Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

23. Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis

Rachid Baz and Mohamad A. Hussein

I. INTRODUCTION

A. Types of plasma cell dyscrasias

Plasma cell dyscrasias represent a heterogeneous group of conditions characterized by an increased number of plasma cells or by the productions of a monoclonal protein. The following plasma cell dyscrasias will be discussed in this chapter: monoclonal gammopa-thy of undetermined significance (MGUS), multiple myeloma (MM), Waldenstrom macroglobulinemia (WM), amyloidosis, and solitary plasmacytomas. Light chain deposition disease, heavy chain dis-eases, immunoglobulin D MM, nonsecretory MM, osteosclerotic myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome and primary plasma cell leukemia are beyond the scope of this text.

B. Monoclonal protein (M-protein)

An M-protein is detected in the serum, urine, or both of most patients with plasma cell dyscrasias. The so-called M-protein is thought to be a measure of plasma cell burden, although a correlation is not always evident. A notable discordance between the M-protein and disease burden could be noted in heavily pretreated patients where the malignant cells might have dedifferentiated and have become less secretory or nonsecretory. This is often accompanied by an increase in the serum lactate dehydrogenase. Exceptions aside, most plasma cell dyscrasias are best followed by serial measurements of the M-protein and parameters of end organ dysfunction. Current standard criteria rely on changes in the M-protein for determining response and progression after treatment. The basic immunoglobulin (Ig) unit comprises two identical heavy chains (G, A, M, D or E) and two identical light chains (kappa or lambda). The serum protein electrophoresis is used to quantify the monoclonal component of the globulin; it fails to do so, however, when the concentration of the latter is low because of lack of secretion or if the M-protein is excreted in the urine. If there is a high clinical suspicion for the presence of an M-protein despite a negative serum protein electrophoresis, an immunoelectrophoresis should be performed on both the serum and the urine, as up to 15% of patients may have a negative serum immunofixation with positive urine immunofixation. The urinary light-chain excretion (expressed in grams per 24 hours) is used to follow the urinary M-protein. This is calculated from the 24-hour urine protein and the percent contribution of light chain to pro-teinuria on the urine protein electrophoresis. It is critical to assess the percent contribution of the light chain to the proteinuria especially in patients with other comorbidities such as hypertension and diabetes mellitus, where the patient could present with an M-protein with the proteinuria consisting mainly of albumin secondary to the other medical processes. Newer assays for serum free light chain are becoming increasingly available and often result in the detection of increased free light chains in the serum of many patients with nonsecretory MM (negative immune fixation of the serum and urine) and amyloid light-chain (AL) amyloido-sis. The latter assay does not demonstrate monoclonality of the light chain but relies on the ratio of kappa to lambda light chain to infer an excess of one of the light chains. While some investigators have correlated changes in the free light chain induced by therapy with outcomes and the use of the serum, and the free light-chain test has been incorporated in the International Myeloma Working Group response criteria, the precise role of these markers beyond their contribution to the diagnosis has not been thoroughly validated. Infections, autoimmune disorders, and poor renal function make interpretation of the free light-chain assay difficult.

II. MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)

MGUS is usually characterized by a low M-protein (less than 3 g/dL), the absence of bone lesions, less than 10% plasma cells on the bone marrow biopsy, and the absence of attributable end organ damage such as anemia, hypercalcemia, and renal dysfunction. The prevalence of MGUS increases with age and has been described in as many as 3% of all individuals over 70 years of age. The rate of progression from MGUS to MM or other lymphoproliferative disorders varies based on several factors, the most notable of which is the level of the serum M-protein. A high serum M-protein (≥1.5 g/dL), a higher bone marrow plasma cell burden, and possibly an abnormal kappa to lambda ratio on free light-chain testing puts select patients at higher risk of progression to MM. While patients with lower risk MGUS may be followed on a yearly or biannual basis, patients with higher risk of progression probably benefit from closer follow-up and may be eligible for enrollment in prevention clinical trials. In a small number of patients, MGUS could be associated with peripheral neuropathy. The majority of patients with MGUS and peripheral neuropathy in association with an Ig M-protein have anti-myelin-associated glycoprotein antibodies. This group of patients responds favorably to therapy with single-agent rituximab.

III. MULTIPLE MYELOMA (MM)

A. General considerations and aims of therapy

1. Diagnosis. MM is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Table 23.1 illustrates diagnostic criteria required for a diagnosis of MM. The Durie and Salmon staging system was initially used for the staging of patients with MM (Table 23.2). Its use has fallen out of favor due to difficulties inherent to its use. A staging system is the International Staging System, which is illustrated in Table 23.3. It relies on the serum β2-microglobulin and on serum albumin. It was found to accurately prognosticate patient outcomes.

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With the increased awareness, an increasing number of patients are being diagnosed with monoclonal gammopathy incidentally, and the decision to monitor or actively treat has become difficult with the old nomenclature.

a. End organ damage. The International Myeloma Working Group has presented the concept of MM with active or inactive disease based on the presence or absence of end organ damage, respectively.

b. Criteria defining end organ damage are anemia, renal failure, hypercalcemia, severe osteoporosis or lytic bony disease, or other organ abnormality that is attributable to the plasma cell dyscrasia.

c. Patients without end organ damage (MGUS or inactive myeloma) should be monitored carefully as early intervention does not affect the outcome of the disease. Patients with inactive MM should be considered for enrollment clinical trials aimed at preventing or retarding the progression to active disease.

d. Alternatively, patients who meet the criteria for MGUS but demonstrate end organ damage related to the plasma cell dyscrasia must be classified as active MM and should receive active therapy.

