Multiple myeloma (MM) is the second most common hematologic neoplasm (10%-15% of cases) and accounts for 15%-20% of deaths from hematologic neoplasms. As the pathogenesis of myeloma has been further understood, new advances have been made in its treatment. Although myeloma is still incurable, current treatment options can significantly extend patient survival, with a median survival of approximately 5 years for newly diagnosed patients. This article reviews the latest advances in the management of multiple myeloma.
1. What is myeloma? What are the high-risk groups?
In myeloma, myeloma plasma cells infiltrate the bone marrow and produce a monoclonal protein that can be detected in the blood or (and) urine, damaging organs or tissues. Epidemiological studies have shown that the onset of multiple myeloma is preceded by monoclonal immunoglobulinemia of unknown mechanism (MGUS), an asymptomatic disease state.
Multiple myeloma occurs most frequently in the elderly (median age 70 years) and can develop at any age, with 15% of diagnosed cases under 60 years of age and 2% under 40 years of age. The incidence of multiple myeloma is twice as high in African-Caribbean as in white people, and is 50% higher in men than in women of all racial groups. There are no known genetic factors or clear environmental risk factors for multiple myeloma.
The patient’s bone marrow biopsy shows a large infiltration of plasma cells, which are highlighted by H-E staining (left) and anti-CD138 immunohistochemical staining (right).
2. What pathophysiological processes are involved?
The pathogenesis of multiple myeloma is due to mutations in genes during the differentiation of B lymphocytes into plasma cells. Chromosomal translocations occur in about half of the cases, i.e., translocation of the oncogene to the immunoglobulin heavy chain gene (IgH gene translocation) on chromosome 14, resulting in overexpression of the oncogene and uncontrolled cell proliferation. Other pathological features are cells with partial odd trisomies, i.e. chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. the manifestation of these numerous trisomies is called hyperdiploidy.
As research has progressed, some genetic mutations, such as mutations in the RAS gene, have also been identified in myeloma. Because myeloma cell growth and survival depend on other cells in the bone marrow, such as fibroblasts, osteoblasts, osteoclasts, stromal cells, and dendritic cells, therapeutic approaches that target the bone marrow microenvironment have progressed.
3. Why does it lead to bone disease and hypercalcemia?
The imbalance of bone reconstruction in myeloma patients is caused by increased osteoclast activity and decreased osteoblast function. Myeloma cells promote increased production of osteoclast activators and cytokines that inhibit osteoblast differentiation. Uncontrolled osteolysis can also cause hypercalcemia.
4. Why does it cause renal impairment?
In most cases, malignant plasma cells produce abnormal proteins called monoclonal immunoglobulins (mostly IgG or IgA). Multiple myeloma does not usually have abnormal IgM proteins, and their presence often suggests other diseases, such as Walden’s macroglobulinemia. Also plasma cells can produce varying amounts of monoclonal free light chains. Light chains, known as pericardial proteins, can be found in the urine of patients with multiple myeloma and MGUS.
About 20% of patients with multiple myeloma have light chains in their serum and urine, while 2% of patients produce neither light chains nor abnormal proteins and are referred to as non-secretory. Light chains are filtered by the glomerulus and reabsorbed by the proximal tubule. When light chain filtration exceeds proximal tubular reabsorption, the light chains precipitate in the distal tubules and form tubular forms, causing tubular obstruction and tubulointerstitial inflammation, leading to acute kidney injury. 90% of renal damage in multiple myeloma is caused by tubular nephropathy. Other causes include amyloid deposition, dehydration, hypercalcemia, hyperviscosemia, and the use of nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs.
5. What are the symptoms of multiple myeloma?
Common symptoms include anemia (75%), hypercalcemia (30%), renal impairment (25%), and bone disease (70%). The clinical manifestations of bone disease are painful osteolytic lesions, vertebral comminuted fractures or long bone fractures (Figure 2). Pathologic degenerative fractures of the spine result in spinal cord compression, and plasmacytomas develop in the extramedullary soft tissue in 5% of patients with multiple myeloma. Hypercalcemia, acute renal failure, and spinal cord compression are all emergencies, and prompt diagnosis and treatment are important to reduce long-term organ damage.
