Fludarabine is now considered the single most active agent in the

treatment of CLL. Fludarabine monotherapy at a dose range of

25 to 30 mg/m2

/dose IV × 5 days has shown a 70% to 80% OR

rate, and CR rates of 20% to 30% with increased progressionfree survival (PFS).94–96 Fludarabine may have improved OS

compared with chlorambucil, but results are inconsistent across

studies.97–99 Toxicities associated with fludarabine are typically

mild and include fever and immunosuppression. Increased incidence of infection and autoimmune hemolytic anemia are also

associated with fludarabine therapy. Infection prophylaxis should

be considered in elderly patients and patients with advanced disease or renal dysfunction.

Fludarabine has been combined with other chemotherapy

and monoclonal antibodies, including cyclophosphamide and rituximab, in an effort to prevent multidrug resistance and increase

response. Although combination regimens including fludarabine

have demonstrated higher response rates and PFS, no difference in OS has been consistently demonstrated.100–102 Additional

toxicities of the combination regimens include higher rates of

leukopenia, thrombocytopenia, nausea, vomiting, and alopecia.

CLADRIBINE

The response to cladribine, a synthetic purine nucleoside, is superior to chlorambucil, with OR and CR rates comparable to singleagent fludarabine.103 A typical dose and schedule is 0.14 mg/

/kg/day IV over 2 hours for 5 days every 28 days for 3 to 6

cycles. The toxicity profile is similar to fludarabine. Although

cladribine in combination with cyclophosphamide with or without mitoxantrone achieved higher CR rates and less multidrugresistant clones, no significant improvement in OS has been

demonstrated.104 A higher percentage of grade 3 to grade 4 neutropenia was seen with the combination regimens compared

with cladribine alone.

BENDAMUSTINE

Bendamustine, a nitrogen mustard/alkylating agent, was

approved in 2008 for the treatment of CLL. In clinical studies

it has been shown to be superior to chlorambucil with OR and

CR rates of 68% and 31%, respectively.105 A typical dose and

schedule is 100 mg/m2 IV on days 1 and 2. Toxicities include

infusion reactions and myelosuppression. It is often used in combination with rituximab and primarily in patients older than or

equal to 70 years or those with comorbidities.

RITUXIMAB

Rituximab is a chimeric human–murine anti-CD20 monoclonal

antibody. The CD20 surface antigen is expressed on a high percentage of CLL cells. Rituximab monotherapy as initial therapy

for untreated patients at a dose of 375 mg/m2 weekly for four

doses yielded OR rates of 58% and CR rates of 9%; these are

lower than those seen with cytotoxic therapy, with a disappointing duration of response.106 Therefore, rituximab monotherapy

is reserved for patients with significant comorbidity. Generally it

is used in combination therapy with cytotoxic agents.

COMBINATION REGIMENS

A regimen for initial treatment is the combination of FCR. In

a study of first-line treatment of CLL, patients were treated

with fludarabine 25 mg/m2 IV on days 1 to 3, cyclophosphamide

250 mg/m2 IV on days 1 to 3, and rituximab 375 mg/m2 IV on

day 1 of cycle 1, escalated to 500 mg/m2 in subsequent cycles. CR

was attained by 44% of patients, OR in 90%.101 Toxicity of this

regimen included infusion-related reactions, nausea, vomiting,

and myelosuppression. Grade 3 or 4 neutropenia was noted in

34% of treatment courses, with an infection rate of 25%. FCR

is recommended in patients younger than 70 years without significant comorbidities or older patients without comorbidities,

and in any patient with the unfavorable del(17p) cytogenetic

abnormality.93

Results for a bendamustine plus rituximab (BR) combination

regimen have recently been reported. In a study of 117 patients

with previously untreated CLL, patients were given bendamustine 90 mg/m2 IV on days 1 and 2, and rituximab 375 mg/m2

IV on day 1 of cycle 1, escalated to 500 mg/m2 in subsequent

cycles for up to 6 cycles. OR was 90% and CR 33%.107 Trials

are ongoing to compare this combination with FCR as first-line

therapy for CLL patients who are able to tolerate combination

chemotherapy. The BR regimen, like chlorambucil with or without prednisone, is commonly used in patients older than or equal

to 70 years or in younger patients with comorbidities.

