Multiple Myeloma
by E. Terpos, M.D., Hematologist

Introduction and Definitions

Multiple myeloma is described scientifically as a B-cell malignancy characterized by a monoclonal expansion and accumulation of abnormal plasma cells in the bone marrow. The clinical manifestations of myeloma include bone complications, symptoms of impaired hemopoiesis (decreased production of blood cells), renal impairment, symptoms of hyperviscosity (thick blood), infections, peripheral neuropathy and symptoms of extramedullary disease (dysfunction of organs outside of the bone marrow).

Myeloma belongs to a group of disorders called “plasma cell dyscrasias” that also include benign monoclonal diseases such as monoclonal gammopathy (gamma immunoglobulins) of undetermined significance, indolent lymphomas such as the lymphoplasmacytic lymphoma (Waldenström macroglobulinaemia), and rare disorders such as POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinology, Monoclonal gammopathy, Skin changes) or monoclonal immunoglobulin deposition diseases. All disorders share common plasma cell morphological features and most are associated with the production of abnormal immunoglobulins.

 

Epidemiology

Myeloma comprises 1% of all cancers, but it is the second most common blood cancer after lymphomas and accounts for 10% of hematological malignancies. The median age at diagnosis is 67-70 years; fewer than 2% of myeloma patients are under 40 years old at diagnosis. Myeloma seems to be more common in men than women. The reasons for this are unclear but may include both hormonal effects and job-related exposure.

Myeloma has a higher incidence in Afro-Caribbean ethnic groups compared to Caucasians in the U.K., while in the U.S.A. the annual incidence also varies by race: from about 1/100,000 for Asians, to about 4/100,000 for Caucasians and to 8-10/100,000 for Afro-Americans. A variety of genetic and environmental factors have been proposed to explain the increased incidence in individuals of African descent. There is a tendency for myeloma to occur in families (3-5%), and recently a meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localizing to a number of genomic regions that are robustly associated with myeloma risk.

 

Pathogenesis

Origin of the malignant plasma cell: Multiple myeloma is a malignant condition caused by clonal (single cell) proliferation of plasma cells. Recent studies have revealed that monoclonal gammopathy of undetermined significance (called MGUS) always precedes multiple myeloma. These plasma cells are usually confined to the bone marrow but may be seen in the peripheral blood in end-stage myeloma. Current evidence suggests that myeloma cell is a long-lived plasma cell. Recent data, based on whole genome analysis of malignant plasma cells, suggest that there are different myeloma sub-clones in the same patient, while a possible “myeloma stem-cell” seems to support the growth of the resistant clones to the given therapy.

Myeloma cells proliferate at a low rate.

 

Environmental exposure: The cause of myeloma is unknown as no single factor has been consistently associated with myeloma. Exposure to chemicals (such as dioxins, solvents, and cleaners) and to radiation may be associated with the development of myeloma in predisposed individuals. Studies of atomic bomb survivors have shown an increased incidence of myeloma 15-20 years after exposure to radiation. Viral infections have also been implicated in the pathogenesis of myeloma. Several studies have suggested a link between myeloma and herpes virus infections (especially herpes virus 8), Epstein-Barr virus, human immunodeficiency virus, hepatitis viruses, as well as to new “stealth adapted” viruses such as mutated cytomegalovirus. However, epidemiological studies attempting to establish definite associations between myeloma and certain infections or autoimmune diseases have, so far, remained inconclusive.

 

Increased karyotypic instability: Increasing evidence suggests that the development of myeloma is a multi-step process that includes the progressive occurrence of multiple structural chromosomal changes. Karyotypes (human chromosomes) of myeloma are more similar to those of epithelial tumors and acute leukemias than to those of other hemopoietic malignancies. Gene expression profile seems to provide a more accurate and comprehensive assessment of molecular changes in myeloma, and is currently used to characterize myeloma at a molecular level and correlate gene-expression with response rates and survival in current trials of novel agents.