High levels of abnormal proteins can lead to symptoms of hyperviscosity (headache, rhinorrhea, blurred vision and confusion) and can cause a decrease in humoral immune function leading to recurrent bacterial infections. 30% of confirmed cases are diagnosed by incidental findings of an increased erythrocyte sedimentation rate, total protein or immunoglobulin. Symptoms such as lethargy or back pain are usually non-specific and lead to delayed diagnosis. A recently published report shows that 56% of patients usually present to the hematology department more than 6 months later. One-third of cases are diagnosed in the emergency setting and are not treated regularly, resulting in a poor prognosis for these patients (one-year survival rates of 51% and 82%, respectively).
Radiograph shows a spiral fracture of the right humerus. This patient was previously in good health, but showed a fracture of the right arm
6. How is multiple myeloma diagnosed?
The International Myeloma Working Group summarizes the diagnostic criteria for multiple myeloma, asymptomatic multiple myeloma, and MGUS, which is defined by a low concentration of plasma cell infiltrates and abnormal proteins, and the absence of the usual clinical manifestations of myeloma, such as hypercalcemia, renal insufficiency, anemia, or bone lesions. Approximately 1% of patients with MGUS develop multiple myeloma each year.
Asymptomatic multiple myeloma occurs when there are high concentrations of plasma cells and monoclonal proteins, but no myeloma-related organ or tissue damage, and approximately 10% of this type progresses to symptomatic multiple myeloma each year. The rise in polyclonal immunoglobulins reflects acute inflammation rather than progression to MGUS or multiple myeloma.
The tests needed when considering a diagnosis of multiple myeloma are summarized, emphasizing the need for screening of patients by general practitioners. Patients with a clinical diagnosis of suspected multiple myeloma and at least 1 of the symptoms of anemia, impaired renal function, hypercalcemia, osteolytic lesions on x-ray, and abnormal protein or urine Benzedrine detected should be referred to the hematology department.
Symptomatic multiple myeloma
3 required criteria for diagnosis.
1. ≥ 10% monoclonal plasma cells in the bone marrow (≥ 30% in the bone marrow of non-secretory patients)
2. presence of monoclonal protein in serum or urine
3. Evidence of organ or tissue damage associated with multiple myeloma.
(1) Hypercalcemia (>10,5 mg/dL (2,6 mmol/L) or upper limit of normal)
(2) Renal insufficiency (serum creatinine >2 mg/dL (176, 8 μmol/L))
(3) anemia: hemoglobin <100 g/L or 20 g/L below the lower limit of normal
(4) Osteolytic lesions, osteoporosis or pathological fractures
Asymptomatic multiple myeloma
2 required diagnostic criteria.
(1) monoclonal protein ≥ 30 g/L or monoclonal plasma cells in the bone marrow ≥ 10%
(2) No myeloma-related organ or tissue damage
MGUS
Required diagnoses.
(1) Monoclonal protein <30 g/L
(2) Bone marrow monoclonal plasma cells <10%
(3) No organ or tissue damage associated with multiple myeloma
Table 2 Tests for the diagnosis of multiple myeloma
Screening test
General practitioner component.
(1) Blood count
(2) Serum urea nitrogen and creatinine
(3) Erythrocyte sedimentation rate or plasma viscosity
(4) Serum calcium and albumin measurement
(5) Immunoglobulin and serum protein electrophoresis
(6) Urine pericardial protein measurement
(7) Imaging of symptomatic areas
Diagnostic tests
Hematologist section.
(1) Bone marrow aspiration and plasma cell phenotyping
(2) Serum and urine immunofixation electrophoresis
(3) Serum free light chain assay
(4) Bone examination
Assessment of tumor load and prognostic tests
Hematologists.