ALEMTUZUMAB

Alemtuzumab is a humanized conjugated anti-CD52 monoclonal antibody and a first-line treatment option for CLL.93 Initial

doses of 3 mg, titrated to 10 mg, and, ultimately, 30 mg, were

administered either subcutaneously or IV three times weekly for

up to 12 weeks. In comparison with chlorambucil, alemtuzumab

had a CR rate of 24% versus 2% with chlorambucil. However, there was no difference in OS.108 Toxicities associated with

alemtuzumab include infusion-related reactions (rigors, fever,

dyspnea), neutropenia, and infectious complications.109,110

Alemtuzumab is usually given to older patients or those with

comorbidities. The role of alemtuzumab maintenance after cytotoxic therapy is also under investigation.111

In summary, first-line therapy for patients older than or

equal to 70 years old or with significant comorbidities generally includes BR, or chlorambucil plus prednisone. For younger

patients without comorbidities, three-drug combinations such as

FCR may be offered. G.R. is now 68 years old with no significant

comorbidities and is likely to tolerate treatment with FCR.

CASE 92-4, QUESTION 4: G.R. receives FCR as initial CLL

therapy. After the third cycle, he has complete regression

of his lymphadenopathy and hepatosplenomegaly, and his

WBC count decreases to 9,000 cells/μL. He finishes six cycles

in total. G.R. comes to clinic 1.5 years after completion of

therapy. A CBC is obtained that reveals a WBC count of

55,000 cells/μL (70% lymphocytes), Hgb of 10 g/dL, and

platelet count of 90,000 cells/μL. On physical examination,

G.R. is found to have cervical, inguinal, and axillary lymphadenopathy with no palpable splenomegaly. He complains of excessive fatigue and fever. Therefore, G.R. has

recurrent disease. What therapies may be helpful to him at

this point?

RELAPSED OR REFRACTORY THERAPY

Second-line therapy should be selected based on criteria similar to those used for initial management. Relapsed patients are

classified as treatment-sensitive if the disease relapses more than

3 years after treatment, or refractory if the disease relapses within

2185Adult Hematologic Malignancies Chapter 92

2 years of treatment.93 G.R.’s relapse occurred less than 2 years

from completion of therapy. He is classified as refractory to his

first-line regimen. He is still younger than 70 years old with minimal comorbidities and is a candidate for aggressive second-line

treatment.

TREATMENT-SENSITIVE

Treatment-sensitive patients are retreated with the same regimen given for first-line therapy as long as they are expected to

tolerate treatment. For patients who are older than 70 years old

or those who have comorbidities, the regimen may be changed

to one with less toxicity. These less toxic regimens include

dose-reduced FCR, chlorambucil-prednisone, BR, single-agent

alemtuzumab, single-agent rituximab, or cyclophosphamideprednisone-rituximab.93

TREATMENT-REFRACTORY

Treatment-refractory patients will be offered a regimen containing at least one anticancer agent not previously given.

For patients older than 70 years old with comorbidities,

options include chemoimmunotherapy combinations: dosereduced FCR, dose-reduced pentostatin-cyclophosphamiderituximab, chlorambucil-prednisone, BR, and high-dose

methylprednisolone-rituximab. Other options are alemtuzumab,

ofatumumab, and dose-dense rituximab. Patients younger than

70 years old without significant comorbidities have several

options, including combination chemotherapy, chemoimmunotherapy, and monoclonal antibodies and consideration of

allogeneic HCT.93,112

Alemtuzumab as a single agent is FDA-approved for the treatment of refractory CLL and may be used regardless of age and

presence of comorbidities.113 The OR rate is approximately 30%,

with a 0% to 2% CR rate and an OS of 16 to 27.5 months.114,115

Activity has been demonstrated in patients who relapsed after or

were refractory to alkylator or purine analog therapy, including

those with the del(17p) cytogenetic mutation, which is associated with resistance to most cytotoxic agents.113 Alemtuzumab

is least effective in patients with bulky (>5 cm) disease.116

Major toxicities of alemtuzumab include infusion-related

events, infections, and cytopenias. The occurrence of opportunistic infections, including Pneumocystis carinii [now P. jiroveci]