 

Bone marrow microenvironment in myeloma: The pathogenesis of multiple myeloma is very complex and includes mutual interactions that affect the number and function of both malignant cells and normal bone marrow stromal cells (BMSCs). Bone marrow microenvironment includes the extracellular matrix, and at least five types of stromal cells: fibroblasts, osteoblasts, osteoclasts, vascular endothelial cells and lymphocytes. Reciprocal positive and negative interactions among these cells are mediated by a variety of cytokines and adhesion molecules.  

Angiogenesis is also increased in myeloma patients and correlates with disease activity and survival.

In myeloma, there is an inhibition of T-lymphocyte function, but also a B-cell defect that make the patients to be susceptible to infections.

 

Biology of bone disease in myeloma: Bone destruction in myeloma is related to increased osteoclastic (bone tissue breakdown) activity, which is not accompanied by a comparable increase in osteoblast (bone tissue creation) formation. This leads to rapid bone loss, osteoporosis, lytic lesions, and fractures. In addition, osteoblasts are functionally exhausted in the myeloma environment.

 

Clinical features and symptoms

Plasma cell infiltration of bone marrow results in bone marrow failure and bone lesions. Patients, therefore, present with symptoms due to bone disease, hypercalcemia (increased calcium in the blood), impaired hemopoiesis (decreased production of blood cells), immune paresis (insufficiency of the immune system) and renal failure. In some patients plasma cell infiltration of soft tissues is seen at presentation. High serum paraprotein (immunoglobulins) may result in hyperviscosity and high levels of light chains (pieces of immunoglobulins) in the urine may result in renal failure.

The following section presents symptoms of multiple myeloma, in decreasing frequency.

 

Bone disease: Osteolytic lesions are one of the most prominent features of myeloma, present in up to 80% of patients at diagnosis and are found mainly in the skull, the vertebrae and the pelvis. Bone pain is the most common symptom and results from the osteolytic lesions and from pathological fractures, mainly wedging or collapse of vertebral bodies with or without osteoporosis. Pathological fractures of the long bones, ribs and sternum may also occur, while spinal cord compression may happen in 5% of patients at presentation. Skull lesions, in general, very rarely cause pain. At presentation around 10-15% of patients have hypercalcemia (increased calcium in the blood) associated with bone destruction. Patients may be symptomatic with polydypsia (thirsty), polyuria (large amount of urine) and constipation. Hypercalcemia may be severe enough to cause life-threatening dehydration and renal failure.

 

Immune paresis and impaired hemopoiesis: The vast majority of myeloma patients have reduced serum levels of normal immunoglobulins that make them susceptible to bacterial infections. Immunoglobulin levels rarely return to normal levels following chemotherapy even if the disease has responded. The recent use of immunomodulatory drugs, such as thalidomide, lenalidomide and pomalidomide manages to restore immune function in several responding patients. Immune paresis, renal failure, neutropenia and anti-myeloma therapy can combine to cause severe immuno-deficiency and infections are a major cause of death in these patients.

 

Anemia: Anemia is a common finding in myeloma and symptoms related to this may be a presenting feature at diagnosis. Anemia may be due to the infiltration of the bone marrow by myeloma cells, due to chronic inflammation or the use of cytotoxic drugs.

Serum erythropoetin levels are usually appropriately high in those patients with good renal function and inappropriately low in those patients with poor renal function. Thrombocytopenia (low platelets) and neutropenia (low white blood cells) may also occur due to bone marrow infiltration by malignant plasma cells or due to the use of chemotherapy.

 

Myeloma Nephropathy: Renal dysfunction is present in more than 20% of patients at diagnosis. It occurs when the tubular (part of renal structure) absorptive capacity of light chains is exhausted, resulting in interstitial nephritis with light-chain casts. Other causes of renal dysfunction are hypercalcemia with hypercalciuria, AL amyloidosis associated with l light chain disease, immunoglobulin light-chain deposition, infection, hyperuricemia and the use of anti-inflammatory drugs. The infiltration of the kidneys by myeloma cells may also occur but is rare.