(1) Bone marrow smear fluorescence in situ hybridization analysis
(2) Serum β2 microglobulin concentration
(3) Serum albumin concentration
(4) Quantification of monoclonal proteins in serum and urine
X-ray examination of the skeleton, including the skull, spine, chest, pelvis, and upper extremity bones, is necessary to determine the extent of myeloma involvement. Magnetic resonance imaging (MRI) is the gold standard of imaging and is used to examine cervical spondylosis and spinal cord compression. If MRI is not available, CT can be used.
Radionuclide bone imaging does not work in multiple myeloma because its rationale relies on the uptake of technetium by osteoblasts, which are usually reduced or absent in multiple myeloma. Therefore, myeloma osteolytic lesions show typical “cold” areas on bone scans. Positron emission tomography (PET) may have a role in screening, monitoring disease, and visualizing extramedullary sites, especially in non-secretory multiple myeloma.
7. What are the factors that affect prognosis?
Although the introduction of new drugs has changed the fate of many patients, multiple myeloma remains a heterogeneous disease. Some patients diagnosed with the disease survive up to 8 years, yet a proportion of high-risk patients die within 24 months. The International Staging System classifies risk into three classes based on β2-microglobulin and serum albumin concentrations (Table 3).
IgH translocations involving chromosomes 4 and 16, referred to as t(4;14) and t(14;16), respectively, are high-risk factors and are associated with poor prognosis. The oncogene p53 is located on the short or long arm of chromosome 17, and deletion of the long arm of chromosome 17 (del17p) is associated with a poor prognosis. Patients with t(11;14) or t(6;14) IgH gene translocations as well as hyperdiploid patients were considered to have standard risk disease. Age is an independent prognostic factor and also affects treatment outcome. The presence of complete remission affects the overall survival of patients. Younger patients have a median survival of approximately 7 years with high-dose chemotherapy regimens.
Stage I Serum β2 microglobulin <3, 5 mg/L and albumin ≥35 g/L
Stage II Between stage I and stage III
Stage III serum β2 microglobulin ≥ 5, 5 mg/L (regardless of albumin level)
8. How to treat multiple myeloma?
Patients with MGUS and asymptomatic multiple myeloma are usually under close clinical observation. To date, no interventions have been identified to delay or stop the progression of MGUS to multiple myeloma. Patients with asymptomatic multiple myeloma should be routinely followed in hematology. Randomized controlled trials have shown that chemotherapy has no effect on survival in asymptomatic multiple myeloma. Current drug trials are focused on patients at high risk of progression to symptomatic multiple myeloma.
The British Committee for Standards in Haematology (BCSH) guidelines recommend that patients with MGUS at low risk of progression to myeloma may be monitored in primary care, while patients at high risk must be monitored under the supervision of a haematologist. (Figure 3) The flow of testing shows the initial detection of abnormal proteins, including how often MGUS patients should be followed in primary care and when they should be referred to a hematologist.
Over the past decade, there has been an unprecedented development in the treatment of multiple myeloma with the advent of bortezomib (a proteasome inhibitor) and thalidomide and lenalidomide (immunomodulators) (Table 4). Treatment regimens containing new drugs are currently the mainstay of treatment for multiple myeloma, with initial therapy leading to remission in most patients and a good quality of life as the disease progresses to a stable phase. Relapse is inevitable due to lack of effective treatment, but at least half of patients who relapse can achieve remission with the same or a different chemotherapy regimen.
