24 - Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 24 - Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis

Chapter 24

Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis

Rachid Baz

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 and/or by the production of a monoclonal protein (M-protein). The following plasma cell dyscrasias will be discussed in this chapter: monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenstr m's macroglobulinemia (WM), amyloidosis, and solitary plasmacytomas. Light-chain deposition disease, heavy-chain diseases, immunoglobulin (Ig) D multiple myeloma, nonsecretory multiple myeloma, osteosclerotic myeloma or peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome and primary plasma cell leukemia are beyond the scope of this text.

B. Monoclonal protein (M-protein)

A monoclonal protein is detected in the serum and/or urine 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 de-differentiated and become less secretory or nonsecretory. This is often accompanied by an increase in the serum lactate dehydrogenase (LDH) level. Exception 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 Ig unit comprises two identical heavy chains (IgG, A, M, D or E) and two identical light chains ( or ). The serum protein electrophoresis used to quantify the monoclonal component of the globulin however fails to do so when the concentration of the latter is low because of lack of secretion or secondary to excretion in the urine. If there is a high clinical suspicion for the presence of a M-protein despite a negative electrophoresis, an immunoelectrophoresis should be performed in the serum and the urine as up to 15% of patients could show a negative serum immune fixation with positive urine. The urinary light-chain excretion (ULC, expressed in grams per 24 h) is used to follow the urinary M-protein. This is calculated from the 24 hours urine protein and the percentage contribution of light chain to proteinuria on the urine protein electrophoresis. It is critical to assess the percentage contribution of the light chain to

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the proteinuria especially in patients with other comorbidities such as hypertension and diabetes mellitus where the patient could present with a M-protein with the proteinuria consisting mainly of albumin secondary to other medical processes. Newer assays for serum free light chain are becoming increasingly available and often result in the detection of increased free light chain in the serum of many patients with nonsecretory MM (negative immune fixation of the serum and urine) and AL (primary or immunoglobulin light chain amyloid) amyloidosis. The latter assay does not demonstrate monoclonality of the light chain but relies on the ratio of to light chain to infer an excess of one of the light chains. Although some investigators have correlated changes in the free light chain induced by therapy with outcomes, the precise role of these markers beyond their contribution to the diagnosis remains unclear. Infections, autoimmune disorders, and poor renal function make interpretation of the free light-chain assay difficult.

II. Monoclonal gammopathy of undetermined significance (MGUS)

This condition 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 people older than 70 years. The rate of progression from MGUS to MM or other lymphoproliferative disorders varies on the basis of several factors, the notable of which is the level of the serum M-protein. A high serum M-protein ( 1.5 gm/dL), a higher bone marrow plasma cell burden, and possibly an abnormal to ratio on free light-chain analysis identify patients at higher risk of progression to MM. Patients with lower-risk MGUS may be followed up on a yearly or biannual basis, whereas patients with higher risk of progression are eligible for enrollment in prevention clinical trial and will probably benefit from closer follow-up. In a small number of patients, MGUS could be associated with peripheral neuropathy. Most patients with MGUS and peripheral neuropathy in association with an IgM M-protein have anti-myelin-associated glycoprotein (MAG) antibodies. This group of patients responds favorably to therapy with single agent rituximab.

III. Multiple myeloma (MM)

A. General considerations and aims of therapy

Diagnosis. MM is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Table 24.1 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 (it is illustrated in Table 24.2). Its use has fallen out of favor because of difficulties inherent in its use. One such staging system developed by the Southwest Oncology Group (SWOG) is illustrated in Table 24.3. It relies on the serum 2-microglobulin and on serum albumin. It was found to accurately prognosticate patient outcomes.

With increased awareness, an increasing number of patients are being diagnosed with monoclonal gammopathy. A significant percentage of those patients are noted as an incedental finding and the decision to monitor or actively treat has become difficult with the old nomenclature.

