The Bethesda Handbook of Clinical Hematology, 3 Ed.

17. Multiple Myeloma

Elisabet E. Manasanch, Nishant Tageja and C. Ola Landgren

EPIDEMIOLOGY AND RISK FACTORS

Multiple myeloma is the second most common hematologic malignancy in the United States, with an annual age-adjusted incidence rate of 6 per 100,000 and a prevalence of 70,000 as of January 1, 2009.1Myeloma is diagnosed predominantly in the elderly, with a median age at presentation of about 69 years. Men are more affected than women. African American men have the highest incidence rate at 14.3 per 100,000, twice the rate of their Caucasian counterparts.

Most cases are preceded by an asymptomatic plasma cell dyscrasia termed monoclonal gammopathy of undetermined significance (MGUS)2 and smoldering multiple myeloma (SMM).

According to data from the Mayo Clinic, 3% of the general white population older than 50 have MGUS with an average multiple myeloma progression rate of 1% per year3; SMM has a 10% annual risk of progression to multiple myeloma.

Known risk factors are age, race, male sex, obesity, exposure to pesticides, and a family history of MGUS or multiple myeloma. Both environmental and genetic factors (single nucleotide polymorphisms, SNPs, at loci in chromosomal regions 2p, 3p, and 7p) may play a role in the development of multiple myeloma and its precursors.

Precursor States

The International Myeloma Working Group (IMWG) guidelines published in 2010, define MGUS as a serum M-protein <30 g/L, <10% clonal plasma cells in the bone marrow, and absence of end-organ damage (hypercalcemia, renal insufficiency, anemia, bone lesions (CRAB) criteria; Table 17.1) that can be attributed to the plasma cell proliferative disorder.4 SMM requires an M protein level of ≥30 g/L or ≥10% clonal plasma cells in the bone marrow, but no end-organ damage. After diagnosis, patients should be risk stratified for progression to multiple myeloma. Clinical follow-up depends on the risk of progression to symptomatic disease based on risk stratification (Table 17.2).

An ongoing randomized phase III trial is currently evaluating the role of early treatment with lenalidomide and high-dose dexamethasone in high-risk SMM patients. Preliminary results suggest delayed time to progression in the treatment arm.5 At this time, new phase II trials are being launched to assess whether early treatment can delay/prevent progression to frank multiple myeloma. The 2012 treatment standard for MGUS and SMM is to “watch and wait.” High-risk SMM patients may be treated only after enrollment in clinical trials.

Pathophysiology

Multiple myeloma is a heterogeneous disease and classified as one of the paraproteinemias. It is characterized by the proliferation and infiltration of the bone marrow by abnormal clonal terminally differentiated B lymphocytes (plasma cells) that produce antibodies. Deregulation of plasma cell biology as a result of somatic cell mutations drives the transformation from asymptomatic states such as MGUS and SMM to multiple myeloma and plasma cell leukemia.6

Multiple genetic abnormalities have been identified that contribute to the genesis and progression to multiple myeloma including inherited SNP variations, translocations (mostly involving the immunoglobulin heavy chain (IGH) locus in chromosome 14), trisomies of odd numbered chromosomes (hyperdiploidy), mutations, epigenetic changes, and microRNA abnormalities. Hyperdiploidy and translocations of IGH are the most common primary genetic events in multiple myeloma which can risk stratify the disease into standard, intermediate, and high risk and have prognostic information which correlates with overall survival (Table 17.2).62

Secondary genetic events have been proposed to confer a selective advantage to the clonal plasma cell, which accumulates and interacts with the bone marrow microenvironment (stromal cells, osteoclasts, osteoblasts, and vasculature). Ultimately, there is a decrease in the number of normal plasma cells, high levels of circulating inflammatory cytokines, hypercoagulability, immunosuppression, myelosuppression, lytic bone lesions, and hypercalcemia.