Table 4 Drugs commonly used in the treatment of multiple myeloma
Name
Drug classification
Use
Route of administration
Thalidomide
Immunomodulator
Combination with dexamethasone (can add cyclophosphamide), both as first-line and relapse
Oral
Bortezomib
Proteasome inhibitor
With dexamethasone (can add cyclophosphamide) or thalidomide for relapse; first-line agent for renal failure, in combination with melphalan and prednisolone for patients unsuitable for transplantation
Subcutaneous, intravenous injection
Lenalidomide
Immunomodulator
Combined with dexamethasone for relapse
Oral
Dexamethasone
Steroids
Used in combination with numerous antimyeloma agents as first-line agents and to treat relapse
Oral
melphalan
Alkylating agent
High doses of intravenous melphalan may be used for conditioning prior to autologous stem cell transplantation; oral melphalan with prednisolone and bortezomib or thalidomide may be used in patients who are not candidates for transplantation
Oral, intravenous
Cyclophosphamide
Alkylating agent
Combined with dexamethasone and thalidomide or bortezomib for relapse or as first-line agent; single dose intravenously for mobilization
Oral, intravenous
Adriamycin
Anthracyclines
Combined with bortezomib and dexamethasone as first-line agents and for relapse
Intravenous
Bendamustine
Alkylating agent
Combined with thalidomide and hydrogenated prednisone or dexamethasone for relapse
Intravenous
Carfilzomib
Next generation proteasome inhibitor
Current use limited to clinical trials
Intravenous
Pomalidomide
Next-generation immunomodulator
Current use limited to clinical trials
Oral
Patients relapse and become increasingly drug resistant, the disease enters a refractory end-stage and is quite difficult to treat, sometimes with extramedullary manifestations and complete cytopenias
The choice of initial treatment regimen for multiple myeloma depends on age and the presence of comorbidities. The goal of the initial chemotherapy regimen is to achieve complete remission and maximum control of drug toxicity, and for younger (generally <65 years of age) and more fit patients, a combination of high-dose chemotherapy and autologous hematopoietic stem cell transplantation is required to consolidate therapy. Elderly patients or patients with other serious diseases that are not suitable for autologous stem cell transplantation can only be treated with chemotherapy alone. The treatment effect is graded according to the degree of decrease in abnormal protein or light chains as shown in Table 5. The main side effects of the treatments are listed in Table 6.
Classification of multiple myeloma in remission or progression
Traditionally, classification has been based on the amount of abnormal protein reduction or increase, but the degree of bone marrow plasma cell proliferation, progression of bone lesions, and the presence of soft tissue plasmacytoma should now also be considered. With advances in techniques used to detect residual myeloma cells in the bone marrow, new depths of remission have been recognized, such as strict complete remission.
Complete remission
No detectable abnormal protein and disappearance of plasmacytoma in soft tissues and < 5% plasma cells in the bone marrow
Better partial remission
Abnormal protein reduction > 90% or abnormal protein detectable but too low to quantify
Partial remission
Abnormal protein reduction > 50%
No change or stable disease
No criteria for disease remission or progression encountered
Progressive disease
At least 25% increase in abnormal protein (at least 5 g/L increase), increased bone lesions or plasmacytomas, hypercalcemia (corrected serum calcium >2,65 mmol/L)
Drugs
Remarks
Glucocorticoids
Gastrointestinal side effects
Hyperglycemia
Immunosuppression
Insomnia and mood changes
Alkylating agents (cyclophosphamide, melphalan)
Nausea
Bone marrow suppression
High-dose marfalan
Mucositis
Gastrointestinal toxicity
Alopecia
Thalidomide
Constipation
Drowsiness
Sensory-motor peripheral neuropathy
Autonomic neuropathy (uncommon)
Bradycardia, thyroid function changes
Increased risk of thrombosis
Bortezomib
Sensory neuropathy – pain
Autonomic neuropathy – postural hypotension, altered bowel habits
Thrombocytopenia
Activation of herpes zoster virus
Gastrointestinal toxicity
Lenalidomide
Constipation
Fatigue
Bone marrow suppression
Increased risk of thrombosis
Dynamic observation of the patient’s clinical presentation – dose adjustment or change in chemotherapy regimen as needed
Because of the teratogenic effects of this drug, men and women of appropriate age should be asked if they have plans to have children before using the drug
9. Treatment options for transplant patients
For younger, more institutionalized patients, results from several large phase III trials suggest that high-dose chemotherapy combined with autologous HSCT can benefit most patients. Initial induction therapy should preserve hematopoietic stem cell function and facilitate stem cell collection. The traditional VAD regimen (vincristine-adriamycin-dexamethasone) has been replaced by newer agents. Several randomized studies have shown that induction regimens combined with one or more of the newer agents before and after autologous HSCT resulted in improved induction rates and prolonged progression-free survival.