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Table 24.1. Diagnostic criteria of multiple myeloma

Major criteria	1 Plasmacytoma of tissue biopsy
	2 Bone marrow plasmacytosis (greater than 30% plasma cell)
	3 IgG >3.5 g/dL or IgA >2.0 g/dL or urine light-chain excretion >1.0 g/24 h
Minor criteria	1 Bone marrow plasmacytosis (greater than 10% but less than 30% plasma cells)
	2 M-protein present in lower concentration as noted in major criteria
	3 Lytic bone lesions
	4 Hypogammaglobulinemia (IgM <50 mg/dL, IgA <100 mg/dL, or IgG <600 mg/dL)
The diagnosis of multiple myeloma is made in the following cases: any 2 major criteria; major criterion 1 and minor criteria 2, 3, or 4; major criterion 3 and minor criterion 1 or 3; minor criteria 1, 2, and 3, and minor criteria 1, 2, 4.

Table 24.2. Durie-Salmon staging system

Stage	Criteria
I	All of the following: Hemoglobin >10 g/dL Serum calcium value normal (=12 mg/dL) On radiograph, normal bone structure or solitary bone plasmacytoma only Low M component production rates IgG value <5 g/dL IgA value <3 g/dL Urine light-chain M component on electrophoresis <4 g/24 h
II	Fitting neither stage I nor stage III
III	One or more of the following: Hemoglobin <8.5 g/dL Serum calcium value >12 mg/dL Advanced lytic bone lesions High M component production rates IgG value >7 g/dL IgA value >5 g/dL Urine light-chain M component on electrophoresis >12 g/24 h
Designation A and B are based on serum creatinine (A: serum creatinine <2.0, B: serum creatinine >2.0). Ig, immunoglobulin. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842.

Table 24.3. Southwest Oncology Group (SWOG) staging system for multiple myeloma

₂-Microglobulin (mg/L)	Albumin (g/dL)	SWOG Stage	Percent of Patients (%)	Median Survival (months)
<2.5	Any	I	14	55
2.5 and <5.5	Any	II	43	40
5. 5	3.0	III	32	24
5. 5	<3.0	IV	11	16

End organ damage. The international multiple myeloma working group recently presented the concept of multiple myeloma with active or inactive disease based on the presence or absence of end organ damage respectively.
Criteria defining end organ damage are anemia, thrombocytopenia, renal failure, hypocalcaemia, severe osteoporosis or lytic bony disease, or any organ abnormality that is attributed to the plasma cell dyscrasia.
Patients without end organ damage should be monitored carefully as early intervention does not affect the outcome of the disease. Patients with inactive MM should be considered for clinical trials.
Even though MGUS is considered a premalignant condition, patients who meet the MGUS criteria and demonstrate end organ damage must be classified as having active MM and should receive active therapy.

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 whites in the United States. Several agents have been strongly associated with the development of MM, ionizing radiation being the most described risk factor. Nickel, agricultural chemicals, petroleum products and other aromatic hydrocarbons, benzene and silicon have been considered potential risk factors as well.
Goals of therapy. Despite recent advances in the treatment of MM, the disease remains incurable. Accordingly, therapy is aimed at improving symptoms, preventing complications of the disease, thereby 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, whereas the other approach attempts to eradicate the disease with intensive therapy. Currently, it is unclear which treatment methodology is superior; however, there is evidence that certain subgroups of patients might benefit from one or the other approach. With these uncertainties and
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because standard first-line therapy is not defined, patients with MM, regardless of age, stage of disease, or number of previous therapy must be considered for clinical trial 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, thrombotic, neuronal, and renal complications. Accordingly, response to therapy is based on changes to the M-protein concentration and the percentage of plasma cells in the bone marrow, and monitoring end organs for further change from baseline has been the tradition. The cooperative oncology groups in the United States and Europe have adopted different cutoffs to define response. Table 24.4 illustrates the response criteria adopted by the European Group for Blood and Marrow Transplantation.
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 LDH level, and lower platelet counts, bone marrow with greater than 50% plasma cells, greater than 2% bone marrow plasmablasts, high plasma cell labeling index, elevated serum ₂-microglobulin, and low serum albumin levels. The latter two are the basis for the SWOG staging system. The identification of cytogenetic prognostic factors using metaphase karyotyping relies on cellular growth, which is difficult as the MM plasma cells have a low proliferative rate, and therefore such information is available only in 20% to 40% of the patients. The presence of abnormalities with this method however is meaningful as it indicates a high proliferative index i.e., aggressive disease. Genomic prognostic factors include the deletion of chromosome 13, translocation of the Ig heavy chain (t(4,14), t(14,16)), and loss of 17p13. The t(11,14) on the other hand is not though 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. Non hyperdiploid karyotypes are frequently associated with Ig heavy chain rearrangements and worse clinical outcomes.