2. Epidemiology. The annual incidence of MM is 4 per 100,000 population, with a peak incidence between the sixth and seventh decade of life. Patients of African-American descent have an incidence of MGUS and MM approaching twice the incidence for Caucasians in the United States. Several agents have been strongly associated with the development of MM, ionizing radiation being the most commonly described risk factor. Nickel, agricultural chemicals, petroleum products, and other aromatic hydrocarbons, benzene, and silicon have been considered potential risk factors as well. One particular note is made for Agent Orange exposure by Vietnam veterans imparting an increased incidence of MM.

3. Goals of therapy. Despite recent advances in the treatment of MM, the disease remains incurable. Accordingly, therapy is aimed at improving symptoms and preventing complications of the disease, thus improving quality of life and survival. These goals could be achieved with different approaches: one aim is to transform the disease into a chronic process by using frequent low morbidity therapies, while the other approach attempts to eradicate the disease with intensive therapy. The cure versus control paradigm remains a subject of considerable debate, and it remains unclear which treatment methodology is superior. However, there is evidence that certain subgroups of patients might benefit from one or the other approach, and therapy aimed at control of the myeloma may be inappropriate for patients with more aggressive risk features. Because of these uncertainties and because standard first-line therapy is not well defined, patients with MM, regardless of age, stage of disease, or number of previous therapies, must be considered for clinical trials enrollment.

In addition to the management of the malignant plasma cell clone, particular attention must be made to end organ dysfunction including skeletal health, prevention of infections, and thrombotic, neuronal, and renal complications. Accordingly, response to therapy is based on changes to the M-protein concentration, the percentage of plasma cells in the bone marrow, as well as monitoring end organs for improvement in function. The cooperative oncology groups in the United States and Europe have adopted different cutoffs to define response. Table 23.4 illustrates the uniform response criteria as defined by the International Myeloma Working Group.

4. Prognostic factors. Severe anemia, hypercalcemia, advanced lytic lesions, and very high M-protein are all associated with a high tumor burden and a poor survival and are the basis of the Durie and Salmon staging system. Renal failure, although not clearly correlated with disease burden, is associated with worse outcomes. Other established clinical poor prognostic factors include the following: advanced age, poor performance status at presentation, high serum lactate dehydrogenase level, lower platelet counts, bone marrow with greater than 50% plasma cells, greater than 2% bone marrow plasmablasts, high plasma cell labeling index, elevated serum β2-microglobulin, and low serum albumin. The latter two are the basis for the Southwest Oncology Group (SWOG) and International Myeloma Working Group staging systems. The identification of cytogenetic prognostic factors using metaphase karyotyping relies on cellular growth, which is difficult as the MM plasma cells have a low in vitro proliferative rate and thus such information is available only in 20% to 40% of the patients. The presence of abnormalities with this method, however, is meaningful. Genomic prognostic factors include the deletion of chromosome 13, translocation of the immunoglobulin heavy chain [t(4;14), t(14;16)], and loss of 17p13. The t(11;14), on the other hand, is not thought to portend a worse outcome. Recently, interphase fluorescence in situ hybridization (FISH) has been used to detect specific cytogenetic abnormalities. Even though FISH analysis is more sensitive at detecting certain abnormalities such as chromosome 13, this might not be clinically meaningful without other additional poor prognosticators. Nonhyperdiploid karyotypes are frequently associated with immunoglobulin heavy chain rearrangements and worse clinical outcomes.

B. Initial treatment

1. General measures. Patients with a new diagnosis of MM occasionally have associated complications that require immediate attention, such as hypercalcemia, renal failure, severe cytopenias, and spinal cord compression. These complications should be promptly identified and managed either simultaneously or before the start of therapy. Alternatively, asymptomatic patients and those with smoldering MM may be followed without specific therapy until clear evidence of progression. Ambulation and hydration should be maintained throughout the initial therapy. Avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, and intravenous contrast agents is important for renal health. If radiologic procedures involving the use of intravenous contrast agents are to be considered, appropriate hydration and the use of W-acetyl-cysteine should be considered. The use of bisphosphonates (either pamidronate or zoledronic acid) is recommended for nearly every patient with myeloma with normal renal function, in particularly those with bony disease (see Section III.C.5). The authors recommend holding the initiation of the bisphosphonates in the first cycle of therapy to help decrease renal complications from the use of these agents. In addition, because of the increased awareness for osteonecrosis of the jaw, a rare complication of bisphosphonate therapy, a dental evaluation prior to starting therapy should be considered.

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2. Systemic therapyforthe newly diagnosed patient (see Section IVB.3 for specific regimens). While a plethora of therapeutic options for the treatment of patients with newly diagnosed MM are available, there is no standard first-line therapy. In this text, we will define non-high-dose therapy as traditional therapy and high-dose therapy with stem cell rescue as intensive therapy. The precise role of novel therapeutic agents (such as bortezomib, lenalidomide, and thalidomide) in the management of newly diagnosed MM remains unclear and is the subject of ongoing clinical trials. As therapy for MM does not result in cures, treatment recommendations are often individualized and based on a patient's comorbidities, performance status, and preference, as well as disease characteristics. For example, if high-dose therapy is considered during the course of therapy, avoidance of agents that impair stem cell collection is important (e.g., melphalan and other alkylating agents). In the patient with significant symptoms from the disease, the choice of highly active first-line therapy that results in rapid responses is reasonable. Similarly, in patients with renal dysfunction at presentation, the choice of agents with a safe renal profile is recommended (e.g., bortezomib-based therapy).

