic MM [6]. Treatment with melphalan plus prednisone improved median OS of such patients to approximately three years [7]. Additional OS improvements came with the transition from two-drug regimens to three-drug or four-drug regimens and the incorporation of additional novel therapies at progression. (See "Multiple myeloma: Initial treatment".)

Prevention and management of complications — In addition to therapy directed at the malignant clone, the management of most patients with MM includes preventative measures to reduce the incidence of skeletal events, kidney damage, infections, neuropathy, and thrombosis.

●Skeletal lesions and bone health – Osteoclast inhibitors (eg, bisphosphonates) are administered to prevent skeletal events in patients with one or more lesions on skeletal imaging and those with osteopenia (algorithm 2). While denosumab is commonly used in patients with kidney impairment in resource-abundant settings, access is limited in resource-limited settings. Zoledronic acid requires dose adjustment for kidney impairment. (See "Multiple myeloma: The use of osteoclast inhibitors".)

Skeletal lesions can result in bone pain, pathologic fractures, and spinal cord compression.

•Pathologic fractures or impending fractures of long bones require stabilization. Vertebral fractures may benefit from kyphoplasty or vertebroplasty. Most pain related to lytic lesions can be controlled with the combination of analgesics and active myeloma therapy. (See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)

•Spinal cord compression is a clinical emergency and should be suspected in patients with severe back pain, weakness, or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence. (See "Treatment and prognosis of neoplastic epidural spinal cord compression".)

●Kidney impairment – All patients with MM should take measures to minimize kidney damage (eg, avoid nephrotoxins such as aminoglycosides and nonsteroidal anti-inflammatory drugs [NSAIDs] and maintain adequate hydration). Treatment of kidney impairment is directed at the underlying cause. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

●Infection – Prophylactic measures used to minimize infection in patients with MM include yearly influenza vaccines; pneumococcal vaccine at the time of diagnosis; and prophylactic antibiotics during the first months of induction chemotherapy. Antiviral and pneumocystis prophylaxis may also be indicated. (See "Infections in patients with multiple myeloma".)

Patients suspected of having an infection should be treated promptly with empiric antibiotics. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

●Thromboprophylaxis – Patients with MM are at increased risk of having comorbidities known to be risk factors for the development of venous thromboembolism (VTE) in the general population. In addition, treatment with immunomodulatory drugs (eg, thalidomide) is associated with high rates of VTE. All patients with MM should have an assessment of their VTE risk so that appropriate prophylaxis may be employed (algorithm 3). (See "Multiple myeloma: Prevention of venous thromboembolism".)

●Neuropathy – Peripheral neuropathy, often painful, can occur in association with various MM treatments, including thalidomide and bortezomib. The frequency and severity of peripheral neuropathy with bortezomib can be reduced by adjusting the route (subcutaneous rather than intravenous administration) and frequency (once versus twice weekly) of administration. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Specific recommendations for bortezomib'.)

Peripheral neuropathy is more frequent and severe in those who have previously received neurotoxic therapy and those with pre-existing neuropathy [8]. When neuropathy occurs, it can impair quality of life and ability to perform activities of daily living. Management is discussed separately, including dose modification and/or treatment discontinuation. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Thalidomide and related agents' and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Bortezomib'.)

●Hypercalcemia – Patients with hypercalcemia may be asymptomatic or present with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, or stupor. The treatment of hypercalcemia depends on the calcium level, the rapidity with which it developed, and the patient's symptoms. Emergency treatment with hydration, glucocorticoids, bisphosphonates, and/or hemodialysis/calcitonin is indicated for symptomatic patients. (See "Treatment of hypercalcemia".)

INITIAL TREATMENT — The initial treatment of patients in resource-limited settings is individualized based on access to drugs/modalities and patient comorbidities. There is no standard of care and different experts use different regimens. Our approach is largely influenced by (algorithm 4):

●Eligibility for and access to autologous hematopoietic cell transplantation (HCT)

●Access to bortezomib

Both of these modalities improve overall survival (OS) in patients with MM.