B. Initial treatment

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

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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 nonsteroid anti-inflammatory drugs (NSAIDs), aminoglycosides, and intravenous contrast agent 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 N-acetyl cysteine should be considered. The use bisphosphonates (either pamidronate or zoledronic acid) is recommended for nearly every myeloma patient with normal renal function, particularly in those with bony disease (see Section III.C.5.). We recommend holding the initiation of the bisphosphonates in the first cycle of therapy to help decrease renal complications from the use of these agents.

Table 24.4. Criteria for response by the European Group for Blood and Marrow Transplantation (EBMT), Southwest Oncology Group (SWOG) and Eastern Cooperative Oncology Groups (ECOG)

	EBMT	SWOG	ECOG
Complete remission (CR)	Disappearance of all evidence of serum and urine M components on electrophoresis and by immunofixation studies for 6 weeks	75% decrease in calculated tumor mass and 90% decrease in Bence Jones proteinuria to <0. 2 g in 24 h	Disappearance of all evidence of serum and urine M components on electrophoresis and by immunofixation and in the bone marrow
Partial remission (PR)	A >50% reduction in the serum paraprotein, and if present, a >90% reduction in the urine light-chain excretion for 6 weeks	50% 74% decrease in calculated tumor mass and 50 90% decrease in Bence Jones proteinuria	50% decrease in serum M-protein and 24 h urine light-chain excretion. Bence Jones proteinuria must decrease to <10% of baseline
Minimal remission (MR)	A 25% 49% reduction in serum paraprotein and a 50% 89% reduction in urine light-chain excretion for 6 weeks	Not defined	Not defined
Plateau phase (P) or stable disease (SD)	A stable serum and urine paraprotein (within 25%) maintained for at least 3 months	Does not meet criteria for progression or response	Does not meet criteria for progression or response

Systemic therapy for the newly diagnosed patient (see Sections III.B.3. for specific regimens). Although a plethora of therapeutic options for the treatment of newly diagnosed MM patients 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. 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 are based on a patient's comorbidities, performance status, and preference, as well as on disease characteristics. For example, if high-dose therapy is considered during the course of therapy, avoidance of agents (e.g., melphalan and other alkylating agents) that impair stem cell collection is important. 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.

Patients with poor prognostic factors at presentation (chromosome 13 deletion by metaphase cytogenetics or t(4,14), high ₂-microglobulin, or increased plasma cell labeling index) fare poorly with all traditional therapy. Accordingly, these patients are best managed by enrollment to clinical trials. Alternatively, it is intuitive though unproved that intensive therapy (combination induction therapy followed by high-dose therapy) would result in improved outcomes.

For patients in whom high-dose therapy is not considered in first remission, therapy with thalidomide and dexamethasone, dexamethasone alone, or the combination of chemotherapy and thalidomide results in a higher response rate than melphalan and prednisone (MP) at the cost of increased toxicities. Overall survival benefit has not been demonstrated but avoidance of MP is reasonable to preserve bone marrow function. Although the duration of therapy remains unclear, we recommend treatment to
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best response or one to two cycles beyond best response. Chemotherapeutic regimens are described in the subsequent text.

