Multiple myeloma treatment and management in the elderly.

in Practice

Multiple Myeloma Treatment and Management in the Elderly Tali M. Johnson More than 60% of Americans with multiple myeloma are older than 65 years of age, and the number of new patients is expected to double by 2030. In addition to this anticipated increase, most patients have advanced disease at diagnosis and require some level of intervention. During the past 10 years, standard care has advanced from chemotherapy and autologous stem-cell transplant to newer targeted agents, introducing the proteasome inhibitors and immunomodulatory agents to the myeloma armamentarium. Myeloma patients live longer because of these novel treatments and better supportive care measures. However, improved disease control comes with new toxicities, and treatment choices need to be balanced with quality of life. Recent clinical trials studied elderly cohorts, and the results can help with geriatric treatment decisions. Expert consensus guidelines and limited trial results in frail individuals provide dose-reduction and monitoring strategies for geriatric practitioners. Ultimately, each patient’s physical limitations and vulnerabilities determine optimal myeloma management, and a comprehensive geriatric assessment assists with this aim. KEY WORDS: Bortezomib, Carfilzomib, Geriatric assessment, Lenalidomide, Melphalan, Multiple myeloma, Pamidronate, Pomalidomide, Thalidomide, Zoledronic acid. Abbreviations: ASCT = Autologous stem-cell transplant, DFS = Disease-free survival, DVT = Deep vein thrombosis, ESAs = Erythropoietin-stimulating agents, FDA = Food and Drug Administration, FLC = Free light chain, IMiDs = Immunomodulatory agents, LD = Lenalidomide plus high-dose dexamethasone, Ld = Lenalidomide plus low-dose dexamethasone, LMWH = Low molecular-weight heparin, MGUS = Monoclonal gammopathy of undetermined significance, MM = Multiple myeloma, MP = Melphalan plus prednisone, MPR = Melphalan plus prednisone plus lenalidomide, MPT = Melphalan plus prednisone plus thalidomide, ONJ = Osteonecrosis of the jaw, Pd = Pomalidomide plus low-dose dexamethasone, PE = Pulmonary embolism, PLD = Pegylated liposomal doxorubicin, SREs = Skeletal-related events, TD = Thalidomide plus high-dose dexamethasone, VAD = Doxorubicin plus vincristine plus high-dose dexamethasone, Vd = Bortezomib plus low-dose dexamethasone, VISTA = Velcade as Initial Standard Therapy in Multiple Myeloma, VMP = Bortezomib plus melphalan plus prednisone, VMPT = Bortezomib plus melphalan plus prednisone plus thalidomide, VT = Bortezomib plus thalidomide, VTd = Bortezomib plus thalidomide plus low-dose dexamethasone, VTE = Venous thromboembolism, VTP = Bortezomib plus thalidomide plus prednisone.

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The Consultant Pharmacist JULY 2014 Vol. 29, No. 7

Introduction

A

lthough multiple myeloma (MM) is regarded as a complex disease, its trajectory is predictable and treatment approaches in older adults are straightforward. Because the median age for diagnosis is 69 years, and median age of death is 75 years, it is likely that consultant pharmacists will encounter MM patients. For 2013, 22,350 American men and women will be diagnosed, and 10,710 will die of MM.1 There are several general principles for consultant pharmacists to consider in the older adult: • Patients start treatment only when symptomatic • Most patients present with advanced disease and require supportive care, if not palliative treatment • Most older adults are considered ineligible for autologous stem-cell transplant (ASCT) because of excessive morbidity associated with high-dose chemotherapy and stem-cell rescue • Recent advancements using novel agents may prolong survival, but MM remains incurable2 Fortunately, a number of MM studies include elderly cohorts, providing a basis for treatment selection.2,3