Unlike in resource-abundant settings, resource-limited settings have limited access to fluorescence in situ hybridization (FISH) for risk stratification. As such, treatment is selected without knowledge of whether the patient has high- or standard-risk MM. As discussed in more detail separately, limited data suggest that proteasome inhibitors such as bortezomib may abrogate the prognostic impact of at least some high-risk genetic markers making bortezomib-containing therapies an attractive option regardless of risk. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)

All patients are strongly encouraged to participate in clinical trials, where available.

Determine transplant eligibility — Eligibility for and access to autologous HCT impacts our choice of therapy (algorithm 4). When compared with chemotherapy alone, autologous HCT delays progression and improves OS, as discussed in detail separately. (See "Multiple myeloma: Overview of management", section on 'Benefits of autologous HCT versus chemotherapy alone'.)

Access to HCT in resource-limited settings is variable, and a lower percentage of patients will be eligible due to diagnostic delays and a higher incidence of advanced disease. (See 'Common challenges in the resource-limited setting' above and "Multiple myeloma: Overview of management", section on 'Determine transplant eligibility'.)

Practical issues regarding the use of autologous HCT in MM are presented separately. (See "Multiple myeloma: Use of hematopoietic cell transplantation".)

Patients eligible for transplant

Induction therapy — In patients who are candidates for and have access to autologous HCT, induction chemotherapy is administered for three to six cycles prior to stem cell collection in order to reduce the number of tumor cells in the bone marrow and peripheral blood, lesson symptoms, and reverse end-organ damage (algorithm 4).

As in resource-abundant settings, three-drug regimens are preferred over two-drug regimens because randomized trials show that they delay progression and may improve OS. Use of four-drug regimens is evolving, but it is generally cost-prohibitive in the resource-limited setting.

Our preferred three-drug regimen for HCT-eligible patients in resource-limited settings is influenced by whether there is access to bortezomib:

●If bortezomib is available, we suggest either of the following:

•Bortezomib, thalidomide, and dexamethasone (VTd) (table 4) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, thalidomide, dexamethasone')

•Bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 5) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, cyclophosphamide, dexamethasone')

VTd is preferred for most patients, except for those with underlying neuropathy. In a multicenter phase 3 trial (IFM2013-04) comparing these two regimens in patients undergoing HCT, VTd resulted in deeper responses and less hematologic toxicity, yet more neurotoxicity [9].

In some resource-limited settings, lenalidomide may be available at low cost and approved for use in initial therapy. In such countries, bortezomib, lenalidomide, dexamethasone (VRd) is preferred instead of VTd or VCd, similar to the approach used in resource-abundant settings. (See "Multiple myeloma: Initial treatment", section on 'Bortezomib, lenalidomide, dexamethasone'.)

●If bortezomib is not available or not tolerated, we offer cyclophosphamide, thalidomide, and dexamethasone (CTd). (See 'Cyclophosphamide, thalidomide, and dexamethasone (CTd)' below.)

Our preference for a bortezomib-containing regimen, if available, is based on data that suggest that proteasome inhibitors such as bortezomib may abrogate the prognostic impact of at least some high-risk genetic markers making bortezomib-containing therapies an attractive option regardless of genetic risk. (See "Multiple myeloma: Initial treatment", section on 'High-risk myeloma'.)

Melphalan-based therapy should not be used for patients who plan to undergo HCT. Although melphalan is an active drug in MM, it is associated with damage to the hematopoietic stem cell compartment as well as an increased risk of myelodysplasia following transplantation [10-12].

Timing of HCT — In resource-limited settings, we suggest induction therapy followed by early autologous HCT rather than delaying transplant until relapse. This preference places a high value on delaying progression and recognizes the limited availability of stem cell storage and decreased availability of effective treatment options at the time of relapse in resource-limited settings.

In resource-abundant settings, HCT can be offered as part of initial therapy (early HCT) or delayed until the time of first relapse (delayed transplant). Factors that may impact the choice between early and delayed HCT are discussed in more detail separately. (See "Multiple myeloma: Overview of management", section on 'Eligible for autologous transplant'.)