Patients with poor prognostic factors at presentation [chro-mosome 13 deletion by metaphase cytogenetics or t(4;14), high p2 microglobulin, or increased plasma cell labeling index] fare poorly with all traditional therapies. Accordingly, these patients are best managed by enrollment in clinical trials. Alternatively, it is intuitive, though unproven, that intensive therapy (combination novel agent induction therapy followed by consideration of high-dose therapy) would result in improved outcomes. While some reports suggest that bortezomib-based therapy overcomes the negative implications of high-risk disease, these observations are based on small numbers and relatively short follow-up, and other investigations did not confirm these findings.

For patients eligible for intensive therapy, the use of dexamethasone in combination with an immunomodulator (lenalidomide) or a proteasome inhibitor is reasonable. At the time of best response, collection of stem cells is recommended. Lenalidomide-based therapy is usually continued until progression or until high-dose therapy, while bortezomib-based therapy is usually planned for six to eight cycles (or until high-dose therapy).

While many patients over the age of 65 years remain excellent candidates for intensive therapy, high-dose therapy may not be appropriate for some; therapy with melphalan, prednisone, and either thalidomide or bortezomib has been demonstrated to be superior to melphalan and prednisone. In addition, therapy with low-dose dexamethasone and lenalidomide may also be reasonable. In addition, for the much older patient with significant comorbidities, less intensive therapy may be appropriate (e.g., melphalan or cyclophosphamide in combination with prednisone). Chemotherapeutic regimens are described below.

3. Traditional chemotherapy recommendations. While numerous additional chemotherapeutic regimens have been described, only commonly used agents in the treatment of MM are reviewed below.

a. Dexamethasone is considered the standard corticosteroid for many induction regimens for MM. Recently, the Eastern Cooperative Oncology Group study comparing lenalidomide and low-dose dexamethasone to lenalidomide and high-dose dexamethasone demonstrated a survival benefit in the lower dose of dexamethasone. This was more pronounced in patients older than 65 years but was noted in all age groups. High-dose dexamethasone, for a few cycles, in combination with lenalidomide remains reasonable in younger patients with high disease burden.

High-dose dexamethasone is given at a dose of 40 mg by mouth on days 1 to 4, 9 to 12, and 17 to 20. Cycles are repeated every 28 days. Low-dose dexamethasone consists of 40 mg by mouth weekly or on days 1 to 4 of a 28-day cycle. Significant early toxicities include hyperglycemia, dyspepsia, fatigue, and muscle weakness. Additionally, patients often report agitation and insomnia with the use of this schedule of dexamethasone. Longer term toxicities include increased infections, cataract, osteoporosis, and avascular necrosis offemoral heads. As a single agent in patients with newly diagnosed myeloma, responses are observed in about 50% of patients, and the median time to response is approximately 1 month. However, the median duration of response is only 6 months. As such, single-agent dexamethasone is generally not the treatment of choice.

b. Thalidomide and dexamethasone. The addition of thalidomide to the above schedule of dexamethasone results in an increased response rate (about 70%) at the cost of additional toxicity (in the form of thromboembolic events, rash, sedation, peripheral neuropathy, and constipation). While thali-domide was started at 200 mg daily at bedtime on the pivotal clinical trial, our experience suggests improved patient tolerance with a more gradual start of thalidomide.

We recommend initiating thalidomide at 50 mg daily at bedtime and increasing the daily dose by 50 mg increments every week to a desired target dose not exceeding 200 mg daily or as dictated by patient tolerance. It should be noted, however, that there is no known minimal dose required for response: some (though rare) patients respond to dosages as low as 50 mg three times a week.

In addition, in responding patients receiving high-dose dexamethasone, reduction of dexamethasone to 40 mg on days 1 to 4 monthly (or low-dose dexamethasone) results in improved patient tolerance.

With the increased risks of thromboembolic events (about 17% of patients receiving this combination), we recommend the use of prophylactic low dose aspirin (81 mg). Other investigators have used different prophylactic strategies, which include low-molecular-weight heparin and therapeutic anticoagulation with warfarin. A recent randomized trial of these thromboprophylactic strategies did not demonstrate the superiority of any one of the above regimens. Given that thalidomide use has been associated with the development of neuropathy with long-term use, this agent has largely been replaced with lenalidomide in this setting. This regimen may be considered in patients with significant cytopenias or renal insufficiency with disease refractory to bortezomib.

c. Lenalidomide and dexamethasone. Lenalidomide is an immunomodulatory drug with more potent tumor necrosis factor-α inhibition than thalidomide. In addition, lenalidomide has a different adverse event profile than thalidomide and does not usually cause significant sedation or neuropathy; it does result in myelosuppression. In patients with relapsed or refractory MM, the combination of lenalidomide and dexamethasone resulted in responses in approximately 60% of patients with a progression-free survival of approximately 12 months.