Although most patients older than 70 years remain excellent candidates for aggressive induction therapy, those with significant comorbidities and decreased performance status are often better able to tolerate the combination of an alkylating agent (melphalan or cyclophosphamide) and prednisone. It remains a reasonable line of therapy in this patient group as it is well tolerated and results in responses in approximately 50% of patients. Modifications to this regimen have been described and patients with a good performance status benefit from the addition of thalidomide to first-line therapy with melphalan and corticosteroids. Alternative regimens in this patient population include the use of cyclophosphamide with prednisone as cumulative doses of this agent are not stem cell toxic.
Traditional chemotherapy recommendations. Although numerous additional chemotherapeutic regimens have been described, only commonly used agents in the treatment of MM are reviewed in the subsequent text.
- Dexamethasone. Dexamethasone is considered by many as the standard induction strategy in patients with MM.
  - Dexamethasone is given at a dose of 40 mg PO on days 1 to 4, 9 to 12, and 17 to 20. Cycles are repeated every 28 days.
  Treatment is usually given for a minimum of 4 cycles or 2 cycles beyond best response. Significant toxicities include hyperglycemia, dyspepsia, fatigue, and muscle weakness. Additionally, patients often report agitation and insomnia with the use of this schedule of dexamethasone. Responses are observed in approximately 50% of patients and the median time to response is approximately 1 month.
- Thalidomide and dexamethasone. The addition of thalidomide to the earlier schedule of dexamethasone results in an increased response rates (~70%), at the cost of additional toxicity (in the form of thromboembolic events, rash, sedation, peripheral neuropathy, and constipation). Although thalidomide 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 increase the daily dose by 50 mg increments every week to a desired target dose not exceeding 400 mg daily or as dictated by patient tolerance. It should be noted however that there is no known minimal dose required for response where some (though rare) patients respond to dosages as low as 50 mg three times a week.
  - In addition, after the second cycle of therapy, reduction of dexamethasone to 40 mg on days 1 to 4 does result in improved patient tolerance.
  - With the increased risks of thromboembolic events (~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.
- DVd. The DVd regimen consists of the combination of an anthracycline, vincristine and dexamethasone, which is the backbone of the so-called VAD regimen. Intravenous chemotherapy is given on day 1 without the need for lengthy continuous infusions. This makes delivery easier in an outpatient setting. While efficacy is not compromised, tolerability is improved with this regimen.
  - The DVd regimen consists of the following:
    - Vincristine 2 mg IVP on day 1, and
    - Pegylated liposomal doxorubicin 40 mg/m² IVPB on day 1, and
    - Dexamethasone 40 mg PO on days 1 to 4.
  - Repeat cycles of DVd every 28 days for two cycles beyond best response and a minimum of four cycles.
  Pegylated liposomal doxorubicin should be used with caution in patients with cardiac dysfunction and in patients with prior doxorubicin use (particularly those with higher cumulative doxorubicin doses). In addition, thalidomide can be combined with the DVd regimen (DVd-T) with the resultant overall response rate exceeding 90% and a rate of complete or near-complete response of approximately 30% to 40%. Caution must be used with the DVd-T regimen as toxicity is additive where prophylactic antibacterial (amoxicillin 250 mg PO b.i.d.), antiviral therapy (acyclovir 400 mg PO b.i.d.), low-dose aspirin (81 mg daily), and growth factor support should be given with this regimen.
- Melphalan and prednisone (MP). Although more complex chemotherapy induction regimens have not clearly been proved to improve the overall survival as compared to MP, the use of this combination has fallen out of favor in younger patients because of concern over long-term bonemarrow health and ability to collect stem cells. MP results in approximately 50% overall response rate in patients with newly diagnosed myeloma and a median time to progression of approximately 15 months. Although a number of different dosages and schedules for MP exist, we recommend the following:
  - Melphalan 9 mg/m² PO on days 1 to 4, and
  - Prednisone 100 mg PO on days 1 to 4.
  For reliable absorption, melphalan should be taken on an empty stomach. Repeat cycle every 4 to 6 weeks depending on recovery of counts. MP is usually given for 6 to 9 cycles and treatment beyond 1 year does increase risks of myelodysplasia. Responses to MP tend
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  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 myeloma patients with myelosuppression being the most significant adverse event.
- Cyclophosphamide and prednisone (CP). CP is a forgotten alternative to melphalan and prednisone where 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 approximately 50% and a progression-free survival of 12 to 15 months in treatment na ve patients. CP is given as follows:
  - Cyclophosphamide 1,000 mg/m² IV on day 1, and
  - Prednisone 100 mg PO on days 1 to 5
  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.