Consolidation — Patients with a very good partial response (VGPR) or better after HCT proceed to maintenance therapy without consolidation. In such patients, consolidation with additional cycles of the same triplet regimen used for induction is unlikely to offer benefit above that attained with maintenance alone. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Tandem HCT and/or consolidation'.)

Consolidation may be considered on a case-by-case basis for patients with less than a VGPR after HCT. Limited data suggest that an additional two to four cycles of induction therapy may result in a modest improvement in depth of response, but at a cost of increased toxicity, and no clear OS benefit.

In a prospective trial of bortezomib, thalidomide, dexamethasone (VTd) used as induction before and consolidation after double autologous HCT for newly diagnosed MM, VTd consolidation increased the complete response (CR) and near CR rates by 12 and 10 percent, respectively [13]. Among the 82 patients who had not achieved a CR after double HCT, VTd consolidation deepened the response in 45 patients (55 percent) and 25 patients (30 percent) achieved a CR. In the same trial, deeper responses were not seen in those who received consolidation with thalidomide and dexamethasone alone.

Other trials incorporated an agent not previously used in the consolidation regimen. As an example, in one randomized trial of 370 bortezomib-naïve patients who had undergone autologous HCT, consolidation with a five-month course of bortezomib improved median progression-free survival (PFS; 27 versus 20 months) but not OS [14]. Toxicities included sensorimotor peripheral neuropathy and neuropathic pain. While the induction regimen used was not specified, most patients received cyclophosphamide plus dexamethasone.

Maintenance — Following autologous HCT, we offer maintenance therapy rather than observation until progression. In resource-limited settings where lenalidomide is not available or affordable, we offer thalidomide maintenance until progression or unacceptable toxicity. When compared with no maintenance, thalidomide maintenance prolongs PFS by approximately 10 months but is associated with a significant increase in long-term toxicities, including peripheral neuropathy and thromboembolism, leading to thalidomide discontinuation in a substantial number of patients (30 to 80 percent by two years). While some have [15], most trials have not shown an improvement in OS [16-19]. Careful monitoring and dose adjustment for toxicities is critical [20].

The use of thalidomide maintenance after HCT was analyzed in a 2012 meta-analysis of six randomized trials that included data from 2786 patients who had undergone HCT, with the following findings [21]:

●Thalidomide maintenance improved PFS (hazard ratio [HR] 0.65, 95% CI 0.59-0.72); a benefit seen in trials that used thalidomide during both induction and maintenance and in those that used thalidomide during maintenance alone.

●While there was a statistically significant increase in OS (HR 0.84; 95% CI 0.73-0.97) demonstrated, caution must be used in interpreting these results as there was significant heterogeneity among the results of individual trials. This heterogeneity may be due to differences in patient population and in therapies available at relapse. In most studies, a survival benefit is only seen in a subset of patients, such as those who fail to achieve a VGPR with transplant or those with certain cytogenetic abnormalities.

In resource-abundant settings, maintenance is routinely given after HCT using drugs with more tolerable side effect profiles (eg, lenalidomide). In some resource-limited settings, lenalidomide may be available at low cost and approved for use as maintenance therapy. In such countries, maintenance with lenalidomide is preferred instead of thalidomide, similar to the approach used in resource-abundant settings. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Maintenance'.)

Patients not eligible for transplant — For patients who are not candidates for or who do not have access to autologous HCT, we offer 8 to 12 cycles of a three-drug regimen followed by observation until progression rather than further chemotherapy (algorithm 4). While thalidomide maintenance prolongs remission, use is limited by toxicity, especially neurotoxicity.

Our preferred three-drug regimen for these patients is influenced by whether there is access to bortezomib:

●If bortezomib is available, we suggest either of the following:

•Bortezomib, thalidomide, and dexamethasone (VTd) (table 4) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, thalidomide, dexamethasone')

•Bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 5) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, cyclophosphamide, dexamethasone')

If both are reasonable options for the patient, VTd is preferred as it may be more effective. However, many patients will have comorbidities (eg, diabetes with neuropathy) that may preclude administration of nine cycles of VTd. VCd may be a better choice in such cases.