pneumonia and cytomegalovirus (CMV) in as many as 15% to

25% of patients treated with alemtuzumab, warrants the use

of prophylactic therapy. An increased risk of infection occurs

3 to 8 weeks after treatment, which corresponds to the T-cell

nadir. Viral prophylaxis for herpes infections (e.g., acyclovir or

equivalent) should be continued for at least 2 months after completion of therapy, and P. jiroveci pneumonia prophylaxis (e.g.,

sulfamethoxazole-trimethoprim) should be continued until the

CD4 count is at least 200 cells/μL.117,118

Younger patients with relapsed disease or high-risk features

may benefit from allogeneic HCT. Both clinical and molecular

remissions have been reported after autologous HCT, with a

4-year survival of 42%.119 Allogeneic HCT is the only curative

treatment for CLL to date. However, the high risk of treatmentrelated morbidity and mortality must be considered. Patients

with relapsed CLL after fludarabine therapy or with high-risk

features should be referred to a transplant center to determine

candidacy.112

In conclusion, G.R.’s disease relapsed within 18 months of

completing initial therapy and is treatment refractory; therefore,

he should receive a second-line regimen, which includes an agent

he has not been previously exposed to. G.R. received FCR as his

initial treatment; therefore, the BR regimen is a good choice for

him now. In addition, he is younger and in relatively good health

and should tolerate combination therapy.

Infectious Complications

CASE 92-4, QUESTION 5: Six weeks after the initiation

of alemtuzumab, G.R. complains of progressive shortness

of breath and fever. On questioning, he reveals that he

quit taking his trimethoprim-sulfamethoxazole and valacyclovir because “I felt fine.” Radiography of the chest reveals

bilateral infiltrates. G.R. is admitted to the hospital for

further evaluation and treatment. A CBC reveals a WBC

count of 22,000 cells/μL (80% lymphocytes) and an absolute neutrophil count of 800 cells/μL, Hgb of 11 g/dL, and

platelet count of 70,000 cells/μL. Quantification of serum

immunoglobulins reveals profound hypogammaglobulinemia. What are the possible causes of G.R.’s pneumonia,

and what treatment is indicated?

Infections contribute significantly to morbidity and mortality in patients with CLL. The immune compromise of CLL is

attributable to immunoglobulin deficiency, abnormal T-cell function, neutropenia and chemotherapy, which contribute to the

increased rate of both common and opportunistic infections.120

Up to 80% of patients will develop an infectious complication; therefore, the use of IV immune globulin, antibacterials

(trimethoprim-sulfamethoxazole), and antivirals (acyclovir for

herpes simplex virus) and vaccinations (influenza, pneumococcal, live vaccines) are common. Opportunistic infections are particularly common in patients receiving a purine analog or alemtuzumab therapy, and ganciclovir prophylaxis may be given. The

most commonly reported opportunistic infection associated with

alemtuzumab is CMV reactivation. The use of supplemental IV

immune globulin for prophylaxis of future infection is often used

in patients with low immunoglobulin levels (IgG <500 mg/dL)

and recurrent infections requiring hospitalization.113

For a table titled “Types of infections in

patients with chronic lymphocytic leukemia

undergoing immunosuppressive therapy,” go

to http://thepoint.lww.com/AT10e.

Hospitalization is warranted for G.R. so he can receive broadspectrum antimicrobials for neutropenic fever and a thorough

workup for opportunistic etiologies. Because G.R. has a significant pulmonary infection requiring hospitalization with a documented hypogammaglobulinemia, prophylactic IV immune

globulin therapy should be considered to prevent future infections.

MULTIPLE MYELOMA

Incidence and Epidemiology

Multiple myeloma (MM) is defined as a malignancy of “plasma

cells,” terminally differentiated B lymphocytes responsible for

the production of antibodies and for the rapid response of the

immune system to antigen exposure.121,122 The abnormal proliferation and accumulation of plasma cells leads to excessive

antibody (immunoglobulin) production, typically IgG or IgA.