Clinical Features

Multiple myeloma has different clinical presentations: it does not represent a single disease entity but rather a spectrum of clonal plasma cell disorders. Table 17.1 depicts the most common clinical abnormalities at diagnosis as well as type of monoclonal protein involvement.7

The most common symptom at diagnosis is bone pain (up to 70% of patients in most case series) affecting the lumbar and rib areas and causing pathologic fractures. Up to 90% of patients develop osteolytic lesions during the course of their disease. Increased risk of infections, weight loss, fatigue (anemia), and malaise are common. Around 10% to 20% of patients can present with hypercalcemia (somnolence, confusion, constipation, nausea) or renal insufficiency. Most patients (>95%) do not have symptoms of hyperviscosity (uncommon if serum viscosity level is not four times the upper limit of normal) or amyloidosis. About 1% of patients have extramedullary disease (EMD) at the time of presentation and about 8% develop EMD in their disease course.

Initial Evaluation

Recommended

Complete history and physical examination.8

Hematology Complete blood counts with differential and peripheral blood smear review.

Chemistries Serum electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, uric acid, β2 microglobulin, serum albumin, C-reactive protein, and serum lactate dehydrogenase (LDH).

Serum protein electrophoresis (SPEP) with serum immunofixation and the serum-free light chain (FLC) nephelometric assay. About 20% of multiple myeloma patients have a light-chain myeloma (abnormal FLC ratio in the absence of an M-spike). About 1% of multiple myeloma patients have nonsecretory disease without evidence of an M-spike and without an abnormal FLC ratio.

Routine urine analysis, 24-hour collection for proteinuria, electrophoresis, and immunofixation.

Quantitative immunoglobulins.

Bone marrow aspirate plus trephine core biopsy. Standard metaphase cytogenetics and fluorescent in situ hybridization (FISH) for common chromosomal abnormalities found in multiple myeloma [t(11;14), t(4;14), t(14;16),t(6:14), t(14;20), hyperdiploidy, deletion 17p and 13q, gain of 1q].

Gene expression profiling (usually for research).

Imaging

Radiographic skeletal survey including the spine, pelvis, skull, humeri, and femurs is still the gold standard imaging technique; however, it has some limitations since it reveals a lytic lesion only after >30% to 50% of the trabecular bone is lost. 9

Whole-body low-dose multidetector-row computed tomography (MDCT) is very sensitive at detecting small lytic lesions that may be negative on skeletal survey, but delivers a 1.3 to 3.0 times higher radiation dose. In some centers, MDCT has replaced conventional radiography for diagnosis and follow-up of multiple myeloma patients and it may be used if available.

Magnetic resonance imaging (MRI) is particularly useful to rule out cord compression if spinal symptoms are present. Whole-body MRI is more sensitive than MDCT without radiation exposure. It is the preferred method to assess and follow osseous and extraosseous solitary bone plasmacytoma (SBP), with the suggestion that MRI should be included in the initial evaluation of SBP since it may reveal occult lesions elsewhere and lead to upstaging. MRI is recommended in patients with normal conventional radiography as part of the initial workup of multiple myeloma.

Whole-body fluorodeoxyglucose/positron emission tomography (FDG/PET) imaging is not recommended for routine use outside of clinical trials.

Technetium bone scans cannot be used for the evaluation of MGUS/SMM or multiple myeloma since

osteolytic lesions do not have increased uptake and up to 50% of bone lesions can be missed.