Lenalidomide is usually started at 25 mg by mouth daily for 21 of 28 days. Lower starting doses are recommended in patients with renal dysfunction as lenalidomide is renally cleared. Lenalidomide toxicities include thromboembolic events, myelosuppression, rash, and diarrhea. Myelosuppres-sion is often noted early during the course of therapy, and febrile neutropenia is rare. Lenalidomide with low-dose dex-amethasone results in a response in 75% to 90% of patients. The optimal duration of therapy with lenalidomide is unclear. Because in clinical trials this agent was used until progression, we recommend a similar approach in patients tolerating this agent well and not proceeding with immediate high-dose therapy. After two cycles of therapy, consideration for decreasing the frequency of dexamethasone to 4 days must be given. In addition, in responding patients after 1 year of therapy, omitting dexamethasone and continuing with single-agent lenalidomide is reasonable. Long-term lenalidomide therapy may make stem cell collection difficult, and the use of chemotherapy in combination with granulocyte colony-stimulating factor (G-CSF) may be needed for stem cell collection.

d. Melphalan and prednisone (MP) has fallen out of favorwith the availability of novel agents, and combinations of thalidomide or bortezomib with MP have resulted in superior survival than MP alone. Nonetheless, MP remains a reasonable option for very elderly patients with many comorbidities. MP results in about a 50% overall response rate in patients with newly diagnosed myeloma and a median time to progression of about 15 months. While a number of different dosages and schedules for MP exists, we recommend the following:

bull Melphalan 9 mg/m2 by mouth on days 1 to 4, and

bull Prednisone 100 mg by mouth on days 1 to 4.

For reliable absorption, melphalan should be taken on an empty stomach. Repeat the cycle every 4 to 6 weeks depending on recovery of counts. MP is usually given for six to nine cycles, and treatment beyond 1 year does increase risks of myelodyspla-sia. Responses to MP tend to occur slower on average, making this a less attractive regimen in patients with significant symptoms. On the other hand, MP is well tolerated in patients with myeloma, with myelosuppression being the most significant adverse event. MP should not be used in patients who are candidates for intensive therapy as it may impair stem cell collection.

e. Melphalan, prednisone, and thalidomide (MPT). Thalidomide has been added to MP in the MPT regimen. Similar recommendations to Section IV.B.3.b pertaining to the use of thalidomide can be made. In addition, thalidomide up to 100 mg at bedtime is usually recommended. In some studies involving MPT, thalido-mide was continued for 1 year after MP therapy was discontinued, while in other MPT studies thalidomide was discontinued at the time of stopping MP. In patients with a good tolerance to thalidomide, continuing such therapy would be reasonable.

f. Bortezomib is a proteasome inhibitor approved for relapsed or refractory MM and more recently for newly diagnosed disease in combination with MP. In addition, combination ther-apy with dexamethasone or pegylated liposomal doxorubicin or with thalidomide or lenalidomide has shown promising results. As a single agent in relapsed and refractory patients, it was shown to result in a response rate of about 30% to 40% and a median time to progression of 6 to 7 months. This was found to be superior to high-dose dexamethasone.

bull Bortezomib is given at 1.3 mg/m2 intravenously over 3 to 5 seconds on days 1, 4, 8, and 11 on a 21-day cycle.

bull Dexamethasone 20 mg on the day of and the day after bortezomib is often added after two cycles in patients with suboptimal responses. The addition of steroids, however, results in only a modest improvement in the response and/or the quality of the response.

Treatment is continued for a maximum of eight cycles. Grade 3 and 4 adverse events of bortezomib include the following: thrombocytopenia (30%), neutropenia (14%), anemia (10%), and neuropathy (8%). Neuropathy should be monitored carefully with special attention to autonomic neuropathy in the form of paralytic ileus and delayed peripheral neuropathy after the discontinuation of therapy. Neuropathy is often painful in nature but is also reversible in about two-thirds of patients after 3 to 6 months of discontinuation of therapy. Bortezomib-based therapy is often the treatment of choice in patients with significant renal impairment.

g. Melphalan, prednisone, and bortezomib (VMP). Two 3-week bortezomib cycles are added to a 6-week MP cycle in standard VMP. In addition, “lite” and “superlite” VMP regimens, in which bortezomib is given on a standard schedule for the first cycle and subsequently weekly or bortezomib is given weekly instead of twice weekly, respectively, have been described. These reduced intensity regimens result in less grade 3 neuropathy and gastrointestinal toxicity than standard VMP. While VMP “lite” and “superlite” have comparable response rates to VMP, efficacy was not compared in a randomized study, and these reduced intensity regimens did not demonstrate a survival advantage to MP as standard VMP has. The risk of varicella zoster reactivation can be effectively reduced/eliminated with the use of acyclovir prophylaxis, which is recommended for all bortezomib-containing regimens.

bull Standard VMP

bull Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 for four cycles followed by bortezomib 1.3 mg/m2 on days 1, 8, 22, and 29 for five cycles

bull Melphalan 9 mg/m2 on days 1 to 4

bull Prednisone 60 mg/m2 on days 1 to 4

bull Cycles are repeated every 6 weeks.

bull VMP lite

bull Similar MP dosing with bortezomib given on days 1, 4, 8, 11, 22, 25, 29, and 32 for one cycle and on days 1, 8, 22, and 29 for eight cycles.

bull VMP superlite

bull Similar MP dosing with bortezomib given on days 1, 8, 22, and 29 for all nine cycles.

h. Cyclophosphamide and prednisone (CP) is a forgotten alternative to MP. Cyclophosphamide does not need dose adjustments for renal failure, making it a useful agent in patients with a decreased performance status and/or comorbidities. It results in a response rate of about 50% and a progression-free survival of 12 to 15 months in treatment naive patients. CP is given as follows:

bull Cyclophosphamide 1000 mg/m2 intravenously (IV) on day 1, and

bull Prednisone 100 mg by mouth on days 1 to 5

bull Cycles are repeated every 21 days.