A variety of laboratory and clinical manifestations can be seen

in MM and are related to the extent of excessive monoclonal

immunoglobulin (M-protein) production, plasma cell infiltration, and immune deficiency. In the United States in 2010, there

were an estimated 20,180 new diagnoses of MM. The average age

at diagnosis is 70 years (98% of patients are 40 years or older) and

55% of patients are male.121,123 The disease occurs twice as often

2186Section 17 Neoplastic Disorders

in African Americans compared with whites and has increased

in incidence each decade since the 1970s.121

Pathophysiology

Although MM may present as a de novo diagnosis, most

cases are believed to arise from a benign precursor condition

known as monoclonal gammopathy of undetermined significance (MGUS). MGUS is characterized by the accumulation of

abnormal clonal plasma cells and may be differentiated from MM

by the serum concentration of M-protein (<3 g/dL) and the lack

of clinical manifestations typically associated with MM (osteolytic bone lesions, hypercalcemia, renal dysfunction, etc.).124

By way of a complex multistep process involving a variety of

genetic events and changes in the plasma cell’s microenvironment, a transformation from MGUS to smoldering MM or symptomatic MM occurs at a rate of approximately 1% of patients

per year.125,126 Cellular events promoting the growth of malignant plasma cells, i.e., induction of angiogenesis, suppression

of immunity, and the production of osteoclast-activating factors

(e.g., IL-6, tumor necrosis factor, parathyroid hormone-related

peptide), occur during the conversion of benign plasma cells to

their malignant counterparts.127,128

Smoldering myeloma represents an indolent form of the disease in which patients produce M-protein (>3 g/dL) at a level

consistent with the diagnosis of MM or have greater than 10%

plasma cells in the bone marrow but remain asymptomatic.127

Smoldering myeloma progresses to MM at a rate of 10% per

year for the first 5 years after diagnosis, 3% per year for the next

5 years, and 1% per year for the next 10 years.127

Clinical Presentation, Diagnosis, and

Treatment

Patients presenting initially with symptomatic MM frequently

complain of bone pain, fatigue, and recurrent infections resulting from immune suppression. These patients may also have

end-organ damage, including hypercalcemia, renal dysfunction, anemia, and bone lesions (which may be remembered

using the pneumonic CRAB). The final diagnosis requires confirmation of abnormal M-protein production and serum β2

microglobulin concentration. Because MM is not generally considered to be a curable malignancy, the goal of treatment is

to achieve and maintain a clinical response through the combination of induction therapy, HCT, and maintenance therapy.

See the following video for more general information on MM:

http//www.youtube.com/watch?v=uxdgFn1ZMRk.

Clinical Presentation

CASE 92-5

QUESTION 1: B.B. is a 62-year-old, otherwise healthy, man

who presents with acute musculoskeletal chest and back

pain after performing light maintenance work. He was

initially prescribed muscle relaxers and over-the-counter

nonsteroidal anti-inflammatory drugs (NSAIDs), but has

achieved little relief. Computed tomography (CT) scan of

the spine reveals osteolytic bone lesions from T6 to T11.

Further workup reveals an Hgb of 7 g/dL, serum calcium of

11.8 mg/dL, and serum creatinine of 2.0 mg/dL. Serum and

urine protein electrophoresis show M-protein typed as IgGkappa of 5.3 g/dL. A serum β 2 microglobulin was 4.4 mg/L.

Bone marrow biopsy reveals 90% plasma cells with normal

cytogenetics. Skeletal survey shows additional lesions in the

ribs. A diagnosis of MM stage II is made. Is this presentation

consistent with the diagnosis of MM?

B.B. presents with a number of the classic features of MM.

Bone pain and skeletal disease are common and occur when

plasma cells infiltrate the bone marrow and secrete osteoclastactivating factors. Plain radiographic films will reveal osteopenia

or multiple osteolytic bone lesions (punched out areas on radiographs). Hypercalcemia and pathological fractures often accompany the osteolytic lesions associated with this disease. When

plasma cells infiltrate the bone marrow, they can also lead to

a normocytic normochromic anemia in up to 70% of patients.

Comparatively, neutropenia and thrombocytopenia are rarely

present at the time of diagnosis. Renal dysfunction is generally

attributable to deposition of kappa or lambda light chains of

immunoglobulin in the distal tubule, and up to 40% of patients

have or will develop renal insufficiency with the disease.129 In

most patients with MM, only light chains are found in the urine.

Myelomas that overproduce light chains are most commonly

associated with renal dysfunction. Renal dysfunction can be further complicated by dehydration secondary to hypercalcemia,

the use of NSAIDs for pain relief, and the use of contrast dyes

in radiographic evaluation. B.B. should receive hydration with a

sodium chloride–containing solution to restore euvolemia and

reduce his calcium; he should avoid NSAIDs and other nephrotoxic therapies. Another feature that may accompany MM is

hyperviscosity syndrome, more commonly seen with IgA subtype. Hyperviscosity causes CNS, renal, cardiac, and pulmonary

symptoms and complications. Plasmapheresis may be used emergently to alleviate life-threatening cases. Patients may experience

recurrent infections as a result of depressed production of other

immunoglobulin classes, leading to an inability to opsonize bacteria.

