Multiple Myeloma and Other Plasma Cell Dyscrasias

June 1, 2007

Multiple myeloma is a disseminated malignancy of monoclonal plasma cells that accounts for 8% of all hematologic cancers. In the year 2007, an estimated 19,900 new cases will be diagnosed in the United States, and 10,790 Americans will die of this disease. Incidence rates for myeloma (5.3 in men and 3.5 in women) and mortality rates (3.7 in men and 2.5 in women) per 100,000 population have remained stable for the past decade.

MULTIPLE MYELOMA

Multiple myeloma is a disseminated malignancy of monoclonal plasma cells that accounts for 8% of all hematologic cancers. In the year 2007, an estimated 19,900 new cases will be diagnosed in the United States, and 10,790 Americans will die of this disease. Incidence rates for myeloma (5.3 in men and 3.5 in women) and mortality rates (3.7 in men and 2.5 in women) per 100,000 population have remained stable for the past decade.

Epidemiology

Gender Men are affected more frequently than women (1.4:1.0 ratio).

Age The median age at presentation is 71 years, according to most tumor registries, although the median age reported in studies is approximately 60 years.

Race The annual incidence per 100,000 population is 6.4 among white men and 4.1 among white women. Among black men and women, the fre­quency doubles to 12.7 and 10.0, respectively, per 100,000 population. This racial differ­ence is not explained by socioeconomic or environmental factors and is presumably due to unknown ­genetic factors.

Geography There is no clear geographic distribution of multiple myeloma. In Europe, the highest rates are noted in the Nordic coun­tries, the United Kingdom, Switzerland, and Israel. France, Germany, Aus­tria, and Slovenia have a lower incidence, and developing countries have the lowest incidence. This higher relative incidence in more developed countries probably results from the combination of a longer life expectancy and more frequent medical surveillance.

Survival The 5-year survival rate for all patients treated with conventional therapy is approximately 25%–30%. The 5-year survival rate is lower among patients ≥ age 65 (20%–25%) than in those < age 65 (30%–35%).

Etiology and risk factors

No predisposing factors for the development of multiple myeloma have been confirmed.

Environment Some causative factors that have been suggested include ­radiation exposure (radiologists and radium dial workers), occupational ­ex­posure (agricultural, chemical, metallurgical, rubber plant, pulp, wood and paper workers, and leather tanners), and chemical exposure to form­alde­hyde, ­epi­chlorohydrin, Agent Orange, hair dyes, paint sprays, and asbestos. None of these ­associations has proven to be statis­tically significant, and all have been con­tradicted by negative cor­relations. The ini­tial report that survivors of the atomic ­bombings in Japan had an increased risk of developing myeloma has been re­futed by longer ­follow-up.

Viruses A preliminary report in a limited number of patients noted the presence of herpesvirus 8 in the dendritic cells of pa­tients with multiple myeloma. However, further evaluation by a number of investigators has failed to confirm this result. Patients with myeloma also do not appear to have a significant immune response against this virus.

Cytogenetics Karyotypic abnormalities in myeloma are complex, with both numeric and structural abnormalities. DNA aneuploidy is observed in more than 90% of cases, predominantly hyperdiploid, and less than 10% have hypodiploidy, which carries a poor prognosis. Recurrent nonrandom structural abnormalities have been identified and linked to the pathogenesis and prognosis of myeloma. The immunoglobulin heavy-chain gene at 14q32 is frequently involved in translocations with partner chromosomes 4, 6, 8, 11, and 16. The location and oncogenes involved are shown in Table 1. Translocations involving chromosomes 4 and 16 as well as del1q and del17p13 (p53) have been associated with a poor prognosis. Del13q or monosomy 13 is observed in 15%–20% of patients with conventional cytogenetics and also carries a poor prognosis across standard and high-dose therapies. Interphase fluorescence in situ hybridization (FISH) with a specific probe for chromosome 13q34 (retinoblastoma gene, Rb 1) identifies this abnormality in up to 50% of patients, with a less clear prognostic implication.

Genetic factors Although multiple mye­loma is not an inherited disease, there have been numerous case reports of multiple incidence in the same family. However, a case-control study revealed no significant increase in the incidence among relatives of patients who had multiple mye­loma, other he­matologic malignancies, or other ­cancers.

 

Monoclonal gammopathy of unknown ­significance (MGUS) Patients with MGUS ­develop myeloma, macroglobulinemic lymphoma, or amyloi­dosis at a rate of 1% per year.

 

 

 

Signs and symptoms

The clinical features of multiple myeloma are variable. Findings that suggest the diagnosis include lytic bone lesions, anemia, azotemia, hypercal­cemia, and recurrent infections. Approximately 30% of patients are free of symptoms and are diagnosed by chance.

Bone disease Bone pain, especially from compression fractures of the vertebrae or ribs, is the most common symptom. At diagnosis, 70% of pa­tients have lytic lesions, which are due to accelerated bone resorption. These changes are induced by factors modulating osteoclastic activity and produced by the bone marrow microenvironment and, to a lesser extent, myeloma cells. These factors include interleukin (IL)-1B, tumor necrosis factor (TNF)-α, and IL-6 as well as newly identified factors such as osteoprotogerin, TNF-related activation-induced cytokine (TRANCE), and receptor activator of nuclear factor kappa B (RANK) ligand. DKK-1 has been described as a soluble factor produced by multiple myeloma cells inhibiting osteoblastic activity.