In some resource-limited settings, lenalidomide may be available at low cost and approved for use in initial therapy. In such countries, bortezomib, lenalidomide, dexamethasone (VRd) can be used instead of VTd or VCd similar to the approach used in resource-abundant settings (approximately eight cycles of VRd followed by lenalidomide maintenance). (See "Multiple myeloma: Initial treatment", section on 'Maintenance for patients who are ineligible for or defer HCT'.)

●If bortezomib is not available, we suggest either of the following:

•Cyclophosphamide, thalidomide, and dexamethasone (CTd) (see 'Cyclophosphamide, thalidomide, and dexamethasone (CTd)' below)

•Melphalan, prednisone, and thalidomide (MPT) (table 6) (see 'Melphalan, prednisone, and thalidomide (MPT)' below)

Either regimen is a reasonable choice. A randomized trial comparing these two regimens was closed early due to slow accrual, and small numbers limit interpretation [22]. When compared with MPT, CTd resulted in numerically higher overall response rates (90 versus 68 percent), and a similar median PFS (24 versus 26 months).  

The number of cycles used for an individual patient depends on how well they tolerate the regimen and the response to treatment. If the disease continues to respond and the patient is tolerating therapy, we will offer up to 12 cycles of initial therapy.

The use of melphalan has declined in much of the world due to concerns of toxicity (eg, hematopoietic stem cell damage, risk of myelodysplasia) and the availability of other effective regimens. In resource-abundant settings, clinicians have shifted towards initial therapy that incorporates agents such as immunomodulatory drugs (eg, lenalidomide, thalidomide), proteasome inhibitors (eg, bortezomib), and monoclonal antibodies (eg, daratumumab). (See "Multiple myeloma: Initial treatment".)

REVIEW OF CHEMOTHERAPY REGIMENS — The following sections will present data regarding the administration, efficacy, and toxicity of regimens that may be considered in patients in resource-limited settings largely defined as those areas with limited access to thalidomide analogs, proteasome inhibitors, monoclonal antibodies, and other novel agents that are commonly used in resource-abundant settings. More modern regimens are presented separately. (See "Multiple myeloma: Initial treatment".)

Bortezomib, cyclophosphamide, and dexamethasone (VCd or CyBorD) — The combination of bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 5) is one or our preferred treatment options for patients who have access to bortezomib, regardless of whether they are candidates for autologous hematopoietic cell transplantation (HCT) (algorithm 4).

VCd is also used in resource-abundant settings to treat patients at higher risk of complications with lenalidomide (eg, acute kidney failure, increased thromboembolic risk). Details on efficacy, toxicity, and administration are described separately. (See "Multiple myeloma: Initial treatment", section on 'Bortezomib, cyclophosphamide, dexamethasone'.)

Bortezomib, thalidomide, and dexamethasone (VTd) — The combination of bortezomib, thalidomide, and dexamethasone (VTd) (table 4) is one or our preferred treatment options for patients who have access to bortezomib, regardless of whether they are candidates for autologous HCT (algorithm 4).

VTd is also used in resource-abundant settings to treat patients presenting with acute kidney failure. Details on efficacy, toxicity, and administration are described separately. (See "Multiple myeloma: Initial treatment", section on 'Bortezomib, thalidomide, dexamethasone'.)

Cyclophosphamide, thalidomide, and dexamethasone (CTd)

●Clinical use – The all-oral combination of cyclophosphamide, thalidomide, and dexamethasone (CTd) is one of our preferred regimens for patients who do not have access to bortezomib (algorithm 4). It can be used as induction therapy prior to stem cell collection and autologous HCT or at attenuated doses as initial therapy for patients who are not candidates for HCT.

Further details on class-specific toxicities and ways to mitigate them are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs' and "Multiple myeloma: Administration considerations for common therapies", section on 'Corticosteroids'.)

●HCT-eligible patients – A multicenter randomized trial (MRC Myeloma IX) compared CTd versus CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 1111 HCT-eligible patients with newly diagnosed MM [23].  