TABLE 92-6

Diagnostic Criteria for Plasma Cell Disordersa

Multiple Myeloma

1. Presence of a serum or urinary monoclonal immunoglobulin

protein

2. Presence of clonal plasma cells in the bone marrow or a

plasmacytoma

3. Presence of end-organ damage related to plasma cell proliferation,

including:

Elevated calcium (1 mg/dL above the upper limit of the normal

range, or >11 mg/dL)

Renal insufficiency (creatinine >1.9 mg/dL)

Anemia (2 g/dL below the lower limit of the normal range, or

<10 g/dL)

Bone lesions (lytic lesions or osteoporosis with compression

fractures)

Asymptomatic (Smoldering) Multiple Myeloma

1. Serum monoclonal immunoglobulin >3 g/dL or bone marrow

plasma cells >10%

2. No end-organ damage related to plasma cell proliferation

Monoclonal Gammopathy of Undetermined Significance

(MGUS)

1. Serum monoclonal immunoglobulin <3 g/dL

2. Bone marrow plasma cells <10%

3. No end-organ damage related to plasma cell proliferation

a

All criteria must be met.

Source: International Myeloma Working Group. Criteria for the classification of

monoclonal gammopathies, multiple myeloma and related disorders: a report of

the International Working Group. Br J Haematol. 2003;121:749.

2187Adult Hematologic Malignancies Chapter 92

Diagnosis and Staging

Diagnostic criteria for all plasma cell disorders is shown in Table

92-6. B.B. clearly meets the criteria for MM. Two staging systems

have been used for patients with MM. The older Durie-Salmon

system, developed in 1975, relies on the extent of M-protein

production, serum creatinine, hemoglobin, serum calcium, and

presence and number of bone lesions.130,131 More recently, a large

international study demonstrated that staging and prognosis can

be predicted reliably from serum β2 microglobulin (a light chain

protein expressed on all nucleated cells) and albumin (Table 92-

7). Based on the International Staging System, B.B.’s serum β2

microglobulin, is consistent with stage II MM.

Treatment

INITIAL THERAPY

CASE 92-5, QUESTION 2: The decision is made to begin

B.B. on treatment with a regimen including bortezomib,

lenalidomide, and dexamethasone. What advantages and

TABLE 92-7

International Staging System for Multiple Myeloma

Stage I—β2 microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL

Stage II—neither stage I nor stage III

Stage III—β2 microglobulin ≥5.5 mg/L

Source: Greipp PR et al. International staging system for multiple myeloma.

J Clin Oncol. 2005;23:3412.

disadvantages does this regimen have compared with others?

Patients who meet the diagnostic criteria for MM and who

are symptomatic are candidates for systemic chemotherapy

(Table 92-8). Choice of induction therapy is based on the patients’

eligibility for HCT. When possible, the most effective treatment is

induction chemotherapy to achieve a complete clinical response

(defined by elimination of M-protein in plasma and elimination

of plasma cells in the bone marrow) followed by autologous

TABLE 92-8

Multiple Myeloma Treatment Regimens

Regimen Agents Comments

Induction Therapy

Eligible for High-Dose Chemotherapy With Autologous HCT

RVD Lenalidomide 25 mg PO daily, days 1–14

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

Dexamethasone 40 mg PO daily, days 1–2, 4–5, 8–9, 11–12

Repeat cycle every 21 days

Antithrombotic prophylaxis is recommended

with lenalidomide.

Antiviral prophylaxis with acyclovir is

recommended with bortezomib.

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

Thalidomide 200 mg PO daily

Dexamethasone 40 mg PO daily, days 1–4 and 9–12

Repeat cycle every 21 days

Thalidomide should be given in the evening

to minimize sedation.

Antithrombotic prophylaxis is recommended.