Anemia Normocytic, normochromic anemia is present in 60% of pa­tients at diagnosis. It is due primarily to the decreased production of RBCs by ­marrow, infiltration with plasma cells, and the suppressive effect of various cytokines. Patients with renal failure may also have decreased levels of erythropoietin, which may worsen the degree of ­anemia.

Hypercalcemia Among newly diagnosed patients, 20% have hyper­calcemia (corrected serum calcium level, > 11.5 mg/dL) secondary to pro­gressive bone destruction, which may be exacerbated by prolonged immo­bil­ity. Hypercalcemia should be suspected in patients with myeloma who have nausea, fatigue, confusion, polyuria, or constipation. It may suggest high tumor burden. It should be considered an oncologic emergency and promptly treated.

Renal failure Approximately 20% of patients present with renal insuffi­ciency and another 20% develop this complication in later phases of the dis­ease. Light-chain cast nephropathy is the most common cause of renal failure. Additional causes include hypercalcemia, dehydration, and hyperuricemia. Uncommonly, amyloidosis, light-chain deposition disease, nonsteroidal anti-inflammatory agents taken for pain control, intravenous radiographic contrast administration, and calcium stones may contribute to renal failure. More recently, bisphosphonate therapy has been associated with renal failure.

Infections Many patients with myeloma develop bacterial infections that may be serious. In the past, gram-positive organisms (eg, Streptococcus pneu­moniae, Staphylococcus aureus) and Haemophilus influenzae were the most com­mon pathogens. More recently, however, gram-negative organisms have become frequent. The increased susceptibility of patients with myeloma to bacterial infections, specifically with encapsulated organisms, has been attributed to impairments of host-defense mechanisms, such as hypogammaglobulinemia, granulocytopenia, and decreased cell-­mediated ­immunity.

Screening and diagnosis

No screening measures for multiple myeloma have demonstrated any benefit.

The diagnosis usually requires the presence of bone marrow plasmacytosis and a monoclonal protein in the urine and/or serum (Table 2). One immu­noglobulin class is produced in excess, whereas the other immunoglobulin classes are usually depressed.

Initial work-up The initial work-up for patients suspected of having a plasma cell dyscrasia should include:

  • CBC with differential count and platelet count

  • routine serum chemistry panel (eg, calcium, BUN, creatinine)

  • bone marrow aspirate and biopsy to assess plasmacytosis

  • serum protein electrophoresis and immunofixation to define protein type

  • 24-hour urine protein, electrophoresis, and immunofixation

  • quantitative immunoglobulin levels

  • skeletal survey (bone scans contribute little since isotope uptake is ­of­ten low in purely lytic bone disease)

  • cytogenetics, including FISH.

The recently available serum free light-chain assay is useful in patients with light-chain–only disease, oligo- or nonsecretory myeloma, renal failure, and amyloidosis.

MRI is an excellent tool for evaluation of spinal cord compression/impingement. In addition, MRI identifies generalized signal abnormalities and focal lesions that can be monitored after therapy. MRI is especially useful in staging nonsecretory disease presenting as macrofocal lesions.

In addition, prognostic factors, such as β2-microglobulin (β2M), serum albumin, C-reactive protein, lactic dehydro­ge­nase (LDH) levels, plasma cell labeling index, and ploidy, may provide additional useful data.

 

 

 

 

 

 

Laboratory and pathologic features

Peripheral blood The peripheral blood smear may reveal a normocytic, normochromic anemia with rouleaux formation. Plasma cells may also be seen.

Bone marrow Bone marrow examination usually reveals an increased ­number of plasma cells. These cells are strongly positive for CD38, CD138, and cytoplasmic immunoglobulin (cIg). The majority of myeloma cells also express CD40 and CD56. Myeloma cells are negative for CD5, CD20, and surface immunoglobulin (sIg) expression. Whereas normal plasma cells express CD19, malignant plasma cells lose its expres­sion. CD10 expres­sion is generally negative but has sometimes been noted in advanced disease. Monoclonality may be demonstrated by immunoperoxidase staining with κ and λ ­antibodies.

The pattern of bone marrow involvement in plasma cell myeloma may be macrofocal. As a result, plasma cell count may be normal when an aspirate misses the focal aggregates of plasma cells that are better visualized ­ra­diographically or on direct needle biopsy.

Monoclonal proteins The types of monoclonal protein produced are IgG (60%), IgA (20%), IgD (2%), IgE (< 0.1%), or light-chain κ or λ only (18%). Biclonal elevations of myeloma proteins occur in < 1% of patients, and < 5% of patients are considered to have nonsecretory disease because their plasma cells do not secrete detectable levels of monoclonal ­immunoglobulin.