 

Hyperviscosity: Hyperviscosity occurs in less than 10% of patients, and is more frequent among IgA myeloma patients compared to IgG myeloma ones. Among patients with IgG myeloma, those who have IgG3 subclass paraprotein are more likely to develop this syndrome.

It leads to cerebral, pulmonary, and renal dysfunction as well as a hemorrhagic tendency.

Visual dysfunction may range from mild visual disturbance to sudden loss of vision, and is evaluated via endoscopy of the eye (called fundoscopy). The neurological symptoms include headache, consciousness, mental slowing, dizziness, and very rarely coma.

The increased viscosity increases plasma volume and may compromise cardiac function.

 

Neurological complications: Neurological abnormalities are mainly caused by tumor growth compressing the spinal cord or cranial nerves. Peripheral neuropathy is frequently due to perineuronal amyloid deposition. Polyneuropathy may also be observed as a part of the POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes). Plasma-cell leukemia may involve the meninges, while intracerebral mass lesions are very rare.

 

Coagulopathy: Coagulopathy (dysfunction of coagulation system) in multiple myeloma is well documented but is rarely a clinical problem. Bleeding may be the result of hyperviscosity, perivascular amyloidosis, acquired coagulopathy, or thrombocytopenia. Some patients may develop thrombosis as a result of hyperviscosity or secondary to acquired deficiency of protein C or due to lupus anticoagulant.

 

Amyloidosis: Amyloidosis is clinically evident in around 5% of patients with myeloma. The disease becomes clinically significant when organ function is affected by its diffuse form.

Clinical features include:

  • renal impairment (usually manifesting as nephrotic syndrome)
  • congestive cardiac failure
  • macroglossia (large tongue)
  • gastrointestinal disturbances (dysmotility i.e. poor bowel movements, gastrointestinal wall thickening, and gastroesophageal reflux disease)
  • neuropathies (peripheral and autonomic), and
  • the carpal tunnel syndrome.

 

Diagnosis

Diagnostic criteria

Table 1 below summarizes the diagnostic criteria for multiple myeloma, asymptomatic myeloma, and monoclonal gammopathy of undetermined significance (MGUS). 

A: Smoldering Multiple Myeloma (Asymptomatic Multiple Myeloma)

The following criteria must all be met:

  1. Serum monoclonal protein (IgG or IgA) >=3gm/dL and/or clonal bone marrow plasma cells >=10%
  2. Absence of end-organ damage such as lytic bone lesions, anemia, hypercalcemia, or renal failure that can be attributed to a plasma cell proliferative disorder

 

B: Symptomatic Multiple Myeloma

The following criteria must all be met, except as noted:

  1. Clonal bone marrow plasma cells >=10%
  2. Presence of serum and/or urinary monoclonal protein (except in patients with non-secretory multiple myeloma, where >=10% clonal plasma cells are required for its diagnosis)
  3. Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder:
  1. Hypercalcemia (Serum calcium > 11.5 mg/dL) or
  2. Renal insufficiency (Serum creatinine > 2mg/dL)
  3. Anemia: Normochromic, normocytic with a hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value <10 g/dL
  4. Bone lesions: Lytic lesions, severe osteopenia or pathologic fractures

 

C: Monoclonal gammopathy of undetermined significance (MGUS)

The following criteria must all be met:

  1. Serum monoclonal protein < 3gm/dL
  2. Clonal bone marrow plasma cells <10%

Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder

Table 1: Diagnostic criteria for plasma cell disorders

 

Furthermore, the clinical and laboratory work-up for the diagnosis of myeloma is described below: 

  1. History and physical examination
  2. Complete blood count and differential; peripheral blood smear
  3. Chemistry screen including calcium and creatinine
  4. Serum protein electrophoresis, immunofixation
  5. Nephelometric quantification of serum immunoglobulins
  6. Routine urinalysis, 24 hour urine collection for electrophoresis and immunofixation
  7. Bone marrow aspirate and/or biopsy.
  8. Cytogenetics (metaphase karyotype and FISH).
  9. Radiological skeletal bone survey including spine, pelvis, skull, humeri and femurs. Magnetic Resonance Imaging and Whole Body Low-Dose Computed Tomography in patients with normal conventional radiography or in certain circumstances.
  10. Serum B2 microglobulin and lactate dehydrogenase.
  11. Measurement of serum free light chains.