Bortezomib + Dexamethasone Bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11

Dexamethasone 20 mg PO daily, days 1–2, 4–5, 8–9, 11–12

Repeat cycle every 21 days

Ineligible for High-Dose Chemotherapy With Autologous Stem Cell Support

MPB Melphalan 9–12 mg/m2 PO daily, days 1–4

Prednisone 60 mg/m2 PO daily, days 1–4

Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11, 22, 25, 29, 32 for

the first 4 cycles, then days 1, 8, 22, 29 in subsequent cycles

MPT Melphalan 4 mg/m2 PO daily, days 1–7

Prednisone 40 mg/m2 PO daily, days 1–7

Thalidomide 100 mg PO daily

Repeat cycle every 28 days

Melphalan should be given on an empty

stomach owing to variable absorption

when administered with food.

MP Melphalan 8–10 mg/m2 PO daily, days 1–4

Prednisone 60 mg/m2 PO daily, days 1–4

Repeat cycle every 28–42 days

Salvage Therapy

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

Repeat cycle every 21 days

Dose reduction to 1 mg/m2 may be necessary

in patients with neuropathy or

thrombocytopenia.

Addition of dexamethasone may be required

in patients who do not respond.

Bortezomib + liposomal

doxorubicin

Bortezomib 1.3 mg/m2 IV once

Liposomal doxorubicin 30 mg/m2, day 4

Repeat cycle every 21 days

Lenalidomide + dexamethasone Lenalidomide 25 mg PO daily, days 1–21

Dexamethasone 40 mg PO daily, days 1–4, 9–12, 17–20 for the

first four cycles, then days 1–4 only in subsequent cycles

Consider prophylactic antithrombotics.

CIV, continuous intravenous infusion; HCT, hematopoietic cell transplantation; IV, intravenously; MP, melphalan and prednisone; MPB, melphalan, prednisone, and

bortezomib; MPT, melphalan, prednisone, and thalidomide; PO, orally; RVD, lenalidomide, bortezomib, and dexamethasone; VTD, bortezomib, thalidomide, and

dexamethasone.

2188Section 17 Neoplastic Disorders

HCT.132 Many patients are not eligible to receive HCT, however. Determination of HCT eligibility includes consideration of

patient age (typically 65 years of age or younger) and comorbidities. In the case of B.B., his age (62 years) and relative good

health make him a candidate for further consideration of HCT

as a component of his MM management. Those who are eligible

for HCT should not be treated with agents such as melphalan,

which may compromise the ability to collect a sufficient number of hematopoietic cells necessary to perform the autologous

HCT. Although a number of drugs have shown efficacy in treating patients with MM, the most current NCCN Clinical Practice

Guidelines recommend bortezomib, lenalidomide, and dexamethasone as initial induction therapy.133

The proteosome inhibitor bortezomib represents a novel class

of agents for the treatment of MM. Bortezomib acts by inhibiting

the 26S proteosome, a multienzyme complex responsible for regulation of proteins that promote cell survival, stimulate growth,

and reduce susceptibility to programmed cell death.134 Bortezomib is generally dosed as 1.3 mg/m2 on days 1, 4, 8, and 11 of

a 3-week cycle in combination with thalidomide, lenalidomide,

and/or dexamethasone. Patients should be monitored for common adverse events, including fatigue, diarrhea, mild nausea,

thrombocytopenia, and peripheral neuropathy (the most common cause of discontinuation of bortezomib in clinical trials).135

Reactivation of herpes zoster has been observed in greater than

10% of patients treated with bortezomib; therefore, consideration should be given to prophylactic use of acyclovir in these

immunocompromised patients.136,137 An additional benefit of

bortezomib is the ability to induce responses in MM patients

with poor prognosis, such as the high-risk cytogenetic abnormalities del(13) and t(4;14).138

Lenalidomide, an oral immunomodulatory agent with antiangiogenic properties, is also effective in patients with MM. The

dose of lenalidomide is most commonly 25 mg daily for 14 days

of a 3-week cycle. Common adverse events include hematologic

toxicities, muscle weakness, fatigue, and rash.139 Less commonly,

lenalidomide has been associated with thromboembolic events,

and venous thrombotic embolism prophylaxis is recommended.

Several recent cooperative group studies have revealed a small

but concerning risk of secondary malignancies, including AML.