Staging and prognosis

The Durie-Salmon staging system is employed most ­frequently to stage multiple myeloma (Table 3). However, the variability in interpretation of staging criteria has resulted, in part, from imprecise quanti­fication of the extent of bone lesions and from factors other than myeloma that contribute to hypercalcemia (eg, immobility) or anemia (eg, renal failure). Additionally, this staging system has not been predictive of response or survival in the studies using high-dose therapy or novel agents. An alternate staging system is proposed using simple laboratory measurements of serum β2M and albumin (International Staging System [ISS]).

Prognosis

Cytogenetic abnormalities Chromosomal abnormalities, especially loss of whole chromosome 13 (monosomy) or deletions of parts of chromosome 13 (13q), with hypodiploid have been associated with inferior survival after both ­standard ­chemotherapy and high-dose therapy. Primary translocations involving 14q32 and 6p21 (cyclin D3), 4p16 (FGFR3), and 16q23 (c-maf ) in multivariate analysis have been shown to be important predictors of survival.

β2M Serum β2M level is an im­portant and con­venient prognostic indicator. When cytogenetic changes are not studied, β2M is consistently the most important prognostic indicator on multivariate analysis. As β2M is excreted by the kidneys, high levels are observed in patients with renal failure; in this setting, the interpretation of an elevated value is unclear.

LDH High LDH levels also have been associated with plasmablastic disease, extramedullary tumor, plasma cell leukemia, plasma cell hypodiploidy, drug resistance, and shortened survival.

Other indicators of shortened survival include elevated C-reactive protein, DNA hypodiploidy, high plasma cell labeling indices, and plasmablastic his­tology. Patients with DNA hypodiploidy are also less likely to respond to ­chemotherapy.

 

 

 

 

 

 

Treatment response criteria

Since the criteria for treatment response in patients with multiple mye­loma have varied among institutions, response rates have been difficult to compare in the past. Bence Jones protein is reduced more rapidly in respond­ers than is serum myeloma protein because of the rapid renal catabolism of light chains.

IBMTR (EBMT) Response Criteria:

Complete response requires all of the following:

  • No serum/urine M protein by immunofixation electrophoresis for > 6 weeks

  • < 5% plasma cells in bone marrow aspirate

  • No increase in the size or number of lytic bone lesions

  • Disappearance of soft-tissue plasmacytomas.

Partial response requires all of the following:

  • > 50% reduction in serum M protein > 6 weeks

  • ≥ 90% reduction in 24-hr urinary light chain excretion

  • ≥ 50% reduction in soft-tissue plasmacytomas

  • No increase in the size or number of lytic bone lesions.

Treatment

Exciting advances in the understanding of tumor biology and microenvironment-and their potential interaction-have helped to identify unique targets for rational therapeutic intervention to enhance outcome, which has not improved with conventional chemotherapy over the past 3 decades. Until recently, only 5%–10% of patients with multiple myeloma lived longer than 10 years, and cure remains elusive.

NEWLY DIAGNOSED PATIENTS

Chemotherapy

Dexamethasone/thalidomide Thalidomide (Thalomid) has been employed alone and in combination with dexamethasone as initial therapy in newly diagnosed patients. When employed alone, response (50% reduction in paraprotein) was observed in 36% of patients; when it was used along with dexamethasone, the response rate was higher (72% and 64% in two studies), including a 16% complete response rate in one study. The results of a randomized Eastern Cooperative Oncology Group (ECOG) trial showed that the combination of thalidomide and dexamethasone was superior to dexamethasone alone (63% vs 41%; P = .001) and comparable to VAD (vincristine, Adriamycin [doxorubicin], and dexamethasone). This combination does not damage stem cells and allows adequate stem-cell collection. A definite increase in thrombotic episodes has been observed with this combination, prompting prophylactic administration of aspirin, coumadin, or low molecular weight heparin.

VAD or VDD (vincristine, liposomal doxorubicin [Doxil], and dexamethasone) regimens spare stem cells and do not impair stem-cell collection (Table 4). Such regimens produced a response rate of approximately 45–55% in untreated patients, without improvement in overall survival over MP (melphalan [Alkeran] and prednisone). Responses occurred more rapidly with VAD-based regimens than with MP; these rapid responses may provide an advantage in patients with hypercalcemia, renal failure, or severe bone pain. No dosage adjustment is necessary for renal failure. Use of this combination has decreased since the introduction of dexamethasone/thalidomide and other combinations due to the need for a central line, the inconvenience of IV administration, and attendant toxicities.

Pulse dexamethasone alone has also been used in older patients and patients who need ver­te­bral radiotherapy for spinal cord compression or for painful vertebral com­pressions, as this approach avoids severe myelosuppression (Table 4).

MP The combination of melphalan and prednisone has been used over the past 30 years, and other combinations of multiple alkylating agents have not been found to be superior to MP. A meta-analysis of 18 published randomized trials comparing MP with other combination regimens arrived at the same conclusion. Approxi­mately 40% of patients have responded to the MP regimen, with a median remis­sion duration of 18 months and an overall ­median survival of 3 years. The MP regimen should be avoided in patients considered to be transplant candidates.