- Bortezomib. Bortezomib is a proteasome inhibitor approved for relapsed or refractory MM. Although it is yet to have a defined role in newly diagnosed patients, combination therapy with dexamethasone, and with thalidomide and dexamethasone have shown promising results in this setting albeit at the cost of increasing toxicity. As a single agent in relapsed and refractory patients, it was shown to result in a response rate of approximately 30% to 40% and a median time to progression of 6 to 7 months, this was found to be superior to high-dose dexamethasone.
  - Bortezomib is given at 1.3 mg/m² IVP on days 1, 4, 8 and 11 on a 21-day cycle.
  - Dexamethasone 20 mg, on the day before and on the day of bortezomib, is often added after 2 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. We do not recommend the use of this agent in newly diagnosed patients outside the context of a clinical trial.
- Lenalidomide. Lenalidomide is an immunomodulatory drug with more potent tumor necrosis factor (TNF- ) inhibition than thalidomide. In addition, lenalidomide has a different adverse event profile than thalidomide and does not usually cause significant sedation or neuropathy but does result in myelosuppression. Lenalidomide is currently approved in the United States for
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  the treatment of myelodysplastic syndrome with 5q abnormalities but has significant activity in MM. 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. Similar combination in a small study of newly diagnosed patients resulted in response rates in more than 90% of patients. Lenalidomide and dexamethasone are given as follows:
  - Lenalidomide 25 mg PO on days 1 to 21 of a 28-day cycle
  - Dexamethasone 40 mg PO on days 1 to 4, 9 to 12, and 17 to 21
  The optimal duration of therapy with lenalidomide is unclear and because clinical trials with this agent used continuing therapy, we recommend a similar approach in patients tolerating this agent well. After two cycles of therapy, consideration for decreasing the frequency of dexamethasone to 4 days must be given. Lenalidomide can also result in thromboembolic events and prophylaxis with low-dose aspirin daily is recommended. In addition, we have reported that the combination of lenalidomide with chemotherapy (specifically the DVd regimen) results in a high response rate (greater than 85%) and high complete and near-complete response rates (~30%). Lenalidomide is given at 10 mg for the first 21 days of the 28-day cycle with this combination. Similar to the DVd-T regimen, we recommend the use of prophylactic antimicrobials and growth factor support as in the preceding text. Until lenalidomide is approved for use in MM in the United States, we recommend that the use of this agent be restricted to clinical trials.
Treatment of patients with relapsed or refractory multiple myeloma (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 despite possible original responses. This patient population has a worse outcome than patients with relapse do. Enrollment of patients with relapsed or refractory myeloma into clinical trial 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 the immunomodulatory drugs (lenalidomide and actimid), histone deacetylase inhibitors, mTOR (mammalian target of rapamycin) inhibitors, and RANK-L antibodies. Many of these will likely be approved first for the treatment of relapsed or refractory patients before gaining indication in newly diagnosed patients.
High-dose therapy with bone marrow or peripheral blood stem cell transplantation. (See also Chapter 5.)
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The role of high-dose therapy and autologous stem cell transplantation for MM 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. 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 therapy and the availability of novel active salvage therapies. Despite the lack of consistent overall survival advantage, high-dose therapy might be useful for a subgroup of patients that is yet to be defined. One such group are patients planning to receive a tandem transplant where the second transplant is administered in a timed manner following the first transplant (i.e., within 4 months of the first transplant). 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 dexamethasone alone, the combination of thalidomide and dexamethasone, or chemotherapy in the form of pegylated liposomal doxorubicin, vincristine, and dexamethasone (DVd) with and without the addition of thalidomide. Preliminary data suggest that patients achieving a more than 90% reduction of the M-protein might be the group benefiting most from a single high-dose therapy and stem cell support. If the patient and the treating physician are in agreement with this concept, the addition of thalidomide to the DVd regimen would be desirable to increase the number of high quality responders. It can be argued however that this group of patients will fare well regardless of therapy, and minimizing toxicity and therapy is a reasonable goal. Stem cells can be derived from the peripheral blood or the bone marrow. The former can be done with the use of granulocyte colony stimulating factor (G-CSF) with or without chemotherapy. Novel agents to facilitate stem cell collection are entering 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. Although 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.