CP is well tolerated and, in distinction to MP, does not result in significant compromise to stem cell reserve. Furthermore, thalidomide and bortezomib have been added to this backbone with demonstrated efficacy.

i. Bortezomib, lenalidomide, and dexamethasone (RVD). The combination of lenalidomide, bortezomib, and dexamethasone was evaluated in patients with newly diagnosed as well as previously treated MM. In newly diagnosed myeloma, the combination has a demonstrated high response rate and appears to be well tolerated. An ongoing intergroup trial will be comparing this combination to lenalidomide and dexamethasone in newly diagnosed patients. However, it remains unclear if thehigh response rate for this triplet will translate into improved patient outcomes. For newly diagnosed patients, RVD is administered as follows:

bull Lenalidomide 25 mg by mouth on days 1 to 14

bull Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11

bull Dexamethasone 20 mg by mouth on days 1, 2, 4, 5, 8, 9, 11, and 12

bull Cycles are repeated every 21 days.

Supportive therapy includes acyclovir and aspirin pro-phylaxis for varicella zoster virus reactivation and throm-boembolic disease, respectively.

In relapsed and refractory myeloma, the RVD regimen has demonstrated the ability to induce responses in patients refractory to both lenalidomide and bortezomib. Due to the marrow compromise often present in patients with relapsed and refractory myeloma, the lenalidomide starting dose is 15 mg orally on days 1 to 14 of a standard bortezomib cycle.

j. Bortezomib and pegylated liposomal doxorubicin. Bortezomib has been combined with pegylated liposomal doxorubicin. A pivotal phase III trial, which led to the approval of pegy-lated liposomal doxorubicin, compared this combination to single-agent bortezomib in patients with relapsed and refractory myeloma. The combination results in a similar overall response rate to single-agent bortezomib, but the quality responses (very good partial responses and better) were increased with combination therapy. This translated to improved progression-free and overall survival. Pegylated liposomal doxorubicin (30 mg/m2) was given on day 4 of a standard bortezomib cycle in this combination, but in our experience, it can also be safely given on day 1 of the cycle. Notable toxicities of pegylated liposomal doxorubicin include palmar plantar erythrodysesthesia syndrome (hand-foot syndrome), myelosuppression, and cardiotoxicity. In addition, dexamethasone can be added to this regimen, and intriguing early results with this combination have been reported but have not been replicated.

4. Treatment of patients with relapsed or refractory MM. Despite original responses to therapy, virtually all patients develop recurrent or refractory MM. In patients who experience a relapse more than 1 year after receiving chemotherapy, remission can frequently be obtained using the same regimen. Patients relapsing earlier will likely require an alternate treatment regimen. Patients with refractory myeloma have evidence of progressive disease while receiving active therapy or within 60 days from last therapy despite possible original responses. This patient population has a worse outcome than relapsed patients do. Enrollment of patients with relapsed or refractory myeloma into clinical trials should be a first consideration in the choice of antineoplastic therapy. A number of novel therapeutic tools are emerging in the treatment of MM. These include novel im-munomodulatory drugs (pomalidomide), novel proteasome in-hibitors (carfilzomib), histone deacetylase inhibitors (LBH589, vorinostat), mammalian target of rapamycin inhibitors (temsi-rolimus), and RANK-L antibodies (denosumab). Many of these will likely be approved first for the treatment of relapsed or refractory patients prior to gaining indication in newly diagnosed patients.

5. High-dose therapy with bone marrow or peripheral blood stem cell transplantation. The role of high-dose therapy and autologous stem cell transplantation for MM in the era of novel agents remains poorly defined. Initial reports of high-dose therapy generated significant enthusiasm for this approach, as it was associated with a survival advantage over standard therapy using alkylating agents. Contemporary clinical trials comparing high-dose therapy to conventional therapy have failed to consistently confirm the results of initial trials, likely because of the improvement in standard therapies and the availability of novel active salvage therapies. Despite the lack of consistent overall survival advantage, early high-dose therapy does offer a prolongation in the Time Without Symptoms of Disease or Toxicity of Treatment, a quality-of-life measure surrogate. With the advent of novel agents, the role of high-dose therapy and its timing in MM therapeutic armamentarium will require revalidation.

For patients electing to proceed to high-dose therapy, available induction therapies include the use of lenalidomide or thalidomide-dexamethasone or bortezomib-dexamethasone. Three-agent induction has been shown to result in a higher rate of quality responses prior to high-dose therapy compared to two-agent induction. While this may translate in improved posttransplant quality responses, it remains unclear whether three-agent induction will improve survival. As such, the use of three-agent induction therapy should be considered only in the context of clinical trials.