Diagnostic Criteria

International Myeloma Working Group Criteria

The diagnosis of multiple myeloma must include the following10,11:

  1. Clonal bone marrow plasma cells≥10% (bone marrow involvement can be patchy and several random biopsies may be needed) and
  2. Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory multiple myeloma) and
  3. Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder:
  4. Hypercalcemia: serum calcium≥11.5 mg/100 mL or
  5. Renal insufficiency: serum creatinine>1.73 mmol/L (2 mg/dL) or
  6. Anemia: normochromic normocytic with a hemoglobin value of>2 g/100 mL below the lower limit of normal or hemoglobin value<10 g/100mL or
  7. Bone: lytic lesions, severe osteopenia, or pathologic fractures

Staging

In 1975, the Durie-Salmon Staging System (DS SS) for multiple myeloma was proposed based on the mathematical correlation of individual clinical, laboratory, and X-ray features with multiple myeloma tumor burden.12 Depending on the severity of anemia, levels of M-protein, hypercalcemia, and lytic lesions patients were classified as being stage I, II, or III. Patients could be further subclassified in stage A (creatinine < 2 mg/100 mL) or B (creatinine ≥ 2 mg/100 mL) (Table 17.3). The DS SS was widely adopted, however because the number and size of lytic lesions on plain X-ray is observer-dependent (subjective) a more objective staging system was proposed in 2005 by the IMWG using only laboratory values of β2 microglobulin and serum albumin. This correlated well with overall survival (Table 17.3).13Both staging systems continue to be used clinically and in research trials.

Criteria to Assess Response, Progression, and Relapse

Since 2006 the IMWG uniform response criteria have been used to categorize patient responses and to report efficacy of new agents in clinical trials (Table 17.4). Major advantages of these criteria include the ability to report on deeper responses, interpretation of response using serum FLC in patients with lack of measurable disease (no serum or urine M-protein), and the addition of the Very Good Partial Response (VGPR) category.14

The current definitions of progressive disease and relapse as per the IMWG are as follows:

  1. Progressive disease: requires any of the following
  2. Increase of≥25% from baseline in
  3. serum M-component and/or (absolute increase must be≥0.5 g/dL)
  4. Urine M-component and/or (absolute increase must be≥200 mg/24h)

iii. Only in patients without measurable serum and urine M-protein levels: the difference between the involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL.

  1. Bone marrow plasma cell percentage: the absolute % must be≥10% (or ≥5% if relapse from CR) v. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
  2. Development of hypercalcemia (corrected serum calcium>11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
  3. Clinical relapse: requires one or more of direct indicators of increasing disease (CRAB features)
  4. Development of new soft tissue plasmacytomas or bone lesions
  5. Definite increase in the size of existing plasmacytomas or bone lesions, defined as a 50% (at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesions
  6. Hypercalcemia (>11.5 mg/dL)
  7. Decrease in hemoglobin of≥2g/dL
  8. Rise in serum creatinine by 2 mg/dL or more
  9. Relapse from CR: any one or more of the following
  10. Reappearance of serum or urine M-protein by immunofixation electrophoresis (IFE), or electrophoresis
  11. Development of≥5% plasma cells in the bone marrow
  12. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcemia).

Differential Diagnosis

Multiple myeloma must be accurately distinguished from other plasma cell disorders in order to offer adequate evaluation, treatment, and follow-up.

Immunoglobulin Light Chain Amyloidosis

Amyloidosis is caused by the accumulation of β-sheet secondary structure proteins that aggregate in tissues in the form of nonbranching fibrils causing organ-specific dysfunction (most notably the heart, kidneys, skin, peripheral nerves, autonomic nerves, and liver). In AL systemic primary amyloidosis the precursor protein is a bone marrow plasma cell derived immunoglobulin light chain (AL) (2:1, λ to κ). Treatment is directed toward eradicating the clonal plasma cell, however regimens derived from treatment of multiple myeloma are always more toxic if used in AL amyloidosis. Diagnosis must include all the following:

Presence of an amyloid-related systemic syndrome

Positive amyloid staining by Congo red in any tissue (fat aspirate, bone marrow biopsy, or involved

organ biopsy)

Evidence that the amyloid is light-chain related (via mass spectrometry-based proteomic analysis, or immune-electronmicroscopy)

Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M-protein, abnormal FLC ratio, or clonal plasma cells in the bone marrow). 15

Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma with IgM monoclonal protein that causes anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. Patients can often be observed before treatment is indicated. Diagnosis must include the following:

IgM monoclonal gammopathy

≥ 10% bone marrow lymphoplasmacytic infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (surface IgM+, CD5±, CD10−, CD19+, CD20+, CD23−) that excludes Mantle cell lymphoma and chronic lymphocytic leukemia

Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.