French investigators reported promising results with a tandem transplant strategy. While awaiting confirmatory clinical trials, tandem transplants should be considered only as part of a clinical trial as long-term outcomes are not well defined and not all patients appear to benefit from
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a second course of high-dose therapy. Allogeneic transplantation remains experimental for patients with MM and is precluded by high transplant-related mortality. Reduced intensity conditioning regimen followed by allogeneic transplantation relies solely on graft-versus-myeloma effects. This approach remains experimental as well as long-term outcomes are unproved. Furthermore, only small subsets of patients with MM are candidates to receive such intensified therapy.

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 is needed to further increase the safety of this approach.
Duration of therapy and the role of maintenance therapy. Patients with stable M-protein for more 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. 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 the 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 10mg of prednisone every other day. Although 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 induction chemotherapy that included this agent is common practice and has been associated with a survival benefit post 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.
Role of radiotherapy. Although 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 extra skeletal 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 chemotherapy.

C. Complications of disease or therapy

Toxicity of each chemotherapeutic agent is described elsewhere. In addition, complications characteristic of MM are described here.

Hypercalcemia. Once a very 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
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patients with MM is likely related to increased osteoclast activation as a result of binding of the latter to malignant plasma cells. Receptor activator of nuclear factor- B (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 and overlap with adverse events of thalidomide, and a strong index of suspicion is required. Symptoms include anorexia, constipation and polyuria, and lethargy. Coma and death are the result of untreated hypercalcemia. Dehydration and potentially reversible renal dysfunction are frequently associated with hypercalcemia. Treatment of hypercalcemia 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 but hemodialysis is reserved for refractory cases. When hypercalcemia occurs in previously untreated patients, prompt initiation of therapy for the MM in addition to the above usually results in effective, durable control.
- Bisphosphonates
  - Pamidronate 90 mg given as a 2-h IV infusion that can be repeated every 30 days or
  - Zoledronic acid 4 mg IV over 15 to 30 min in the absence of renal dysfunction.
- Calcitonin 100 to 300 U SC every 8 to 12 h for up to 2 to 3 days. Calcitonin is usually given with prednisone 60 mg PO daily to prolong its effectiveness.
- Hemodialysis is very effective but rarely needed.
Infections. (See also Chapter 28.) Patients with MM are at increased risk for infectious complications usually related to capsulated microorganisms. Deficiency of normal Igs, 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 are essential. The prophylactic and therapeutic use of growth factors (such as G-CSF) is often considered. Intravenous immunoglobulin (IVIG) is administered to patients with recurrent significant infectious complications.
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 (that is often subtle and noted as difficulty concentrating and headaches), and occasionally as congestive heart failure. Plasmapheresis is the treatment of symptomatic hyperviscosity; however, therapy should be combined with systemic therapy directed at the myeloma as benefits of plasmapheresis are short lived, owing to the fact that IgG and IgA are not confined to the vascular space.
Renal dysfunction. The possible causes of renal dysfunction in patients with MM include all of the following:
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myeloma kidney or cast nephropathy, drugs such as nonsteroid anti-inflammatory drugs, 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, MM patients are particularly susceptible to intravascular volume depletion and pre-renal azotemia. Adequate hydration, avoidance of possible culprit drugs when possible, high index of suspicion, and early identification of etiology will result in improved 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. Although plasmapheresis does not impact overall survival, it may result in improved dialysis free survival. In patients with severe renal failure that has not improved with interventions mentioned earlier, hemodialysis should be considered if chemotherapy offers the potential for a prolonged remission.
Skeletal destruction. This remains a major cause of disability, pain, and immobilization for patients with MM. Adopting a multidisciplinary 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 skeleton-related events. Pamidronate and zoledronic acid have both been associated with the development of osteonecrosis of the jaw. A dentist experienced in the 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 before and 2 months after any 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 fractures causing pain and loss of height (kyphoplasty).
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 of vitamin B12, folate, and iron levels is recommended. The use of recombinant human erythropoietin yields results in approximately 80% of patients with anemia.
Leukemia. Acute myeloid leukemia (AML) develops in approximately 4% of myeloma patients who have received alkylator-based chemotherapy (melphalan). Myelodysplasia is present at diagnosis in a subset of patients as both conditions occur in older age-groups. Leukemia in this
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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.