Although this concern should not prohibit the use of lenalidomide, patients should be closely monitored, and practitioners

should be aware of this risk. As an analog of thalidomide, concerns about teratogenicity prohibit the use of lenalidomide during pregnancy and make it available only through a restricted

distribution program. In comparison with lenalidomide, thalidomide is less potent and has a less favorable toxicity profile, with

sedation and peripheral neuropathy being common in addition to

constipation and thrombotic events. Like lenalidomide, thalidomide is only available via a restricted access prescription program.

Dexamethasone is moderately effective as MM induction therapy alone and in combination, and has significant adverse effects,

including hyperglycemia, insomnia, and increased infection risk.

However, the combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) has demonstrated

efficacy in early-phase clinical trials with an overall response rate

of 100% in patients with newly diagnosed MM.140 In addition to

the exceptional response rate, RVD is well tolerated with sensory neuropathy, fatigue, and hematologic toxicities being the

most commonly reported adverse events. Additional combination induction regimens in HCT-eligible patients include bortezomib, thalidomide, and dexamethasone; bortezomib and dexamethasone; bortezomib, doxorubicin, and dexamethasone; and

lenalidomide and dexamethasone. Independent of the choice of

induction regimen, patients commonly receive 3 to 6 cycles of

treatment before HCT.141

In patients ineligible for autologous HCT, melphalan-based

regimens are appropriate for induction therapy. Melphalan and

prednisone (MP) was the first regimen to show significant activity in myeloma, but it rarely produces a complete remission.

The addition of thalidomide to MP (MPT) was compared with

MP in patients 60 to 85 years of age.142 OR and CR rates were

significantly improved with MPT (76% and 16%, respectively)

compared with MP (48% and 2%, respectively). In addition,

2-year eventfree survival was superior in patients receiving MPT

compared with MP (54% vs. 27%). Thromboembolic events seen

in the early part of the trial in patients receiving MPT led to the

use of enoxaparin 40 mg subcutaneously daily, which reduced

thromboembolism from 20% to 3%. Other toxicities seen more

commonly with MPT included peripheral neuropathy, constipation, and infection, necessitating discontinuation of thalidomide

in 33% of patients before the completion of 2 months of therapy.

Subsequently, the VISTA trial demonstrated the superiority of

MP combined with bortezomib (MPB) as compared with MP.

Time to disease progression and 3-year OS rates in previously

untreated MM patients significantly favored MPB.143,144 MPB

has also been associated with better outcomes in patients with

high-risk cytogenetics and poor renal function.143,144 Peripheral

neuropathy, gastrointestinal symptoms, and herpes zoster reactivation were more common in patients receiving MPB. Both MPT

and MPB are proven to be superior to the historical standard MP

and should be considered as standard of care treatment options

in transplant-ineligible patients. Superior outcomes have been

associated with RVD; therefore, this combination is appropriate

induction therapy.

HEMATOPOIETIC CELL TRANSPLANTATION

Efforts to improve the outcome of MM treatment have led

to the investigation of high-dose chemotherapy (e.g., melphalan 200 mg/m2) with autologous HCT and nonmyeloablative

preparative regimens with allogeneic HCT. Randomized comparisons of autologous HCT and conventional chemotherapy

in previously untreated patients younger than 65 years have

been conducted.145–147,148 All patients received two to six cycles

of conventional chemotherapy before randomization to autologous HCT or standard chemotherapy. Most trials reported

higher response rates and improved survival in patients randomly

assigned to receive autologous HCT. Younger age, chemosensitive disease, and fewer pretransplant therapies have emerged as

important predictive factors for response to autologous HCT.

Autologous HCT is regarded as the current treatment of choice

for eligible patients with MM who achieve CR after induction

therapy.132,149 The use of allogeneic HCT in MM is a potentially

curative option, but has been associated with excessive mortality. Nonmyeloablative allogeneic regimens (which use lower

doses of chemotherapy) are generally associated with fewer

regimen-related toxicities than full allogeneic transplants, but

allow for a graft-versus-tumor effect that eradicates residual disease (see Chapter 96, Hematopoietic Cell Transplantation). Initial trials have been encouraging, particularly in patients who are

not heavily pretreated and those with chemotherapy-sensitive

disease.150–152 B.B. will receive three cycles of RVD and will be

evaluated for HCT.

BISPHOSPHONATES

CASE 92-5, QUESTION 3: Zoledronic acid 4 mg IV over

15 minutes every 28 days is ordered for B.B. What is the

rationale for bisphosphonate therapy in the presence of normal serum calcium? What benefits and toxicities are associated with bisphosphonate therapy?