Solitary Plasmacytoma

Solitary plasmacytoma (SP) is a mass of monoclonal plasma cells in either the bone (SBP) or the soft tissue (extramedullary plasmacytoma, EMP) without evidence of disease that can be attributed to multiple myeloma. It usually presents in the axial skeleton (bone) or head and neck (soft tissue). The goal of treatment is cure with local radiation therapy; however, while most patients with SBP (60%) progress to multiple myeloma in the years after diagnosis, most patients with EMP (65%) do not. Diagnostic criteria must include all of the following:

Biopsy-proven solitary lesion of the bone or soft tissue with evidence of clonal plasma cells

Normal bone marrow with no evidence of clonal plasma cells

Normal skeletal survey and MRI of the spine and pelvis (except for the primary solitary lesion)

Absence of end-organ damage such as CRAB that can be attributed to a plasma cell disorder.

Other Systemic Plasma Cell Dyscrasias

These include

The rare paraneoplastic polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS)16 syndrome

The recently recognized telangiectasias, erythrocytosis with elevated erythropoietin levels, monoclo-nal gammopathy, perinephric-fluid collections, and intrapulmonary shunting (TEMPI) syndrome.17,18

It is worth noting that an elevated plasma VEGF level of 200 pg/mL has been reported to be 95% specific and 68% sensitive for POEMS syndrome.19

Miscellaneous

Metastatic carcinoma, hyperparathyroidism—Brown tumor, infection, primary bone tumors can all present with lytic lesions. If there is no evidence of a monoclonal gammopathy other diagnoses should be excluded before considering multiple myeloma

Treatment

The treatment of multiple myeloma has undergone a dramatic shift over the past decade with new agents that have been shown to be more effective and less toxic than conventional chemotherapy, which has translated into an improvement in overall survival.20 There have also been major advances in risk stratification and classification of this disease, and risk-adapted therapy has been proposed as an approach to treatment.15

High-Risk Smoldering Multiple Myeloma

Recently, the first randomized phase III study designed to treat asymptomatic high-risk multiple myeloma with lenalidomide and dexamethasone was initiated with encouraging preliminary results. In the future, high-risk SMM individuals may have therapeutic options before they develop full-blown symptomatic multiple myeloma in an attempt to gain better and more prolonged control of the disease and maybe a possibility to cure.21

At this time, treatment of these patients outside of a clinical trial is not recommended due to the lack of long-term follow-up data.

Multiple Myeloma

High-dose conventional chemotherapy (HDT) with stem cell rescue is still at the cornerstone of treatment of multiple myeloma. However, major benefit has been added with the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide as well as the proteasome inhibitor, bortezomib. Steroids continue to be an important part of therapy and bisphosphonates (BPs) have been seen to improve overall survival and are thought to have direct anti-myeloma effects.22

Allogeneic stem cell transplantation (SCT) results in high treatment-related mortality (at least 10%– 20%) and graft-versus-host disease (GVHD) rates which have limited its clinical use to investigational trials. Autologous stem cell transplant (ASCT) followed by allogeneic SCT was not found to be more effective than tandem ASCT in a randomized controlled trial.23

In standard clinical practice, patients with multiple myeloma are classified as high risk or low risk based on the ISS and chromosomal abnormalities (Table 17.5). The single most important factor in the frontline treatment of multiple myeloma is to ascertain whether the patient is eligible for high-dose chemotherapy with stem cell rescue. This is usually limited to patients younger than 70 to 75 years of age with good performance status and organ function; thus a significant proportion of newly diagnosed multiple myeloma patients are not found to be good candidates.