The best evidence from this study is in the treatment regimen of bortezomib in combination with other drugs, which is used together with dexamethasone and usually also in combination with one of the three thalidomide, adriamycin or cyclophosphamide. The thalidomide-based regimen: cyclophosphamide – thalidomide – dexamethasone is widely used in the UK as a result of the recent Myeloma IX study. However, this regimen will change when the results of the Myeloma IX study, which used a lenalidomide combination, and the PADIMAC study, which used a bortezomib-based induction regimen, are published.
Randomized controlled trials have explored improving remission rates and prolonging progression-free survival in patients by sequential or double-dose autologous stem cell transplantation, however patients who responded poorly after the first transplant did not appear to benefit from this trial. Allogeneic hematopoietic stem cell transplantation has the potential to cure the disease, but transplantation-related mortality is high and meta-analysis showed no survival advantage over autologous hematopoietic stem cell transplantation. This approach is only being considered in clinical trials.
10. Treatment options for patients unsuitable for transplantation
Since the 1960s, marfarin combined with prednisone has been the main drug used to treat elderly patients. A meta-analysis of 6 trials showed that a regimen including thalidomide prolonged progression-free survival by 5 or 4 months and overall survival by 6 or 6 months.
Regimens that included bortezomib increased remission rates and prolonged remission and disease progression, while also increasing overall patient survival by 13 months. Therefore, marfalan, prednisone, plus thalidomide or bortezomib are standard of care regimens for patients who are not suitable for transplantation. In the Myeloma IX study, the cyclophosphamide-thalidomide-dexamethasone regimen had a higher remission rate than marfalan combined with prednisone, but neither improved progression-free survival or overall survival.
11. How are relapses treated?
The choice of relapse treatment option depends on the patient’s previous treatment regimen, duration of remission, drug toxicity, and the presence of comorbidities. In general, the choice of a previous treatment regimen depends on whether the patient has achieved long-term progression-free survival (more than 12 months). Relapse treatment relies heavily on new drugs and is more effective in combination with glucocorticoids or alkylating agents.
Bortezomib is used for first relapse and lenalidomide for treatment after second relapse, as recommended by the UK National Agency for Healthcare Quality Standards. Second autologous HSCT is suitable for younger, fitter patients and those in remission for a longer period (≥18 months) after the first transplant. Patients who are insensitive to immunomodulators and bortezomib generally have a poor prognosis, with a median survival of 9 months.
12. How to treat acute kidney injury in myeloma?
A linear relationship between reduction in serum free light chains and recovery of renal function has been reported; this emphasizes the importance of timely chemotherapy or direct removal of light chains by plasma exchange or hemodialysis. Randomized controlled trials and retrospective studies have shown that bortezomib is highly efficacious in such patients without nephrotoxicity. The International Myeloma Working Group recommends bortezomib in combination with high-dose dexamethasone for the treatment of patients with renal failure. A recent single-center study of primary patients showed that a treatment regimen based on bortezomib and thalidomide was effective in reversing renal failure.
13. How is cervical spondylosis treated?
If spinal cord compression is suspected, dexamethasone should be started immediately, followed by prompt spinal imaging. Bone related spinal cord compression requires urgent consultation with neurosurgeons and orthopedic surgeons to explore spinal decompression and fixation. When spinal cord compression is caused by an extramedullary tumor, chemotherapy or radiation therapy (or both) may be better options. Vertebral body strengthening is a percutaneous injection of polymethylmethacrylate into the vertebral body of a compression fracture, and experts agree that vertebral body strengthening reduces pain more rapidly than radiation therapy.