CTd was given as up to six 21-day cycles of oral cyclophosphamide (500 mg per week), thalidomide (100 mg per day increasing to 200 mg per day if tolerated), and oral dexamethasone (40 mg per day on days 1 to 4 and 12 to 15). Prophylaxis for venous thromboembolism (VTE) was at the discretion of the clinician and not specified in the protocol. HCT was performed in 67 percent.

CTd resulted in higher rates of overall response (83 versus 71 percent), complete response (13 versus 8 percent), and overall response post-transplant (50 versus 37 percent). After a median follow-up of 47 months, the two arms had similar rates of progression-free survival (PFS; median 27 versus 25 months) and overall survival (OS).  

Among those assigned to CTd, 29 percent required thalidomide dose reduction. When compared with CVAD, CTd resulted in less grade 3 or 4 cytopenias (5 versus 12 percent) and infection (12 versus 21 percent), more grade 3 or 4 constipation (3.6 versus 1.5 percent) and somnolence (3.0 versus 1.3 percent), and similar rates of kidney impairment (3.6 versus 3.2 percent), thromboembolic events (16 versus 18 percent), and early mortality (7 versus 9 percent).

●HCT-ineligible patients – The MRC Myeloma IX trial included a second cohort of 849 patients with newly diagnosed MM ineligible for HCT who were randomly assigned to receive an attenuated regimen of CTd versus melphalan plus prednisone (MP) [24].

Attenuated CTd was given as up to nine 28-day cycles of oral cyclophosphamide (500 mg per week), thalidomide (50 mg per day, increasing every four weeks in 50 mg increments to a maximum of 200 mg per day), and dexamethasone (20 mg/day on days 1 to 4 and 15 to 18).

CTd resulted in higher rates of overall response (64 versus 33 percent), complete response (13 versus 2 percent), and very good partial response (17 versus 2 percent). After a median follow-up of 44 months, the two arms had similar rates of PFS (median 13 versus 12 months) and OS (median 33 versus 31 months). Six percent of patients in each arm died within 60 days of randomization. There were two deaths in each group due to thromboembolism.

Among those assigned to CTd, 31 percent required thalidomide dose reduction. When compared with MP, CTd resulted in more all-grade thromboembolic events (16 versus 5 percent), sensory neuropathy (24 versus 6 percent), motor neuropathy (12 versus 3 percent), constipation (41 versus 18 percent), and rash (15 versus 7 percent).

Melphalan, prednisone, and thalidomide (MPT)

●Clinical use – The combination of melphalan, prednisone, and thalidomide (MPT) is a preferred highly active treatment option for initial therapy in patients with standard-risk MM who are not candidates for HCT in resource-limited settings (algorithm 4 and table 6).

Further details on class-specific toxicities of immunomodulatory drugs and corticosteroids and ways to mitigate them are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs' and "Multiple myeloma: Administration considerations for common therapies", section on 'Corticosteroids'.)

●Administration – Although it has been given at other doses and schedules, the MPT regimen we use is illustrated in the table (table 6). Initial dose reductions to minimize toxicity are suggested for older adults (age 75 and older) and those with comorbidities or frailty [25]. Thus, when using MPT in older or frail patients, we lower the dose of melphalan to 0.2 mg/kg, and use thalidomide at a dose not exceeding 100 mg per day [26].

The MPT regimen requires routine thromboprophylaxis in all patients [27]. Options for prophylaxis are discussed in detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism", section on 'Thalidomide'.)

●Toxicities – Severe (grade 3/4) toxicities associated with MPT include neutropenia (23 to 48 percent), thrombosis or embolism (12 percent), constipation (10 percent), and somnolence/fatigue/dizziness (8 percent) [26,28,29]. MPT is also associated with high rates of all stages of peripheral neuropathy (39 percent) and depression (7 percent).

Thalidomide should be discontinued or dose reduced when paresthesias are accompanied by moderate to severe pain or motor deficit, or when they interfere with activities of daily living [30].