The recommended newly diagnosed anti-myeloma therapies are listed in Table 17.6. A flow chart with treatment options for multiple myeloma is shown in Figure 17.1.

Frontline Therapy for Patients Eligible for Autologous Stem Cell Transplant

Patients who are eligible for ASCT undergo two to four cycles of induction therapy before stem cell collection. Thereafter, patients can elect to undergo frontline ASCT or resume induction therapy with delay of ASCT until relapse. An ongoing clinical trial (DFCI-IFM RCT 2009) is investigating the role of upfront versus delayed ASCT. Preliminary data show no statistical significance observed in terms of overall survival and progression-free survival, however final results are pending. Alkylating agents (melphalan) and IMiDs (lenalidomide) can decrease the yield of stem collection due to their damaging properties on stem cells. As such, melphalan and prolonged lenalidomide treatment should be avoided as frontline therapy in patients who are eligible for SCT.

In the 1990s and early 2000s conventional chemotherapy with VAD (V = vincristine, A = adriamycin, D = dexamethasone) was used as the standard induction treatment before ASCT. However, with the advent of IMiDs and proteasome inhibitors induction regimens have changed drastically while achieving higher tumor reduction, better response rates, and improvement in progression-free survival and overall survival.34-36 Thus, VAD is no longer preferred as frontline therapy.

Different combinations of bortezomib, lenalidomide, or thalidomide with dexamethasone were effective and safe in multiple myeloma with high response rates. Three or four drug combination regimens were studied to assess whether higher response rates could be achieved without added toxicity. Bortezomib was added to the combination treatment consisting of thalidomide (Thal) and dexamethasone (Dex) (VTD) and was seen to be superior to ThalDex alone.37 It was also superior to aggressive regimens combining conventional cytotoxic chemotherapy such as VBMCP (V = vincristine, M = melphalan, BCNU/carmustine, cyclophosphamide, prednisone), and vincristine, bortezomib, adriamycin, dexamehtasone (VBAD) (A= adriamycin).38

ThalDex was less active and more toxic than lenalidomide-based regimens and is not recommended as frontline therapy. Lenalidomide combined with low-dose dexamethasone (Rd) [40 mg po weekly] had an overall survival advantage with less toxicity than used with high-dose dexamethasone (RD).39

All patients treated with lenalidomide should receive deep venous thrombosis (DVT) prophylaxis with aspirin, low molecular weight heparin, or Coumadin.40

Table 17.5 Risk Stratification of Multiple Myeloma by Mayo Clinic Model24

Standard risk (overall survival 6–7 yr)

Hyperdiploidy

t(11;14)

t(6;14)

Intermediate risk

t(4;14)

Deletion 13 or hypodiploidy by conventional karyotyping

High risk (overall survival 2–3 yr)

17p deletion

t(14;16)

t(14;20)

High-risk gene expression profiling signature

FIGURE 17.1. Current treatment algorithm for patients with multiple myeloma.

* Maybe dose reduced to 140 or 100 mg/m2 in selected patients who would otherwise not tolerate 200 mg/m2. MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone; VCR, bortezomib, cyclophosphamide, dexamethasone; VMP, bortezomib, melphalan, prednisone; VRD, bortezomib, lenalidomide, dexamethasone.

Bortezomib combination regimens including bortezomib, lenalidomide, and dexamethasone (VRD)41 and bortezomib-cyclophosphamide-dexamethasone (VCD)42 have high activity as induction treatments. Treatment with bortezomib seems to overcome the poor prognosis conferred by cytogenetic abnormalities.43 Neurotoxicity from bortezomib can be significantly decreased by administering the drug subcutaneouosly.44

Maintenance Therapy

In the past, corticosteroids and interferon alpha were used as maintenance agents. However, they failed to consistently provide improvement in overall survival and had increased toxic effects. Thalidomide was first seen to provide a consistent modest benefit with increased event-free and overall survival following autologous transplantation but was poorly tolerated.45,46

Very recently, three randomized trials have shown improved progression-free survival with lenalidomide.47-49 Only one of the trials showed better overall survival, perhaps due to the length of follow-up. A small but meaningful risk of increased secondary malignancies was reported in all three studies.50 It is unclear whether maintenance with lenalidomide should be used in all patients post ASCT. An informed discussion with the patient, taking into account risks and benefits in each individual case is the preferred approach.