Two techniques are currently available, including vertebroplasty and balloon-expandable vertebral kyphoplasty, which involves inflating a balloon prior to injecting the fractured vertebrae. Vertebroplasty can be effective in reducing pain. The International Myeloma Task Force guidelines indicate that vertebral body strengthening is the procedure of choice for the treatment of painful compression fractures. If there is only pain without fracture, radiotherapy should be used.
14. How is hyperviscosity treated?
Clinical signs of hyperviscosity are caused by high concentrations of abnormal proteins (IgA antibodies >40 g/L and IgG antibodies >60 g/L). If clinical symptoms develop, emergency plasma exchange and systemic anti-myeloma therapy should be administered. If plasma replacement is not possible, isovolemic bloodletting may be an effective method.
15. How to treat bone disease?
The following three drugs are approved for the treatment of multiple myeloma: disodium clodronate, disodium pamidronate, and zoledronic acid. A meta-analysis covering 16 randomized controlled trials showed that bisphosphonates significantly reduced vertebral fractures, bone-related events and bone-related pain compared to placebo. results from the Myeloma IX study showed that zoledronic acid was significantly more effective than clodronate in reducing bone-related disease, while improving overall survival.
Bisphosphonates are recommended for all symptomatic patients with multiple myeloma regardless of the presence of bone lesions, and although zoledronic acid is the drug of choice, it is used with caution in patients with renal failure. Most guidelines recommend taking the drug for at least two years. Bisphosphonates are associated with an increased risk of osteonecrosis of the jaw, so an examination and evaluation of the teeth before starting treatment is recommended.
16. Important supportive care measures
Pain control is often an important aspect of clinical care due to bone disease or treatment side effects. Radiotherapy can be effective in treating painful skeletal lesions as well as soft tissue disorders. Vertebral body strengthening and bisphosphonate medication may be effective. Bone pain control often requires opioids rather than NSAIDs because of the potentially severe nephrotoxicity of NSAIDs. For neuropathic pain, calcium channel blockers (e.g., gabapentin) or 5-hydroxytryptamine and norepinephrine reuptake inhibitors (e.g., amitriptyline) can be effective. For clinical symptom control and psychological support, early collaboration with a multidisciplinary team is very important.
Multiple myeloma is associated with an increased risk of venous thromboembolism, which is further increased by the use of immunomodulatory agents, especially in combination with glucocorticoids or cytotoxic drugs and in patients with a primary diagnosis. The British Committee for Standards in Haematology guidelines recommend that patients start immunomodulatory therapy with aspirin or low molecular heparin based on risk assessment. Anaemia can be treated with blood transfusions or erythropoietin.
The British Committee for Standards in Haematology guidelines recommend that this drug needs to be tested if the haemoglobin is <100 μg/L. Multiple myeloma and its treatment can reduce immunity, with 10% of patients dying within the first 60 days primarily due to infection. Patient education and 24-hour compliance with hematology recommendations are important preventive measures, as is the timely administration of antibiotics.
17. Outlook
Despite high remission rates with initial therapy, most patients relapse within 36 months, so consolidation or maintenance regimens that prolong progression-free survival need to be studied in depth. The goal of consolidation therapy is to consolidate remission so that it does not recur. Maintenance therapy is the process of maintaining disease remission for an extended period of time (unless the disease has relapsed). Studies have shown that maintenance therapy with thalidomide or lenalidomide can benefit patients, but longer follow-up is needed.
Treatment of patients with high-risk asymptomatic multiple myeloma is also being investigated. Several current clinical studies are evaluating the efficacy of new treatment regimens, novel combinations of existing treatment regimens, and the sequencing and duration of different treatment regimens on disease. Pomalidomide is a next-generation immunomodulator and carfilzomib, a proteasome inhibitor, has been cleared for marketing by the FDA. Cell surface molecular antibodies such as CD38 and CS1 antibodies have also shown early advantages. Treatment of multiple myeloma, a heterogeneous disease, remains challenging, and more detailed delineation of its classification remains important. As the pathophysiological mechanisms of myeloma continue to be understood, bone anabolic pathways and anti-bone resorption therapies are being investigated.