Stem cells can be derived from the peripheral blood or the bone marrow. The former can be done with the use of G-CSF with or without chemotherapy. Novel agents to facilitate stem cell collection (plerixafor) have entered the clinical arena. Peripheral stem cell rescue results in faster engraftment as compared to bone marrow stem cell rescue and has accordingly supplanted the former in clinical use. High-dose therapy is usually in the form of melphalan given at 200 mg/m2 for younger patients with intact renal function. Total-body radiation has mostly been abandoned in this setting in view of inferior results associated with its use. While purging the graft of malignant cells seems intuitively useful, it has not been shown to improve outcomes, and in vivo purging (with systemic therapy) remains the preferred modality. High-dose therapy with peripheral stem cell rescue has been carried out in an outpatient setting at some transplant centers but remains an inpatient therapy for 2 to 3 weeks at most other centers.

Advances in high-dose therapy will likely involve defining the role of vaccination and immunomodulatory drugs post autologous stem cell transplantation and supportive care improvement needed to further increase the safety of this approach.

6. Duration of therapy and role of maintenance therapy. Patients with stable M-protein for greater than 6 months (the so-called plateau phase) appear to have a favorable prognosis and should be monitored carefully at least every 3 months. No study has conclusively demonstrated benefit by continuing chemotherapy beyond 1 year in responding patients (except with treatment with immunomod-ulators, in which therapy is usually continued until progressive disease or significant toxicity). Several investigators have noted earlier re-emergence of active myeloma after complete cessation of therapy, hence suggesting a benefit for maintenance therapy. A study by SWOG has shown that maintenance therapy with prednisone given at 50 mg every other day improves overall and progression-free survival when compared to maintenance therapy with 10 mg of prednisone every other day. While interferon maintenance resulted in a prolonged progression-free survival, overall survival was not increased and toxicity from interferon was notable. The use of thalidomide to maintain responses observed after intensive therapy has been associated with a survival benefit in patients, not in a very good partial response or better after high-dose therapy. On the other hand, patients receiving continued thalidomide should be closely monitored for peripheral neuropathy, and doses as low as 50 mg every other day are often all that patients are able to tolerate. Thalidomide maintenance is currently not routinely recommended for all patients post intensive therapy. Emerging data from the Cancer and Leukemia Group B and the Institute for Functional Medicine have evaluated maintenance with lenalidomide. Both studies reported a significant benefit to lenalidomide maintenance on progression-free survival, while overall survival remains not statistically different with maintenance lenalidomide. The consideration of lenalidomide maintenance should be individualized with discussion of risks and benefits with the patient.

7. Role of radiotherapy. While radiotherapy is sometimes curative in patients with solitary plasmacytomas, its use in patients with MM is palliative and adjunctive to the use of systemic therapy. Patients with symptomatic extraskeletal plasmacytomas, large lytic lesions threatening fracture of long bones, spinal cord or root compression by plasma cells, and certain pathologic fractures are good candidates for radiotherapy. Conservative use of radiotherapy is wise as radiation of bone marrow can impair marrow reserves and render the patient less able to tolerate subsequent therapy.

C. Complications of disease or therapy

Notable toxicity of each chemotherapeutic agent is described in Chapter 33. In addition, complications characteristic of MM are described here.

1. Hypercalcemia. Once avery frequent complication of MM, hypercalcemia is less often noted, likely as a result of more widespread use of bisphosphonate therapy for bone health. The pathophysiology of hypercalcemia in patients with MM is related to increased osteoclast activation as a result of binding of the latter to malignant plasma cells. Receptor activator of nuclear factor-κB (RANK)-ligand produced by bone marrow stromal cells is the best-described cytokine mediating this effect. Antibodies to RANK-ligand are entering the clinical arena and are currently being tested in clinical trials in patients with MM. Symptoms of hypercalcemia are often protean, often overlap with adverse events of thalidomide, and require a strong index of suspicion. Symptoms include anorexia, constipation, polyuria, and lethargy. Coma and death can be the result of untreated hypercal-cemia. Dehydration and potentially reversible renal dysfunction are frequently associated with hypercalcemia. Treatment of hy-percalcemia involves aggressive saline hydration, use of loop diuretics once fluid overload occurs, use of corticosteroids (such as prednisone 60 mg for 7 days), and bisphosphonate therapy. Calcitonin is sometimes used, and hemodialysis is reserved for refractory cases. When hypercalcemia occurs in previously un-treated patients, prompt initiation of therapy for the MM in addition to the above usually results in effective, durable control.

a. Bisphosphonates

bull Pamidronate 90 mg given as a 2-hour IV infusion that can be repeated every 30 days or

bull Zoledronic acid 4 mg IV over 15 to 30 minutes in the absence of renal dysfunction.

b. Calcitonin 100 to 300 U subcutaneously every 8 to 12 hours for up to 2 to 3 days. Calcitonin is usually given with prednisone 60 mg by mouth daily to prolong its effectiveness.

c. Hemodialysis is very effective but rarely needed.

2. Infections (see Chapter 27). Patients with MM are at increased risks for infectious complications usually related to capsulated microorganisms. Deficiency of normal immunoglobulins, diminished bone marrow reserves, therapies for MM, and immobilization due to skeletal disease are important predisposing factors. Prompt evaluation of fever or other manifestations of infection and institution of empiric antimicrobial therapy is essential. The prophylactic and therapeutic use of growth factors (such as G-CSF) is often given consideration. Intravenous Ig is administered to patients with recurrent significant infectious complications.