 

Laboratory findings

The section below provides some further detail on the laboratory findings associated with multiple myeloma, their frequency among myeloma patients, as well as some further scans which may be performed.

 

Diagnostic work

The diagnostic work reveals an abnormal immunoglobulin (paraprotein) in the serum and/or the urine of the patients but less than 1% of patients have non-secretory disease. Nearly 60% of the patients have detectable IgG paraprotein, 20% have IgA paraprotein, 15%-20% light-chain only paraprotein, and less than 1% have IgD or IgE paraprotein. Suppression of the normal immunoglobulins is a typical finding in most cases. Patients have often a normochromic, normocytic anemia (~70% of them), hypercalcemia (~15%), low serum albumin or abnormal renal function (~20%). Other biochemical findings include elevated serum levels of C-reactive protein and b2-microglobulin, increased levels of lactate dehydrogenase, which is associated with poor prognosis and abnormal free light chain (FLC) ratio. Serum measurement of FLC may help in the distinction of oligo- or non-secretory myeloma.

Skeletal survey would indicate the presence and the extent of lytic bone lesions (present in up to 80% at diagnosis. Measurement of bone density with DEXA scan may be useful to monitor myeloma patients with osteoporosis only. If there are symptoms or signs of spinal cord compression then further imaging with computerized tomography (CT) scans or magnetic resonance imaging (MRI) scan is recommended.

 

Magnetic Resonance Imaging

A Magnetic Resonance Imaging (MRI) scan is also recommended: 

  1. for all patients with normal skeletal survey
  2. for staging of solitary plasmacytoma
  3. to discriminate myeloma vs. normal marrow (i.e. for the discrimination of myeloma versus non-malignant pathological fracture)
  4. for the detection of avascular necrosis of the femoral head
  5. for the detection of amyloid/light chain deposits in the heart and other sites. 

 

Computed Tomography (CT)

A new technique, the Whole-Body Low-Dose CT, can be used in patients with normal skeletal surveys, as it is more sensitive than conventional radiography in revealing osteolytic bone disease. Finally, the positron emission tomography-computed tomography (PET-CT) is currently recommended for the staging of solitary plasmacytoma, the evaluation of patients with suspicion of extramedullary presentation and/or progression especially in cases with oligo- or hypo-secretory myeloma or rising LDH.

 

Differential diagnosis

The differential diagnosis includes monoclonal gammopathy of undetermined significance (MGUS), which is associated with lower paraprotein levels, less plasmacytosis in the bone marrow, and no anemia, renal dysfunction or lytic lesions (see Table 1). Patients with solitary plasmacytoma have no evidence of systematic disease, while AL amyloidosis can be distinguished by renal or rectal biopsy, or fine-needle aspiration of subcutaneous fat and staining the tissue with a solution called “Congo red”. Amyloidosis may be suspected in cases with renal dysfunction with non-selective proteinuria or significant albuminuria, cardiomegaly associated with arrythmias, low-voltage and conduction defects on electrocardiogram, carpal tunnel syndrome or macroglossia.

 

Staging

Once the diagnosis of multiple myeloma has been established, staging of the disease should be performed. The standard system for staging a myeloma patient is the Salmon-Durie staging system (shown in Table 2). 