MP and thalidomide (MPT) In a prospective, randomized trial in patients older than age 65, MPT produced an overall response rate of 78%, including a 28% rate of near complete response, compared with a response rate of 44% and a near complete response rate of 5% with MP. MPT offers a possible alternative for older people who generally are not candidates for high-dose therapy.

Melphalan and other alkylating agents damage bone marrow stem cells, affecting the ability to mobilize an adequate number of cells for high dose-therapy. Extensive use of alkylating agents may also predispose patients to the subsequent development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). These limitations have now substantially reduced the use of MP in newly diagnosed patients.

High-dose therapy following induction

High-dose therapy employed after induction therapy improves the response rate as well as event-free and overall survival. The impressive improvement in event-free (median, 28 vs 18 months) and overall survival (57 vs 42 months) reported in a randomized trial (IFM 90) has been confirmed by another large randomized trial (median overall survival, 54.8 vs 42.3 months; MRC VII). Most of these studies enrolled patients < 65 years old. Older individuals (< age 70) may tolerate high-dose therapy with peripheral stem-cell support well, without excess mortality. Moreover, outcome, in terms of event-free and overall survival, is comparable to that in matched cohorts < 65 years old, making older individuals (≥ 65 years old) also candidates for high-dose therapy. More recently, older patients (> age 70) receiving intermediate-dose melphalan (100 mg/m2) with stem-cell support have been shown to have a better outcome than matched controls receiving conventional therapy.

A high-dose alkylating agent, most commonly melphalan at 200 mg/m2 with peripheral blood stem-cell support, is a standard conditioning regimen. Addition of total-body irradiation (TBI) does not improve the outcome but increases morbidity and results in higher mortality. Interestingly, in a randomized study, Fermand et al have confirmed an equivalent survival benefit between up-front high-dose therapy vs high-dose therapy as a salvage regimen at relapse following initial induction therapy.

Tandem transplants Improved outcome reported after tandem transplants in large cohorts of patients in single-institution studies has been confirmed in a mature randomized study. Seven years after initiation of therapy, the event-free (42% vs 21%) and overall survival (20% vs 10%) rates were superior for patients receiving tandem transplants (IFM 94). Another randomized trial with a shorter follow-up has confirmed the superior event-free survival (median, 34 vs 25 months) for patients receiving tandem transplants. However, the added benefit of the second transplant was not seen in a subset of patients with a complete response or a very good partial response (> 90% paraprotein reduction) after the first transplant.

Radiotherapy

Higher doses of radiotherapy (40–50 Gy) are employed for local control and cure of solitary plasmacytoma involving bone and extramedullary sites. Lower doses (20–30 Gy) may be employed for palliation of local bone pain from tumor infiltration, pathologic fractures, and spinal cord compression. It should be emphasized that excellent pain relief may be obtained by prompt institution of high-dose corticosteroid therapy, especially in newly diagnosed patients.

Radiotherapy should be ­employed sparingly, as irradiation of multiple sites may impair stem-cell mobilization in patients who are candidates for high-dose therapy. Employment of high doses of radiation to the spine may preclude the subsequent use of TBI as a conditioning regimen for high-dose therapy.

REMISSION MAINTENANCEAlkylating agents Maintenance therapy with alkylating agents has not prolonged survival, compared with no maintenance therapy. This approach is no longer recommended.

Steroids for maintenance
Two large randomized trials have shown glucocorticoid maintenance prolongs the duration of remission and life expectancy. The first trial by the Southwest Oncology Group (SWOG) used prednisone (50 mg) every other day, whereas the maintenance regimen in the National Cancer Institute (NCI)-Canada trial contained dexamethasone (40 mg) daily for 4 days every 4 weeks.

Thalidomide Patients responding to thalidomide and achieving maximal response have received lower dose thalidomide (50–100 mg) with or without added dexamethasone (40 mg for 4 days every month) as maintenance therapy. In the MPT regimen, continued administration of thalidomide prolongs the duration of remission. The IFM 99-06 study evaluated maintenance therapy with thalidomide plus pamidronate compared with pamidronate alone compared with observation only following tandem autologous transplantation. Superior event-free survival (EFS) and overall survival were reported in the cohort receiving thalidomide plus pamidronate.

α-Interferon Twenty-four randomized trials have investigated α-interferon as maintenance therapy and reported no consistent significant benefit. A recent larger intergroup trial also reported no benefit of interferon maintenance therapy after conventional therapy and autotransplantation.

Novel agents Bortezomib is currently under study as a maintenance strategy. In the APEX study, bortezomib administered weekly proved efficacious and was well tolerated in responding patients who had successfully completed initial treatment. Lenalidomide is also under study as maintenance post-transplant, given at a low dose (10 mg/d).

REFRACTORY OR RELAPSING DISEASE

Approximately 10%–30% of patients with newly diagnosed multiple myeloma are unresponsive to che­motherapy. Moreover, virtually all patients who respond initially will relapse. Of patients who relapse after an unmaintained remission, approximately 60% achieve a second remission or stable disease with resump­tion of the original therapy.

Conventional chemotherapy

Alkylating agents, alone or in combination, have been effective in approximately one-third of patients with VAD-refractory disease. IV melphalan (70–100 mg/m2) and the combination of high-dose cyclophos­pha­mide and etoposide are two examples of such regimens (Table 4).