3. Hyperviscosity. This is a rare manifestation of MM and is more commonly observed in patients with WM. It may present as central nervous system impairment (which is often subtle and noted as difficulty concentrating, visual changes, and headaches) and occasionally congestive heart failure. Plasmapheresis is used for the treatment of symptomatic hyperviscosity; however, therapy should be combined with systemic therapy directed at the plasma cell clone, as benefits of plasmapheresis are short lived.

4. Renal dysfunction. The possible causes of renal dysfunction in patients with MM include the following: myeloma kidney or cast nephropathy, drugs (such as NSAIDs, bisphosphonates, and intravenous contrast agents), hypercalcemia, hyperuricemia and urate nephropathy, amyloid deposition, pyelonephritis and other infections, hyperviscosity syndrome, plasma cell infiltration of both kidneys (rare), and renal tubular acidosis. In addition, patients with MM are particularly susceptible to in-travascular volume depletion and prerenal azotemia. Adequate hydration, avoidance of possible culprit drugs when possible, high index of suspicion, and early identification of etiology will result in i mproved renal outcomes, as most of the causes of renal dysfunction are reversible. Patients with MM with severe renal dysfunction, in whom readily identifiable causes of renal dysfunction have been ruled out, may be assumed to have cast nephropathy without the need for a biopsy. Plasmapheresis in addition to institution of chemotherapy should be considered in such selected cases. While plasmapheresis does not impact overall survival, it may result in improved dialysis-free survival. In patients with severe renal failure that have not improved with the previously discussed interventions, hemodialysis should be considered if chemotherapy offers the potential for a prolonged remission.

5. Skeletal destruction. This remains a major cause of disability, pain, and immobilization for patients with MM. Adopting a mul-tidisciplinary approach to the patient with bone disease cannot be overemphasized. Bisphosphonates are best given monthly in the first 1 to 2 years and less frequently thereafter. They have been shown to reduce the incidence of skeletal-related events. Pamidronate and zoledronic acid have both been associated with the development of osteonecrosis of the jaw. A dentist experienced in management of this complication should promptly evaluate patients with symptoms referable to the jaw or teeth. In addition, bisphosphonates should be held for 1 month prior and 2 months after any elective dental procedure or after confirmation of the total healing after the procedure. Radiation therapy is often used to palliate painful lytic lesions. Surgical intervention is used for prevention of impending fractures of weight-bearing bones and the treatment of compression frac-tures causing pain and loss of height (kyphoplasty).

6. Anemia. Anemia is frequently observed in patients with MM. MM and its treatment are etiologic in most patients. In addition, a subset of patients was found to have vitamin B12 and folate deficiency and treatment with erythropoietic agents is thought to result in decreases in iron stores. Thus, monitoring vitamin B12, folate, and iron levels is recommended. The use of recombinant human erythropoietin results in responses of the anemia in about 80% of patients.

7. Leukemia. Acute myeloid leukemia develops in up to 4% of patients with myeloma who have received alkylator-based chemotherapy (melphalan). Myelodysplasia is present at diagnosis in a subset of patients as it, like myeloma, occurs in older age groups. Leukemia in this setting appears to be caused by the interaction of a carcinogenic drug with a predisposed host. With the avoidance of long-term therapy with alkylating agents, the incidence of this complication is declining. In addition, myelodysplastic syndrome post high-dose therapy and autologous stem cell transplant is increasingly recognized in patients with myeloma who currently enjoy longer survival than with previous therapies.

IV. WM (LYMPHOPLASMACYTIC LYMPHOMA)

A. Diagnosis and presentation

WM is a B-cell lymphoproliferative disorder characterized by the production of a monoclonal Ig of the IgM subtype and by intertrabe-cular bone marrow infiltration with a lymphoplasmacytic infiltrate. The second international workshop on WM has proposed the following diagnostic criteria: an IgM M-protein of any concentration, bone marrow infiltration with small lymphocytes exhibiting plas-macytoid differentiation, and with a suggestive immunophenotype (expression of surface IgM, CD19, CD20, CD25, CD27, FMC7, and CD138 without the expression of CD5, CD10, CD23, and CD103).

Symptoms attributable to WM are related to tumor infiltration or to the M-protein. The former results in constitutional symptoms (fevers, sweats, and weight loss), cytopenias (secondary to bone marrow involvement), lymphadenopathy, and hepatosplenomegaly. Symptoms related to the M-protein include hyperviscosity, cryoglobulinemia, cold agglutinin, neuropathy, and amyloidosis.