●Efficacy – When compared with MP, MPT is associated with improved PFS and OS, but it results in greater toxicity.

MPT has been compared with MP in several large randomized trials. Two large meta-analyses based on these trials confirmed an improvement in response rate with the addition of thalidomide [31,32]. Furthermore, the addition of thalidomide to MP was associated with a significant improvement in PFS (hazard ratio [HR] 0.68, 95% CI 0.56-0.81) and OS (HR 0.81; 95% CI 0.70-0.94) [32].

Bortezomib, melphalan, prednisone, and thalidomide (VMPT) — The combination of bortezomib, melphalan, prednisone, and thalidomide (VMPT) is an experimental four-drug regimen.

A prospective cooperative group trial of 511 patients older than 65 years with newly diagnosed MM randomly assigned therapy with VMPT or VMP [33,34]. After nine cycles, the patients assigned to VMPT received maintenance therapy with bortezomib and thalidomide; those given VMP did not receive maintenance. After an early protocol amendment, bortezomib was given on a weekly schedule, rather than twice weekly, during all induction cycles on both treatment arms.

After a median follow-up of 54 months, VMPT (followed by maintenance therapy) improved PFS (median 35 versus 25 months, HR 0.58) and OS (61 versus 51 percent at five years; HR 0.70) [35]. VMPT was associated with a higher rate of severe (grade 3 or 4) toxicity, which included neutropenia (38 percent), thrombocytopenia (22 percent), peripheral neuropathy (11 percent), and cardiologic events (11 percent).

VMPT has not been compared with other regimens that incorporate novel agents. Further, it is not clear whether the survival benefit is due to the addition of the fourth drug to the induction regimen, or due to the addition of maintenance.

MONITORING DISEASE RESPONSE TO THERAPY — Patients should be evaluated before each treatment cycle to determine how their disease is responding to therapy (table 7). The preferred method is the measurement of monoclonal (M) protein in serum or urine, although responses can be assessed earlier by serum free light chain (FLC) measurements. This is discussed in detail separately. (See "Multiple myeloma: Evaluating response to treatment".)

RELAPSED OR REFRACTORY DISEASE — Most patients with MM will have an initial response to treatment. However, conventional therapy is not curative and MM will ultimately relapse. In addition, a minority will have primary refractory disease that does not respond to initial treatment.

Treatment of relapsed or refractory MM is highly individualized and depends on patient factors and access to therapies. Accompanying tables provide active drugs by class (table 8) and major toxicities of selected treatment regimens (table 9).

Choice among available options is impacted by prior therapy, response and tolerability, and comorbidities.

The following general principles help guide care:

●Patients who are eligible and have access to autologous hematopoietic cell transplantation (HCT) may be candidates for a first or second HCT. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Second autologous HCT after relapse'.)

●Response durations more than the median for a given therapy represents a good response (eg, >12 months after initial treatment with CTd alone or >24 months after initial treatment with CTd plus HCT); repeat treatment with the same therapy may result in a response of equal or shorter duration. This approach aims to derive maximum benefit from available agents prior to switching regimens.  

●Progression on or within 60 days of receiving standard doses of a specific therapy defines disease that is refractory to that agent. Retreatment is not likely to be effective and other agents should be used.

●All patients are strongly encouraged to participate in , where available. This may provide access to otherwise unavailable agents.

Additional information about novel agents, combinations, and modalities used in resource-abundant settings is provided separately. (See "Multiple myeloma: Treatment of first or second relapse" and "Multiple myeloma: Treatment of third or later relapse".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Common challenges – In resource-limited settings, patients with multiple myeloma (MM) have limited access to thalidomide analogs, proteasome inhibitors, monoclonal antibodies, and other novel agents. Additional challenges include heterogenous access to care, diagnostic delays, access to molecular studies, and logistical support. (See 'Common challenges in the resource-limited setting' above.)

●Presentation and diagnosis – Patients in resource-limited settings are more likely to have advanced disease at diagnosis. While the evaluation of suspected cases may differ based on available resources (algorithm 1), the diagnosis uses International Myeloma Working Group criteria (table 1). (See 'Clinical presentation and diagnosis' above.)