Stage 1: All of the following

  • Hemoglobin >10.5 g/dl
  • Serum calcium normal
  • X-rays show normal bone structure or solitary bone plasmacytoma only
  • Low paraprotein levels:
    • IgG <50 g/L
    • IgA <30 g/L
  • Urinary light chain <4g/24h

 

Stage 2: Fitting neither stage 1 nor stage 3

 

Stage 3: One or more of the following

  • Hemobglobin <8.5 g/dl
  • Serum calcium > 3mmol/l
  • Advanced lytic bone lesions (>3 lytic lesions)
  • High paraprotein levels:
    • IgG >70 g/L
    • IgA >50 g/L
  • Urinary light chain >12 g/24h

 

All 3 stages have the following subclassification (either A or B):

A: serum creatinine <2 mg/dL
B: serum creatinine ≥2 mg/dL

Table 2. The Durie-Salmon staging system

 

Prognosis

The system used currently is the International Staging System (ISS) and is shown in Table 3 below. A number of prognostic indices have been proposed to-date using different risk factors, including combination of high-risk chromosomal abnormalities and ISS. 

 

Staging Parameters Median survival (months)
Stage 1

β2M < 3.5 and ALB >= 35

62
Stage 2

β2M < 3.5 and ALB < 35 

or 

β2M between 3.5 and 5.5

44
Stage 3 β2M > 5.5 29

 

β2M: serum b2-microglobulin in mg/L

ALB: serum albumin in g/L

 

Factors predicting for lower risk:

Age < 60 &
β2M < 3.5 mg/L & 
ALB > 35 g/L

 

Factors predicting for higher risk:

β2M > 10 mg/L &
ALB < 35 g/L &
Low platelet count

Table 3. International Prognostic Index for multiple myeloma

 

Treatment

Asymptomatic multiple myeloma

Patients with no organ dysfunction due to myeloma, no hypercalcemia, normal renal function, no anemia and absence of bone lesions, may remain stable for a long time without any chemotherapy. These patients account for about 10-20% of myeloma patients, and have a median time to disease progression of between 2-3 years. The survival is similar when conventional treatment is administered just after diagnosis. However, the disease needs to be evaluated at regular intervals (every 2-3 months) to identify the stable, asymptomatic patients who do not need treatment, and those patients with progressive, symptomatic disease.

Signs of disease progression, such as rising paraprotein levels, falling haemoglobin levels, radiological evidence of bone disease, or an increase in bone marrow infiltration in non-secretory myeloma, are indications to start treatment.

Asymptomatic patients with at least one lytic lesion in X-rays have a median time to progression of 8 months, while abnormal marrow appearance on magnetic resonance imaging (MRI) is also associated with higher risk of disease progression.

Other factors that are associated with high risk of progression of asymptomatic to symptomatic disease includes high infiltration of the bone marrow by plasma cells (>60%) and high ratio of the serum free light chain.

 

However, a recent study using a novel agent based regimen (lenalidomide and dexamethasone, called RD) managed to prolong progression-free survival (PFS) but also overall survival (OS) in patients with asymptomatic myeloma and high-risk for progression to symptomatic disease. In the future, patients with high-risk asymptomatic myeloma may be treated as patients with symptomatic disease.

 

Autologous Stem Cell Transplantation (ASCT)

Autologous Stem Cell Transplantation (ASCT) is transplantation of peripheral blood stem cell, usually taken from blood. It may be part of the treatment for multiple myeloma.

Not all patients are eligible for autologous stem cell transplantation.

 

Front-line therapy for patients who are eligible for autologous stem cell transplantation

Induction therapy using 3-4 cycles of a novel agent-based regimen followed by high dose melphalan and autologous stem cell transplantation (ASCT) is the standard of care for patients who are younger than 65 years of age with no comorbidities (other chronic diseases), or even for elderly patients (up to the age of 70 years) with very good performance status. Bortezomib-based regimens (called VTD or PAD) have produced very good results in terms of both objective response rate (ORR) and survival as induction treatment pre-ASCT.