Thalidomide has an established role in therapy for refractory/relapsed multiple myeloma, with 30% of patients achieving at least 50% reduction in paraprotein levels. Remissions obtained are durable: In a large cohort of patients with multiple myeloma receiving thalidomide, 2-year event-free survival rates of ~25% have been observed. Initially, thalidomide was employed in a dose-escalating schedule, starting at 200 mg and achieving a maximal dose of 800 mg. Recently, lower doses have been employed in combination with steroids (Table 4).

High-dose chemotherapy High-dose melphalan and stem-cell rescue should be offered to patients who have deferred the transplant initially. A randomized trial on early vs late transplantation has shown that a survival benefit is conferred on the patients undergoing salvage transplantation.

Novel agents

Lenalidomide (Revlimid, also known as CC-5013) is a small molecule, thalidomide analog with immunomodulatory effects. It has greater potency than thalidomide in preclinical studies and is better tolerated, with less neurotoxicity, somnolence, or constipation. In a phase II trial, lenalidomide (30 mg daily for 3 weeks on and 1 week off) induced minimal responses or better in 25% of patients with relapsed or refractory myeloma. The addition of dexamethasone in 68 patients who either progressed or remained stable on lenalidomide monotherapy resulted in additional response in 29%.

Two large multicenter phase III trials of lenalidomide with dexamethasone compared with dexamethasone and placebo in relapsed multiple myeloma have demonstrated a significant improvement in response rate (partial response, 59% vs 21%, respectively) and time to disease progression (11.1 vs 4.7 months, respectively) in the cohort receiving the lenalidomide combination in one study and almost identical results in the second study. Deep vein thrombosis was a significant complication of this combination, occurring in approximately 15% of patients.

ProblemTherapy

Chronic anemia (especially with renal impairment)Erythropoietin
Prolonged neutropenia with infectionG-CSF
Recurrent infections with IgG < 400 mg/dLGamma globulin
OsteoporosisBisphosphonates

 

Proteasome inhibition Bortezomib (Velcade, PS-341) is a first-in-class, potent, selective, and reversible small molecule inhibitor of the proteasome. The proteasome plays a key role in the degradation of ubiquinated proteins, which in turn have important functions in controlling tumor cell growth and survival both in vitro and in vivo.

A large multi-institution phase II trial of bortezomib (given IV at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days) demonstrated remarkable activity in a heavily treated, relapsed and refractory patient population, including patients in whom transplantation failed and patients not responding to thalidomide, with durable responses in about 35% receiving bortezomib alone (with a number of complete responses). Side effects related to the drug were predominantly gastrointestinal in nature, with neuropathy, fatigue, and reversible cytopenias also noted. Toxicities were generally manageable with supportive care and dose reduction. Patients who did not respond to bortezomib monotherapy (progressive disease after 2 cycles or stable disease after the first 4 cycles) were permitted to receive combination bortezomib and dexamethasone. Combination therapy induced additional responses in 18% of patients (13 of 74).

The results of a large, randomized phase III trial of bortezomib monotherapy compared with high-dose dexamethasone enrolled 669 patients with relapsed multiple myeloma and showed significant improvement in the median time to disease progression (5.7 vs 3.6 months, respectively; P < .0001) and median overall survival (29.8 vs 23.7 months, respectively; P = .027). Response rates to bortezomib as a single agent were impressive at 38%. The most commonly reported adverse events for bortezomib were gastrointestinal events, fatigue, pyrexia, and thrombocytopenia; for dexamethasone, they were fatigue, insomnia, and anemia.

Clinical studies are ongoing with bortezomib in combination with pegylated liposomal doxorubicin, thalidomide, melphalan, and lenalidomide, and have shown impressive disease control in refractory myeloma. In patients with relapsed or refractory multiple myeloma, the objective response rate for bortezomib plus pegylated liposomal doxorubicin (30 mg/m2 on day 4) in a phase I dose-escalation study was 77%. When bortezomib (1.0 or 1.3 mg/m2) was administered with thalidomide (in doses ranging from 50 to 200 mg starting at cycle 2), 86% of patients with relapsed or refractory disease achieved a complete or partial response. A phase I trial combining bortezomib with lenalidomide has recently been completed and results have revealed less neuropathy than that seen with thalidomide. Remarkable activity has been reported with approximately 60% of patients achieving response despite having received multiple prior therapies, including both agents separately before study entry.

Arsenic trioxide (Trisenox), administered as a daily IV infusion dosed at 0.15 mg/kg in a phase II study, has shown response in 3 of 14 patients with relapsed refractory disease. Adverse effects included cytopenia requiring G-CSF (granulocyte colony-stimulating factor, filgrastim, Neupogen) support. Based on preclinical data suggesting synergism between arsenic trioxide, dexamethasone, and ascorbic acid, a phase II evaluation of this combination is in progress, as are studies with melphalan.