Other agents, including bortezomib and the IMiD pomalidomide, are currently being tested in the maintenance setting and seem to have activity in patients who are refractory to lenalidomide.

Frontline Therapy for Patients Not Eligible for Autologous Stem Cell Transplant

Before the era of novel agents, the combination of oral melphalan and prednisone (MP) used to be the main treatment regimen for those ineligible for ASCT due to its activity and tolerability.51 Currently, several combinations are available with improved overall survival when compared with MP:

Melphalan, prednisone, and thalidomide (MPT)52,53

Bortezomib, melphalan, prednisone (VMP)54

Lenalidomide-low-dose-dexamethasone (Rd)55

An ongoing clinical trial is comparing Rd versus MPT. MPT had high rates of DVT (20%) in the absence of thromboprophylaxis with higher grades of neuropathy in the VMP combination.

Relapsed or Refractory Disease

Almost all patients who respond to their initial treatment will relapse. Responses in the relapse/ refractory setting tend to be short lived and decrease with each added line of therapy. The median overall survival for patients with relapsed myeloma that is refractory to lenalidomide and bortezomib is less than 12 months.56 Alkylating agents, corticosteroids, and thalidomide are possible options for treatment (either alone or in combination); however, combinations of highly active regimens (VRd, VTD) have the best chance of response.57 Liposomal doxorubicin added to bortezomib significantly improved overall survival in a randomized phase III trial and may be used in this setting.58

Newer agents with promising activity in this setting are carfilzomib and pomalidomide with overall response rates as high as 50% in non-randomized trials.

Treatment of Bone Disease in Multiple Myeloma

More than 80% of patients with multiple myeloma will develop osteolytic bone lesions at some point during their disease course. This can result in increased morbidity due to skeletal-related events (SRE) (compression fractures) resulting in hypercalcemia, cord compression, severe pain, and the need for surgical intervention or radiation therapy.

Osteolytic bone disease (OBD) is thought to be the result of generalized osteoclast activation coupled with osteoblast inhibition. BPs are the standard of care for treatment of OBD due to multiple myeloma and are thought to augment osteoclast apoptosis and may inhibit tumor growth in vivo. Treatment with either pamidronate or zoledronic acid has shown to reduce pain due to bone disease and prevent SRE, however pamidronate is the recommended agent in multiple myeloma.59,60

Serious adverse events with BP use include osteonecrosis of the jaw and renal failure. Patients should have a dental evaluation prior to starting BP use and be advised against dental procedures (especially tooth extraction) while on BP treatment. Currently several trials are trying to answer whether using BP less frequently or at decreased doses can maintain efficacy with less toxicity. Different treatment guidelines and recommendations are available for the use of BP in multiple myeloma. Overall, pamidronate and clodronate (not available in the United States) have the lowest risk of osteonecrosis of the jaw: pamidronate 1% to 2% within the first 2 years of treatment and 0% to 0.5% for clodronate. The risk with zoledronic acid is double that of pamidronate. Renal failure is seen in less than 10% of patients and regular monitoring of urinary protein and serum creatinine should be instituted. If osteonecrosis of the jaw occurs, BP should be discontinued.

Supportive Care

Anemia

Normochromic, normocytic anemia is commonly part of the presentation of newly diagnosed patients (>70%) and can be attributed to multiple myeloma itself or due to treatment causing cytopenias. Erythropoiesis-stimulating agents (ESAs) are recommended for symptomatic anemic patients (Hb < 10 g/dL) and associated renal impairment. Treatment should be discontinued after Hb ≥ 12 g/dL or if there is no benefit after 6 to 8 weeks of treatment (rise in Hb or decrease in transfusion requirements).