2189Adult Hematologic Malignancies Chapter 92

Osteolytic bone lesions or osteopenia occur in nearly 80%

of all patients with MM and represent one of the most significant challenges to quality of life in this patient population.125

Although these bone manifestations of MM may occur throughout the body, they are most commonly identified in the vertebral column, where they may lead to clinically significant issues,

including fracture.121

The efficacy of pamidronate and zoledronic acid for the prevention of skeletal fractures in MM patients with osteolytic

bone lesions or osteopenia has been established, and guidelines

for their use have been developed.153 Equivalent efficacy with

monthly infusion has been shown with pamidronate 90 mg and

zoledronic acid 4 mg. Zoledronic acid can be given in 15 minutes, whereas pamidronate is given for 2 hours. Because bisphosphonates can negatively affect kidney function, serum creatinine

should be monitored monthly and urine albumin measured every

3 months. Higher doses and shorter infusion times have been

associated with renal damage; patients with creatinine clearances

between 30 and 60 mL/minute should receive reduced doses

of zoledronic acid. In patients with baseline creatinine values

of more than 3 mg/dL, pamidronate 90 mg over the course of

4 to 6 hours is recommended. Bisphosphonate therapy should

be held in patients who have creatinine elevations above the normal baseline by 0.5 mg/dL or more until renal function returns

to baseline. Osteonecrosis of the jaw is a rare but serious complication of bisphosphonate therapy that appears to increase in

likelihood with prolonged treatment. Baseline dental examinations and avoidance of invasive dental procedures during therapy

are recommended. The use of zoledronic acid has been associated with a 9.5-fold increased risk of osteonecrosis of the jaw

compared with pamidronate. All patients with responsive or stable disease should be strongly considered for bisphosphonate

discontinuation after 2 years of treatment.

Denosumab is a monoclonal antibody to the RANK-ligand

receptor resulting in reduced bone resorption and localized bone

destruction. With fewer side effects than the bisphosphonates and

lack of renal toxicity, denosumab has demonstrated efficacy in

patients with osteolytic bone lesions from MM.153 Denosumab

cannot be recommended at this time to replace bisphosphonates

in the management of MM patients because of an increased risk

of mortality observed in a planned subgroup analysis.154

B.B. is a candidate for bisphosphonate therapy with zoledronic

acid 4 mg IV every 28 days because he has osteolytic disease in

the spine and ribs.

MAINTENANCE THERAPY

CASE 92-5, QUESTION 4: B.B. receives three cycles of RVD,

followed by autologous HCT. He returns to clinic today

8 weeks after HCT. Should he receive any additional treatment at this time?

Given the near certainty that MM will progress after autologous HCT, there exists a growing need for effective maintenance therapy. Two phase III studies have evaluated the benefit of lenalidomide in this setting. The CALGB 100104 study

used a starting dose of 10 mg daily (allowing for escalation to

15 mg/day) for 21 of 28 days per month compared with placebo.

The time to progression was 42.3 months for patients receiving

lenalidomide versus 21.8 months for the placebo arm.155 When

compared with placebo in the IFM 2005-02 trial, lenalidomide

10 to 15 mg/day increased PFS by 18 months (42 months vs.

24 months).156 Although thalidomide also has demonstrated efficacy as maintenance therapy, lenalidomide may be preferred as a

result of its improved toxicity profile. Consideration should also

be given to which drugs patients are exposed to during the entire

course of treatment for MM beginning with induction therapy.

One study evaluating the use of thalidomide during induction

therapy as well as in maintenance therapy after HCT reported

an increased response rate and improved 5-year eventfree survival

but no improvement in OS and increased toxicity.157 These results

have suggested that sequencing of therapies may be important

in the management of MM. Further study is warranted to determine whether patients treated with one drug during induction

should be treated with a different drug for maintenance therapy.

The decision was made that B.B. would receive maintenance

therapy with lenalidomide 10 mg daily until disease progression

was documented.

Relapsed and Refractory Disease

CASE 92-5, QUESTION 5: Four years after autologous HCT,

B.B. is found to have relapsed disease. What other therapies

may offer benefit for his myeloma?

In those patients presenting with relapsed or refractory MM

more than 6 months after the completion of initial induction