Allogeneic transplantation For younger patients with resistant relapse or poor-prognosis disease (ie, deletion of chromosome 13), allogeneic transplantation may be an important option. However, high treatment-related mortality (30%–50%) with myeloablative allogeneic ­transplantation has discouraged the use of allografts in early-phase myeloma. New nonmyeloablative transplantation procedures that reduce mortality and exploit a graft-vs-tumor effect are being studied. In one study, 34 patients, including patients with relapsed or refractory ­disease, received melphalan at 200 mg/m2 with autografting and then (40–120 days later) received allograft after nonmyeloablative ­conditioning. Treatment-related mortality at day 100 was 6%, with 53% of patients achieving complete response. With a median follow-up of 328 days after allografting, the overall survival rate was 81%, but chronic graft-vs-host ­disease ­remains a major challenge, occurring in up to two-thirds of patients.

Supportive therapies

Various supportive therapies may be ben­eficial in patients with multiple myeloma (Table 5).

Chronic anemia Patients with chronic symptomatic anemia may benefit from a trial of epoetin alfa (Epogen, Procrit), 40,000 U given by SC injection once weekly. Darbepoetin alfa (Aranesp), dosed at 200 to 300 µg by SC injection every 2 to 3 weeks, is an alternative approach.

Infection Serious infection with encapsulated organisms is encountered by patients with myeloma due to their inability to mount successful antibody production (and lack of opsonization). Prompt institution of antibiotics is therefore recommended in the face of systemic infection. Antibiotic prophylaxis is also recommended whenever high-dose glucocorticoids are used for treatment. Patients with recurrent serious infections may benefit from monthly gamma globulin. Shingles is not uncommon in these patients, and prophylaxis following transplantation and during bortezomib therapy is advised.

Bone pain or imminent fracture Therapy with bisphosphonates, such as pamidronate, alendronate (Fosamax), or zoledronic acid (Zometa), may prevent or delay bone pain or recurrent or imminent pathologic fracture in patients with stage III disease and at least one bone lesion. Pamidronate administered over the long term (21 monthly treatments) to patients with stage III multiple myeloma with at least one lytic lesion has been shown to reduce skeletal events and decrease the need for irradiation. Moreover, patients without lytic lesions also show a decrease in bone mineral density, and this decrease persists despite chemotherapy. These patients may also benefit from therapy with pamidronate. Several clinical and preclinical studies suggest that pamidronate may have an antimyeloma effect.

Zoledronic acid, a more potent bisphosphonate, has comparable efficacy and safety to pamidronate in treatment of skeletal lesions. The ease of administration of a 4-mg dose, which reduces the infusion time to 15 minutes compared with 2 hours for pamidronate, has led to approval of zoledronic acid by the US Food and Drug Administration (FDA) for prevention of bone-related complications in myeloma. Caution should be exercised with long-term use of bisphosphonates, as renal impairment and osteonecrosis of the jaw bones have been reported.

Percutaneous vertebroplasty provides pain relief that is not only rapid but sustained, and it also strengthens the vertebral bodies. Kyphoplasty is a safer procedure that involves insertion of a balloon followed by injection of polymethyl methacrylate, the principal component of bone cement, in the balloon. It is performed with the patient under local anesthesia. Transient worsening of pain and fever may occur and is responsive to nonsteroidal anti-inflammatory agents.

Smoldering myeloma

Smoldering myeloma is an asymptomtic plasma cell dyscrasia that is diagnosed by the chance finding of an elevated serum protein concentra­tion during a screening examination.

Laboratory features Features of low tumor mass are usually present, without renal disease, hypercalcemia, or lytic bone lesions (Table 2). Marrow plasma cytosis occurs in less than 30% of patients, and anemia, if present, is mild (hemoglobin value > 10.5 g/dL).

Treatment Chemotherapy should be withheld until there is clear disease progression or a risk of a complication. The role of bisphosphonates and thalidomide in this setting is under investigation.

Prognostic factors Recent studies have helped define prognostic criteria for groups at high risk of early disease progression (eg, cytogenetic changes [especially chromosome 13], labeling index of plasma cells [> 0.4%], β2M levels [4 mg/L], and diffuse disease activity or multiple focal lesions on MRI evaluation). Such criteria, along with the presence of lytic lesions, serum ­myeloma protein > 5 g/dL, and Bence Jones protein > 500 mg/24 h, identify patients at high risk of disease progression, in whom the early commencement of chemotherapy may be beneficial.

OTHER PLASMA CELL DYSCRASIAS

Other plasma cell dyscrasias include MGUS, solitary plasmacytoma of bone (SPB), solitary extramedullary plasmacytoma, Waldenstrm’s macroglobulinemia, amyloidosis, POEMS ­(polyneuropathy, organomegaly, endocrino­pathy, monoclonal gammopathy, and skin changes) syndrome, and heavy-chain diseases.

Monoclonal gammopathy of unknown ­significance

MGUS occurs in 1% of normal individuals > 40 years old, and its frequency rises pro­gres­sively with age.

Laboratory features Common laboratory features of MGUS are listed in Table 2.