●Goals of therapy and preventative measures – Treatment is not curative. It alleviates symptoms, reverses cytopenias, and decreases end-organ damage, and it aims to improve quality of life and prolong overall survival. (See 'Goals of therapy' above.)

Preventative measures are key to reducing the incidence of skeletal events, kidney damage, infections, neuropathy, and thrombosis. (See 'Prevention and management of complications' above.)

Myeloma-directed therapies are individualized based on access to drugs/modalities and patient comorbidities. There is no standard of care. Our preferred approach depends on the feasibility of autologous hematopoietic cell transplantation (HCT) and access to bortezomib (algorithm 4). These treatments are effective in standard- and high-risk disease, making them attractive options in the absence of molecular studies for risk stratification. (See 'Initial treatment' above.)

●Patients eligible for HCT – In patients who are candidates for and have access to HCT, we suggest three to six cycles of induction therapy followed by early autologous HCT rather than delaying transplant until relapse (Grade 2C). (See 'Timing of HCT' above.)

If available, we suggest a bortezomib-containing regimen rather than others (Grade 2B); options include (see 'Induction therapy' above):

•Bortezomib, thalidomide, and dexamethasone (VTd) (table 4) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, thalidomide, dexamethasone')

•Bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 5) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, cyclophosphamide, dexamethasone')

If the patient has access to both lenalidomide and bortezomib, then bortezomib, lenalidomide, dexamethasone (VRd) is preferred instead of VTd or VCd, similar to the approach used in resource-abundant settings.

If bortezomib is not available or not tolerated, we offer cyclophosphamide, thalidomide, and dexamethasone (CTd). Melphalan-based therapy should not be used for patients who plan to undergo HCT. (See 'Cyclophosphamide, thalidomide, and dexamethasone (CTd)' above.)

Following autologous HCT, we suggest thalidomide maintenance rather than observation (Grade 2B). Maintenance delays progression by approximately 10 months, but it is associated with risks of neuropathy and thrombosis and does not improve overall survival for most patients. If the patient has access to lenalidomide, lenalidomide maintenance is preferred over thalidomide maintenance. (See 'Maintenance' above.)

●Patients not eligible for HCT – For patients who are not candidates for or who do not have access to autologous HCT, we offer 8 to 12 cycles of induction, as tolerated. Afterwards, we suggest observation until progression rather than further chemotherapy (Grade 2C). While thalidomide maintenance prolongs remission, use is limited by toxicity, especially neurotoxicity.

If available, we suggest a bortezomib-containing three-drug regimen rather than a regimen that does not contain bortezomib (Grade 2B); options include (see 'Patients not eligible for transplant' above):

•Bortezomib, thalidomide, and dexamethasone (VTd) (table 4) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, thalidomide, dexamethasone')

•Bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 5) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, cyclophosphamide, dexamethasone')

If the patient has access to both bortezomib and lenalidomide, then bortezomib, lenalidomide, dexamethasone (VRd) followed by lenalidomide maintenance is preferred over VTd or VCd, similar to the approach used in resource-abundant settings.

If bortezomib is not available, we offer one of the following:

•Cyclophosphamide, thalidomide, and dexamethasone (CTd) (see 'Cyclophosphamide, thalidomide, and dexamethasone (CTd)' above)

•Melphalan, prednisone, and thalidomide (MPT) (table 6) (see 'Melphalan, prednisone, and thalidomide (MPT)' above)

●Monitoring response to therapy – We evaluate response to therapy before each treatment cycle (table 7) based on monoclonal protein in serum and urine and free light chain measurements. (See "Multiple myeloma: Evaluating response to treatment".)

●Relapsed or refractory disease – Treatment of relapsed or refractory MM is highly individualized based on patient factors and access to therapies. Accompanying tables provide active drugs by class (table 8) and major toxicities of selected treatment regimens (table 9).

Choice is impacted by prior therapy, response and tolerability, and comorbidities. (See 'Relapsed or refractory disease' above.)