 

Clinical trials and recent developments

In two large randomized trials the ORR ranges from 80% pre-ASCT to 90% post-ASCT with 30%-40% CR (Complete Response) plus near-Complete Response rates. In a recent randomized trial (known as the “EVOLUTION” trial) the combination of bortezomib, cyclophosphamide (given weekly at a 3-week cycle scheme) and dexamethasone  (called VCD-modified) has produced the more promising results in terms of increased efficacy and reduced toxicity (in comparison to other regimens called VCD, VRD or VRCD).

Lenalidomide has also been evaluated in the frontline setting and its combination with low-dose dexamethasone (called RD) has shown higher probability of 1-year overall survival (OS) compared to the combination of lenalidomide with high-dose dexamethasone, 96% vs. 87%. A retrospective analysis which compared the regimen called RD with the regimen called TD showed that RD patients had longer time to progression (TTP), progression free survival (PFS) and overall survival (OS) than TD patients. Finally, a triple combination with bortezomib, thalidomide and dexamethasone (called VTD) has proven to be superior to the regimen called VD regarding overall response rate (ORR) but not regarding overall survival ( OS).

 

Maintenance therapy post-ASCT in myeloma

Thalidomide has been found in randomized studies that it prolongs PFS, while bortezomib maintenance has also shown increased ORR and PFS in randomized studies. Lenalidomide is an attractive alternative to thalidomide and bortezomib due to the lack of neurological toxicity and its oral administration.

 

Clinical trials and recent developments

Two independent large randomized trials have recently shown a significantly longer PFS for patients randomized to lenalidomide maintenance (5-15 mg per day) in comparison with the placebo group after a single or double ASCT. In a French study (IFM 2005-02) after a median follow-up of 34 months the median PFS was 42 versus 24 months for lenalidomide and placebo arm, respectively. This has not been translated in an overall survival (OS) benefit yet, although an OS benefit may become evident with longer follow-up period. In a US-based trial (CALGB-100104) after a median follow-up of 17.5 months the results for median progression free survival (PFS) were similar with the French study: 43 vs. 21 months for lenalidomide and placebo arm, respectively, but in the International Myeloma Workshop of 2011 a significant increase of OS in lenalidomide arm was reported.

 

Front-line therapy for patients who are not eligible for autologous stem cell transplantation

The standard of care for these patients is the combination of melphalan/prednisone (called MP) with thalidomide (called MPT) or bortezomib (called MPV). In a recent meta-analysis, which included 6 randomized studies with 1682 patients and compared MPT with MP, MPT improved PFS (20.4 vs. 14.9 months) but not OS (39.3 vs. 32.7 months). MPV is the second standard of care in the elderly patients. When compared to MP, MPV produced a significant improvement in ORR (71% vs. 35%), CR rate (30% vs. 4%), TTP (24 vs. 16.6 months), and OS at 3 years (72% vs. 59%). This superiority was also recorded in patients >75 years and in patients with moderate renal impairment.

 

Clinical trials and recent developments

In a UK trial, the CTD regimen was compared with standard MP in 900 patients. CTD produced higher ORR (82% vs. 49%) and CR rates (23% vs. 6%) than MP did.

Another regimen, the combination of melphalan, prednisone, and lenalidomide (called MPR) has been investigated in a phase III study with three arms. MPR or MP was given for 9 cycles followed by placebo till progression, while in the 3rd arm MPR was followed by Lenalidomide (R) maintenance till progression. MPR-R compared with MP resulted in a higher ORR (77% vs. 50%) as well as higher rates of CR (16% vs. 4%) and very good partial response (VGPR) or better (32% vs. 12%). Overall, MPR-R reduced the risk of disease progression by 58% compared with MP with a higher 2-year PFS rate (55% vs. 16%). A landmark analysis comparing MPR-R and MPR initiated at the beginning of cycle 10 demonstrated that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo. In addition, regardless of induction response (≥ VGPR or PR), patients who received maintenance lenalidomide had longer PFS compared with placebo (i.e. no active drug).