Treatment Approximately 25% of patients with this disorder develop multiple myeloma, macroglobulinemia, or non-Hodgkin lymphoma over 20 years. The initial concentration of serum monoclonal protein > 1.5 g/dL, non-IgG-type paraprotein, and abnormal serum free light chain ratio are significant predictors of disease progression at 20 years. The long period of stability supports annual monitor­ing with serum electrophoresis and blood counts and suggests that chemo­therapy may be withheld until there is evidence of a serious ­disorder.

Solitary plasmacytoma of bone

Approximately 3% of patients with myeloma have SPB.

Laboratory features All patients have either no myeloma pro­tein or very low levels in serum or urine (Table 2). MRI may reveal abnor­malities not detected by bone survey and may upstage patients to mul­tiple myeloma. Persistence of monoclonal protein for more than 1 year after irradiation predicts early progression to multiple myeloma.

Treatment of SPB consists of radiation therapy (at least 45 Gy). Multiple myeloma becomes evident in most patients over time, so only 20% of patients re­main free of disease for more than 10 years. The median time for disease progression is 2–3 years.

Solitary extramedullary plasmacytoma

In contrast to SPB, solitary extramedullary plasmacytoma is often truly localized and can be cured in up to 50% of patients with localized radiation therapy (45–50 Gy) and/or resection.

Waldenstrm’s macroglobulinemia

This uncommon disease is characterized by lymphoplasmacytic bone marrow and tissue infiltrate in addition to elevated IgM production. The mutation pattern analysis suggests that final transformation occurs in the postgerminal center IgM memory B cell. Corresponding with variation in cell morphology, there is variation in the immunophenotype. Mature plasma cells exhibit CD38 antigen; however, lymphoid cells are typically CD19, CD20, CD22, and FMC7 positive.

Waldenstrm’s macroglobulinemia usually af­fects people in the fifth to seventh decades of life and can cause symptoms due to tumor infiltration (marrow, lymph nodes, and/or spleen), circulating IgM (hyperviscosity, cryoglobulinemia, and/or cold agglutinin hemolytic anemia), and tissue deposition of IgM (neuropathy, glomerular disease, and/or ­amyloidosis).

Hyperviscosity syndrome With hyperviscosity syndrome, patients may have visual symptoms, dizziness, cardiopulmonary symptoms, decreased consciousness, and a bleeding diathesis. Neuropathy is usually due to an IgM antibody reacting with a myelin-associated glycoprotein (MAG).

Therapy for hyperviscosity consists of plasmapheresis followed by chemo­therapy to control the malignant proliferation. Patients with poor performance status and elderly patients unable to tolerate chemotherapy may be maintained with periodic plasmapheresis.

Treatment Alkylating agents in combination with steroids or purine analogs remain the mainstay of therapy. Alkylating agents alone or in combination with steroids effect a 50% reduction in paraprotein in about half of patients, and the median survival time is around 5 years. The purine analogs fludarabine and cladribine (2-CdA) elicit a more rapid response than other agents, with a response rate of more than 75% observed in small series of patients. Preliminary results of a large, American multi-institution evaluation of fludarabine reported partial responses in only 33% of patients.

Purine analog therapy may result in significant myelosuppression in later cycles of therapy and prolonged immunosuppression with increased opportunistic infections. Purine analogs are effective salvage options in patients refractory to or relapsing following alkylator therapy. Patients refractory to one purine analog are rarely salvaged by a different purine analog. Patients with resistant relapse are less likely to benefit (response rate, 18%) and should be considered for more intensive intervention, including high-dose therapy.

Other treatment options Rituximab (Rituxan), an anti-CD20 monoclonal antibody, is effective in Waldenstrm’s macroglobulinemia because the CD20 antigen is usually present on the lymphoid cell component of macroglobulinemia. Preliminary results indicate that about 30% of previously treated patients (refractory or relapsing off therapy) may benefit from rituximab.

Striking activity of thalidomide in multiple myeloma has prompted its use in Waldenstrm’s macroglobulinemia. In a series of 20 patients receiving thalidomide, 25% achieved a 50% reduction in paraprotein. Higher doses of thalidomide were not well tolerated in an elderly cohort of patients. Interestingly, preliminary results of bortezomib-based therapy in relapsed Waldenstrm’s macroglobulinemia have been promising.

High-dose therapy with autologous bone marrow or blood stem-cell rescue has been effective in achieving 50% reduction in paraprotein in almost all patients in small pilot trials.

Amyloidosis

Amyloidosis occurs in 10% of patients with multiple myeloma. This infiltra­tive proc­ess results from organ deposition of amyloid fibrils, which consist of the NH2 terminal amino acid residues of the variable portion of the light-chain immu­noglobulin molecule. The abnormal protein is produced by clo­nal plasma cells.

Clinical features include the nephrotic syndrome, cardiomyopathy, hepa­tomegaly, neuropathy, macroglossia, carpal tunnel syndrome, and ­periorbi­tal purpura.

Laboratory features Serum and urine immunofixation studies show a monoclonal immunoglobulin in approximately 80% of patients. The light chain is more frequently of the λ than κ type. Diagnosis can be made by the presence of apple-green birefringence on polarized light examination of sub­cutaneous fat aspirates stained with Congo red.