Hemostasis and Thrombosis

Paraproteinemia in multiple myeloma has been associated with acquired von Willebrand Disease (VWD) and AL amyloidosis with factor X deficiency, with increased risk of bleeding. Prothrombin complex and recombinant factor VIIa are used successfully for management of factor X deficiency while desmopressin, intravenous immunoglobulins, and factor VIII/VW are used for VWD.

IMiDs in combination with dexamethasone substantially increase the risk of VTE (50%–70%) and patients treated with these regimens should receive prophylaxis with aspirin, heparin, or Coumadin which reduces the risk significantly (1%–2%).

Skeletal-related Events

Local radiation therapy can alleviate pain for skeletal disease and palliative soft tissue disease. Vertebroplasty (percutaneous injection of polymethacrylate bone cement in the vertebral body) or kyphoplasty (percutaneous insertion of a small inflatable balloon into the vertebral body which is then removed and the space filled with bone cement) are alternative options for controlling pain associated with vertebral collapse. They are best carried out soon after collapse and carry a small risk of cement leakage leading to pulmonary embolus and neural compromise.

Peripheral Neuropathy

The cause of peripheral neuropathy in multiple myeloma patients is multifactorial (disease, chemotherapy, comorbidities) with a potential risk of worsening due to treatment. Management of peripheral neuropathy requires identification and management of B12 deficiency and comorbid conditions with minimization of agents that worsen or induce neurotoxicity. The use of opioid drugs with pain-modulating agents (gabapentin, pregabalin) is recommended.

Osteonecrosis of the Jaw

Management is supportive with good oral care (daily irrigation/oral antimicrobial [0.12% chlorhexidine gluconate]) and antibiotics, however sometimes debridement of the bone is needed. Biopsies should not be routinely performed as additional bone trauma may further delay wound healing. Clinical follow-up and referral to an experienced oral surgeon is recommended.

Hyperviscosity Syndrome

The clinical manifestations of hyperviscosity include neurologic abnormalities, vision changes, renal insufficiency, and mucosal bleeding. Hyperviscosity occurs most frequently in IgM dyscrasias, but it can be seen in all Ig subtypes. It is thought to be present when viscosity levels reach 4 to 5 cp (reference range 1.4–1.8 cp); however, this does not usually correlate well with symptoms. Thus, treatment (aggressive hydration, diuresis, plasmapheresis, chemotherapy/high-dose dexamethasone) should be instituted and guided by symptomatology.

Solitary Plasmacytoma and Extramedullary Plasmacytoma

Plasma cell neoplasms can present as a single lesion, most frequently in bone (SP) but also in soft tissues (EMP). Some patients can have a small monoclonal protein, usually IgA which then disappears following treatment. Radiation therapy is the treatment of choice (40–50 Gy over a 4-week period). The role of adjuvant radiation is unclear if complete surgical resection was achieved as primary treatment. Most patients treated for SP will still progress to multiple myeloma (up to 85% at 10 years). The rate of progression to multiple myeloma for EMP is lower than in SP (up to 30% at 10 years).

Plasma Cell Leukemia

Plasma cell leukemia (PCL) is a rare, aggressive form of multiple myeloma characterized by high levels of circulating plasma cells in the peripheral blood. It occurs in less than 5% of patients with multiple myeloma. It can present de novo or, more frequently, from a secondary leukemic transformation of multiple myeloma. Diagnosis requires an absolute plasma cell count > 2,000 plasma cells/μL or 20% of peripheral blood white cells. These criteria are arbitrary and diagnosis should be considered whenever plasma cells are detected on a complete blood count. Median overall survival has improved recently from < 12 months to reported 24 months in a single institution study, due to the introduction of IMiDs and bortezomib.61 Given the rarity of this disease and grim prognosis patients should be enrolled in clinical trials when feasible.

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