IV. Waldenstr m's macroglobulinemia (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 intertrabecular 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 and bone marrow infiltration with small lymphocytes exhibiting plasmacytoid 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 bonemarrow involvement), lymphadenopathy, and hepatosplenomegaly. Symptoms related to M-protein include those related to 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 complication 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 symptomatic individual is guided by disease characteristics as well as possible patient characteristics. The available therapies include the following: oral alkylating agents, nucleoside analogs, rituximab monotherapy, combination of chemotherapy and rituximab, and autologous stem cell transplantation. Novel therapies include thalidomide, alemtuzumab, bortezomib, and sildenafil and are recommended only within the context of clinical trials. 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 serum M-protein and serum viscosity when that is elevated, and/or by serial computed tomography (CT) 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 greater than 50% reduction in M-protein, and greater than 50% reduction in lymphadenopathy with the resolution 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

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patients with WM has historically been 5 to 10 years, likely as a consequence of the older patient population and comorbidities.

C. Treatment

Cytopenias. 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 erythropoietic agents. Although 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 leukopenia 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.
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 the patient independent of that procedure.
Chemotherapy
- Oral alkylating agents
  - Chlorambucil 2 to 6 mg PO daily, or
  - Cyclophosphamide 50 to 100 mg PO daily.
    
    (Prednisone 40 to 60 mg PO on days 1 to 4 every 4 weeks is often added.)
    
    Complete responses are rare with the use of alkylating agents, whereas 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.
- Nucleoside analog
  - Fludarabine 25 mg/m² IV on days 1 to 5.
    
    Cycles are repeated every 28 days.
    
    Although many patients are able to tolerate this regimen, older individual and patients with significant cytopenias at baseline are best treated by dose reduction in the early cycles. We recommend 2 to 3 days of the above dose of fludarabine in the first two cycles and would 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.
- Rituximab
  - 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
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    70% in the in newly diagnosed patients and approximately 30% in patients with relapse. 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 g 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.
- 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 small series of patients. The small number of patients, the nonrandomized nature of the studies, and the potential for treatment-related morbidity make it difficult to routinely recommend this approach in many patients. It should however be considered in younger patients after cytoreductive treatment with rituximab. Treatment with alkylating agents and nucleoside analog may impair the ability to collect stem cells and should be judiciously used in younger patients.

V. Amyloidosis

Only primary amyloidosis (AL 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 polarizedmicroscopy. These deposit lead to organ dysfunction. AL amyloid characteristically infiltrates the tongue, heart, skin, ligaments, and muscle and occasionally the kidney, liver, and spleen. 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 is often minimal. With primary amyloidosis 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 procedure-related mortality remains high. Patients with cardiac amyloidosis have dismal outcomes, often measured in months, if they have concomitant heart failure. Novel effective therapies are needed and enrollment of patients to clinical trials should be considered early.