Treatment of AL (monoclonal protein–associated) amyloidosis Survival of patients with amyloidosis is variable. Patients with congestive heart failure have a median survival of only 4 months. Oral MP extends the median survival to 17 months, compared with 13 months in untreated patients. Complete hematologic response is rare; similarly, reversal of organ damage is uncommon.

In a large cohort of patients receiving high-dose melphalan with stem-cell support, a complete hematologic response was observed in 47% of patients with at least 1 year of follow-up. However, the transplant-related mortality is high with high-dose therapy (14%–37%). Complete hematologic response was associated with improved clinical response (improved organ function) and survival. Complete hematologic response in the absence of cardiac involvement predicted excellent outcome (1-year survival, 91%).

Patients with the overlap syndrome of myeloma and AL amyloidosis should be treated aggressively for myeloma; response can be seen in terms of both myeloma and resolution of amyloid symptoms.

POEMS syndrome

Clinical features and course The POEMS syndrome is a rare plasma cell dyscrasia that presents with peripheral, usually sensorimotor, neuropathy; monoclonal gammopathy (IgA λ being more common); sclerotic bone le­sions, noted in nearly all patients; and organomegaly, endocrinopathy, and skin changes.

Other features include hyperpigmentation, hypertrichosis, thickened skin, papilledema, lymphadenopathy, peripheral edema, hepatomegaly, spleno­megaly, and hypothyroidism. Diabetes mellitus is not part of this syndrome.

Compared with patients with symptomatic myeloma, individuals with POEMS syndrome are younger (median age, 51 years) and live longer ­(median, 8 years). The clinical course is commonly characterized by progressive ­neuropathy.

Treatment Plasmapheresis does not appear to be of benefit in POEMS syndrome, and patients are often treated similarly to those with myeloma. Patients presenting with isolated sclerotic lesions may have substantial resolution of neuropathic symptoms after local therapy for plasmacytoma with surgery and/or radiotherapy. Autologous SCT has been pursued in selected patients and has been associated with prolonged progression-free survival.

Heavy-chain diseases

Heavy-chain diseases are plasma cell dyscrasias characterized by the produc­tion of heavy-chain immunoglobulin molecules (IgG, IgA, IgM) that lack light chains.

α Heavy-chain disease results from lymphocyte and plasma cell infiltration of the mesenteric nodes and small bowel and has features of malabsorption, such as diarrhea, weight loss, abdominal pain, edema, and nail clubbing. The heavy-chain molecule may be detected in serum, jejunal secretions, and urine.

γ Heavy-chain disease Patients with γ heavy-chain disease may present with fever, weakness, lymphadenopathy, hepatosplenomegaly, and involvement of Waldeyer’s ring. Eosinophilia, leukopenia, and thrombocy­to­penia are common. Treatment with regimens similar to those used for non-Hodgkin lymphoma may be effective.

µ Heavy-chain disease is seen exclusively in patients with chronic lym­phocytic leukemia (CLL). Vacuolated plasma cells are common in the mar­row, and many patients have κ light chains in the urine. Therapy is simi­lar to that used for CLL (see chapter 34).

 

SUGGESTED READING

ON MULTIPLE MYELOMA Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495–2502, 2003.

Badros A, Barlogie B, Morris C, et al: High response rate in refractory and poor-risk multiple myeloma after allo-transplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 97:2574–2579, 2001.

Barlogie B, Desikan R, Eddlemon P, et al: Extended survival in advanced and refractory myeloma after single-agent thalidomide: Identification of prognostic factors in a phase II study of 169 patients. Blood 98:492–494, 2001.

Berenson JR, Crowley JJ, Grogan TM, et al: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99:3163–3168, 2002.

Facon T, Avet-Losieau H, Guillerm G, et al: Chromosome 13 abnormalities identified by FISH analysis and serum b2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97:1566–1571, 2001.

Fermand JP, Ravaud P, Chevret S, et al: High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131–3136, 1998.

Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076, 2001.

Jagannath S, Durie BG, Wolf J, et al: Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776–783, 2005.

Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 351:1860–1873, 2004.

Munshi NC, Hideshima T, Carrasco D, et al: Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood 103:1799–1806, 2004.

Rajkumar SV, Blood E, Vesole D, et al: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431–436, 2006.

Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatory derivative of thalidomide CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100:3063–3067, 2002.

Richardson PG, Sonneveld P, Schuster MW, et al, for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005.

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ON OTHER PLASMA CELL DYSCRASIAS Dhodapkar MV, Jacobson JL, Gertz MA, et al: Prognostic factors and response to fludarabine therapy in Waldenstrm’s macroglobulinemia: Results of US intergroup trial (Southwest Oncology Group S9003). Blood 98:41–48, 2001.

Dimopoulos MA, Zomas A, Viniou NA, et al: Treatment of Waldenstrm’s macroglobulinemia with thalidomide. J Clin Oncol 19:3596–3601, 2001.

Sanchorawala V, Wright DG, Seldin DC, et al: An overview of the use of high-dose melphalan with autologous stem-cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant 28:637–642, 2001.

Weber D, Treon SP, et al: Uniform response criteria in Waldenstrom’s macroglobulinemia: Consensus panel recommendations for the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30:127–131, 2003.