Finally in the last American Society of Hematology (ASH 2013) meeting, the combination of lenalidomide plus low dose dexamethasone till progression prolonged not only PFS but also OS over MPT, offering another standard of care for these patients.

 

Treatment of patients with relapsed/refractory myeloma

Bortezomib-based combinations produce overall response rate (ORR) of 40-50% and time to progression (TTP) of 6-9 months, while Lenalidomide plus high dose Dexamethasone (called RD) produces ORR of 60% and TTP of 13.5 months. Major toxicities with bortezomib include peripheral neuropathy, thrombocytopenia, neutropenia, and gastrointestinal adverse events, while the main toxicities reported with RD include neutropenia, thrombocytopenia, venous thromboembolism and infections. Lenalidomide is also very effective in patients previously treated with thalidomide. Finally, the combination of 3 or 4 agents, including 2 novel agents, have been used in the relapsed/refractory setting with high ORR: the VRD regimen produced an ORR of 63%, the VMDT 66% and the RMPT 75%.

Patients with multiple myeloma who have received “novel” agents (thalidomide-, lenalidomide- and/or bortezomib-based regimens) and their disease has relapsed or has become refractory to these treatments present a particular challenge. These patients can be treated with the novel proteasome inhibitor, carfilzomib or with the novel immunomodulatory drug (IMiD), pomalidomide or they can be encouraged to participate in clinical trials of novel experimental agents.

 

Recent drug approvals for relapsed/refractory myeloma

Carfilzomib was approved by the US FDA in July 2012 based on the results of a phase IIb trial. This study included 266 patients who had been exposed to both bortezomib and an IMiD and who were relapsed and refractory to their most recent line of therapy. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m2 in cycle 1; 27 mg/m2 in cycles 2-12). The response rate was 23.7%. The median time-to-response was <2 months and the response duration was 7.8 months. The median time to progression (TTP) was 3.9 months, and the overall survival (OS) was 15.6 months. Carfilzomib showed very low rates of peripheral neuropathy.

Pomalidomide was approved by the US FDA in February 2013 for the same MM population based on the results of a phase III study in relapsed or relapsed and refractory Myeloma patients who had failed to both bortezomib- and lenalidomide-based regimens and were refractory to last treatment: 302 received pomalidomide at a dose of 4 mg/day for 21 days in a 28-day cycle with low dose dexamethasone and 153 patients received high dose dexamethasone. The objective response rate was 21% in pomalidomide plus dexamethasone arm vs. 3% in high-dose dexamethasone. Median progression free survival (PFS) and overall survival (OS) were 4.0 and 12.7 months, respectively, for pomalidomide plus dexamethasone, compared to 1.9 and 8.1 months, respectively, for high-dose dexamethasone arm.

 

Clinical trials and recent developments

The most promising novel agent that is under investigation is daratumumab. Daratumumab is an anti-CD38 monoclonal antibody and has been given as monotherapy in relapsed or refractory patients to at least two different prior lines of therapy who were ineligible for ASCT. Limited data has been reported: 4 out of 9 patients who received ≥4 mg/kg achieved a partial response. No dose limited toxicities (DLTs) were reported in the 2, 4, 8 and 16mg/kg cohorts, while the most common adverse events reported were infusion related events.

Elotuzumab is a monoclonal antibody against CS1 and is combined with lenalidomide and low dose Dex in phase III studies. This combination has produced very encouraging results in phase II study in relapse/refractory multiple myeloma: ORR 92% and median PFS of 27 months.

Despite advances in anti-myeloma treatment, nearly all patients will eventually relapse or become refractory to these drugs. Numerous agents are currently in development for the treatment of relapsed/refractorymultiple myeloma. Those farthest along in clinical development include new Proteasome Inhibitors (e.g. ixazomib, oprozomib and marizomib), histone deacetylase inhibitors (e.g. panobinostat and vorinostat), other monoclonal antibodies (e.g. tabalumab, siltuximab), and signal transduction modulators (e.g. perifosine). These emerging agents with diverse mechanisms of action have demonstrated promising anti-tumor activity in patients with relapsed/refractory multiple myeloma, and rationally designed combinations with established agents are being investigated in the clinic. These new agents are creating opportunities to target multiple pathways, overcome resistance, and improve clinical outcomes, particularly for those patients who are refractory to approved novel agents.