B. General considerations and aims of therapy

There is no cure for WM. Treatment is palliative and aimed at reduction of symptoms and prevention of complications of the disease. Increasing numbers of patients without signs or symptoms are being diagnosed with WM. Expectant observation is the recommended approach for patients with asymptomatic WM. The level of the M-protein should not be used as an indication for treatment. The choice of the therapeutic option in a symptomatic individual is guided by disease characteristics as well as patient characteristics. The available therapies include the following: oral alkylating agents, nucleoside analogs, rituximab monotherapy, and a combination of chemotherapy, rituximab, and autologous stem cell transplantation. Novel therapies include thalidomide, alemtu-zumab, and bortezomib. Limited randomized clinical trials have been conducted for WM, and treatment recommendations rely mostly on phase II studies. Patients with WM are monitored by repeated measurements of one or more of the following: the serum M-protein, the serum viscosity when that is elevated, and by serial computed tomography scan. A complete response is defined as the disappearance of the M-protein and by resolution of infiltration of lymph node and visceral organs confirmed on two separate evaluations 6 weeks apart. A partial response is defined as a greater than 50% reduction in the M-protein and a greater than 50% reduction in lymphadenopathy with the resolutions of symptoms related to WM. Progressive disease is defined as a greater than 25% increase in the M-protein, worsening of cytopenias, organ infiltration, or disease-related symptoms. After the documentation of the best response, continued therapy is not clearly beneficial. The median survival of patients with WM has historically been 5 to 10 years, likely as a consequence of the older patient population and comorbidities.

B. Treatment

1. Cytopenias in patients with WM are related to bone marrow involvement and occasionally to hypersplenism. Anemia in patients with WM is common and often responds to erythropoi-etic agents. While transfusions are generally safe, it is generally done with caution in patients with hyperviscosity as red blood cells contribute to whole blood viscosity. Thrombocytopenia and anemia usually are indications to initiate treatment, and improvement in these cytopenias is often regarded as evidence of response to therapy. Platelet transfusions are occasionally needed, especially after chemotherapy is given to the patient with baseline thrombocytopenia.

2. Hyperviscosity. Hyperviscosity syndrome readily responds to plasmapheresis. Plasmapheresis should not be regarded as a long-term treatment, and consolidation of that response with chemotherapy is ultimately needed to render patients independent of that procedure.

3. Chemotherapy

a. Oral alkylating agents

bull Chlorambucil 2 to 6 mg by mouth daily, or

bull Cyclophosphamide 50 to 100 mg by mouth daily.

bull Prednisone 40 to 60 mg by mouth on days 1 to 4 every 4 weeks is often added.

While complete responses are rare with the use of alky-lating agents, partial responses approach 50% in some series. The time to response has been slow with alkylating agents. The use of alkylating agents should be considered in older patients in whom rapid control of the disease is not necessary.

b. Nucleoside analog

bull Fludarabine 25 mg/m2 IV on days 1 to 5

bull Cycles are repeated every 28 days.

While many patients are able to tolerate this regimen, older individuals and patients with significant cytopenias at baseline are best treated with a reduced dose. Two to three days of fludarabine 25 mg/m2 in the first two cycles are recommended; consider dose increases if the patient is able to tolerate therapy well and responses are suboptimal. Nucleoside analogs have been shown to result in a higher response rate than oral alkylators, but a survival benefit has not been demonstrated. The time to response is shortened by the use of nucleoside analogs. We recommend the use of these agents in younger patients in whom autologous stem cell transplantation is not considered and who require a fast tumor control.

c. Rituximab

bull Rituximab 375 mg/m2 IV weekly for four doses (consider repeating for another four doses).

Rituximab is a monoclonal antibody targeting CD20 on B-lymphocytes. Response rates range from 20% to 70% in newly diagnosed patients and around 30% in relapsed patients. Time to response to rituximab is in the order of 3 months. A flare reaction has been described in patients treated with rituximab and is characterized by a transient increase in the serum IgM of patients. A serum IgM lower than 5 grams is predictive of response to this agent. We recommend the use of this agent in younger patients with minimal symptoms of their disease and with a lower serum IgM level.

d. High-dose therapy and autologous stem cell transplantation. Autologous stem cell transplantation has resulted in high rates of responses (approaching 90%) and lasting responses (progression-free survival approaching 70 months) in a small series of patients. The small number of patients, the nonran-domized nature of the studies, and potential for treatment-related morbidity makes it difficult to routinely recommend this approach for most patients. It should, however, be considered in younger patients after cytoreductive treatment with rituximab. Treatment with alkylating agents and nucle-oside analogs may impair the ability to collect stem cells and should be judiciously used in younger patients.

V. AMYLOIDOSIS

Only AL (primary) amyloidosis, with or without associated plasma cell neoplasms, is considered in this section. In these disorders, fragments of Ig light chain accumulate and deposit in the affected tissues. These deposits are characterized by a pathognomonic apple green birefringence on polarized microscopy. These deposits lead to organ dysfunction. AL amyloidosis characteristically infiltrates the tongue, heart, skin, ligaments, and muscle and occasionally the kidney, liver, and spleen. The diagnosis requires biopsy of the affected organ; although occasionally, a fat pat biopsy may obviate that need. In patients with documented lymphomas or plasma cell neoplasms, treatment is directed at the underlying neoplasm, but the decline in the amount of amyloid deposits is often minimal. With primary amy-loidosis without a demonstrable underlying neoplasm, treatment with alkylator-based therapy such as MP has been used historically and is of moderate benefits. The use of high-dose dexamethasone is often prescribed as well. High-dose therapy with stem cell rescue is considered in only a minority of patients as most patients are not eligible and the procedure-related mortality remains high in this patient group. Patients with cardiac amyloidosis have dismal outcomes often measured in months if they have concomitant heart failure. Recently, bortezomib-based therapy has been shown to result in high hematologic responses, but long-term follow-up and organ responses have not been clearly defined with this therapy. Novel effective therapies are needed and enrollment of patients onto clinical trials should be considered early.

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