 

Supportive therapy

Anemia: Traditionally, symptomatic anemia has been managed by red cell transfusion. There is now evidence based on randomized studies that recombinant human erythropoietin (rHuEpo) is useful in the management of anemia in myeloma, producing erythroid responses in approximately 60-70% of patients. Although there are no reliable predictors of response to rHuEpo, low endogenous erythropoietin concentration seems to be the most helpful predictive factor for response. These data suggest that a therapeutic trial of rHuEpo should be considered in any myeloma patient with symptomatic anemia.

 

Renal failure: A degree of renal impairment occurs in up to 50% of myeloma patients at some stage of their disease, while advanced renal failure requiring hemodialysis occurs in 3-12% of myeloma patients. In the majority of patients, the renal function will improve in response to simple measures such as fluid rehydration and administration of glucocorticoids, or discontinuation of nephrotoxic drugs such as NSAIDs and treatment of any infections. The risk of renal failure, which may be precipitated by the use of intravenous x-ray contrast media, could be reduced by ensuring adequate hydration and by using dyes of reduced osmolality. Bortezomib-based combinations (VD, but also VTD or PAD) are considered the standard of care for patients who present with renal insufficiency. Half of those who recover do so in the first 6 weeks but late recovery is still possible. Hemodialysis with high cut-off filters can also be used for the removal of free light chains in patients with high levels.

 

Bone Disease: Targeting osteoclastic bone resorption is currently the most important approach to treat patients with myeloma-related bone disease. Bisphosphonates (BPs) are potent inhibitors of osteoclast activity and function. In the recently published MRC-IX trial, zoledronic acid significantly reduced the number of skeletal-related events compared with oral clodronate in patients with newly diagnosed, symptomatic multiple myeloma. More importantly, zoledronic acid reduced the relative risk of death by 16% compared to clodronate and increased the median overall survival by 5.5 months. In another recent trial, 30 mg of intravenous pamidronate, monthly, were equally effective with the standard 90 mg dose, regarding the reduction of SREs (skeletal related events) in 504 symptomatic, newly-diagnosed, myeloma patients who received conventional treatment. The recent International Myeloma Working Group guidelines suggest that bisphosphonates should be considered in all patients receiving frontline anti-myeloma therapy regardless of the presence of osteolytic bone lesions on conventional radiography. However, it is unknown if bisphosphonates offer any advantage in patients with no bone disease assessed by MRI or PET/CT. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) are recommended for preventing skeletal-related events in patients. ZOL is preferred over oral clodronate (CLO) in newly diagnosed multiple myeloma because of its potential antimyeloma effects and survival benefits. Bisphosphonates should be administered intravenously every 3- to 4-weeks during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients at complete or partial response. Bisphosphonates are well tolerated but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty (surgery of the vertebra) should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, or vertebral column instability.

Novel anti-myeloma agents, such as immunomodulatory drugs and bortezomib alter abnormal bone metabolism. Lenalidomide, thalidomide and bortezomib reduce bone resorption either directly (through the inhibition of osteoclast formation) or indirectly (through the modification of interactions between malignant plasma cells and osteoclasts). However, in terms of the restoration of osteoblast function, only bortezomib is able to directly stimulate osteoblast differentiation and activity and leads to increased bone formation and increased bone mineral density, at least in responders. Novel drugs that may effectively manage myeloma bone disease in the future include anti-RANKL agents (denosumab), anti-Dkk1 drugs (BHQ-880), activin-A antagonists (sotatercept) and anti-sclerostin antibodies (romosozumab).

 

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