Figure 1. Multiple Myeloma Manifests as Malignant Plasma Cells

Diagnosis and Staging MM manifests as malignant plasma cells, mature antibody-producing B-cells that infiltrate “multiple” sites with overproduction of “myeloma” proteins. Each myeloma protein (M-protein) consists of a heavy chain and a light chain. The hallmark is the presence of serum or urine M-protein. A precursor disorder called monoclonal gammopathy of undetermined significance (MGUS) involves less than 10% bone-marrow infiltration and some presence of M-protein. Diagnosis of asymptomatic or smoldering disease requires at least 30 g/L serum M-protein and/or at least 10% bone-marrow infiltration. Clinicians monitor patients with either condition for advanced disease, defined by symptoms related to bone-marrow destruction or renal impairment (Figure 1).4 Typical presentations of symptomatic patients are: • Fatigue secondary to anemia • Repeated infections • Bone pain or spontaneous fractures

The top diagram displays plasma cells producing antibodies and attaching to foreign substances to fight infection and disease. The bottom diagram displays the body making too many plasma cells. These cells produce antibodies that the body does not need. Source: National Cancer Institute.

• Altered mental status, constipation, nausea, and vomiting secondary to hypercalcemia • Neurologic or ocular symptoms related to serum hyperviscosity • Change in stools, muscle weakness, shortness of breath, neuropathy, edema of the extremities, or weight loss related to amyloidosis


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Multiple Myeloma Treatment and Management in the Elderly

Treatment of asymptomatic disease is not employed except in clinical research.3,5 Asymptomatic patients need surveillance tests every three to six months: complete blood count, chemistries, serum and urine immunoglobulins, and serum immunoglobulin free light chain (FLC) assay. Annual bone surveys detect skeletal involvement, and PET scans assess active disease extent.5,6 Among MGUS patients,1% to 2% per year progress to symptomatic disease. The International Staging System is based on serum beta-2 microglobulin and albumin levels, markers of tumor burden, with stage III disease representing worse prognosis than stage I or II.6 In addition to the tests used for surveillance and diagnosis, clinicians use bone-marrow karyotyping and soft tissue biopsy to further determine disease characteristics. They also use these tests to monitor treatment response.6 Unlike other hematologic diseases, mutational analysis in MM isn’t currently clinically applicable to treatment. Specific chromosomal abnormalities such as chromosome 13 deletion, however, are associated with poor prognosis. Gene expression profiling is under investigation and will hopefully help with real-world prognoses and guide treatment soon (Table 1).7

Treatment Approach While therapy in advanced disease is often palliative, MM has become more treatable in recent years thanks to novel agents. Practitioners measure treatment response by disappearance of excessive plasma cells and normalization of serum and urine M-protein (Table 2).6 While the ultimate goal is a complete response, complete response alone does not guarantee improved disease-free survival. Because aggressive treatment may not result in complete response, clinical trial results with elderly cohorts provide a basis for therapy recommendations. The most informative trial designs include comprehensive geriatric assessment or health-related quality-of-life measures. If comprehensive geriatric assessment- or health-related qualify-of-lifebased recommendations are unavailable, best practices and expert consensus are the fallback to determine best course of action (Table 2).8

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Table 1. Definitions of Multiple Myeloma Definitions

Requires one or more of the following

Smoldering or asymptomatic disease

M-protein ≥ 30g/L and/or ≥ 10% plasma cell infiltration of bone marrow

Active or symptomatic disease

Calcium > 11.5 mg/dL (> 2.65 mmol/L) Serum creatinine > 2 mg/dL (> 177 micromol/L) Hemoglobin < 10 g/dL or 2 g/dL < normal (< 12.5 mmol/L < normal) Bone disease (either lytic or osteopenic)

Source: References 5, 6.

Since toxicity may outweigh potential benefit from therapy, oncologists must personalize approaches for elderly MM patients. Comprehensive geriatric assessment is fundamental in determining individualized approaches because it elucidates complex problems and emphasizes functional status using an interdisciplinary team. The standard metric of performance status for all oncology patients is insufficient for assessing older adults. Frailty is much more than performance status; it includes indices for disability and comorbidity that together comprise a frailty phenotype.9 Feasibility of assessing frailty in an outpatient oncology clinic was demonstrated using a selfadministered questionnaire. Patients were subsequently referred to specialists as a result of their responses.8 Modern regimens utilize multiple agent classes over extended time to maximize malignant cell clearance, avoid drug resistance, and prevent relapse. Regimens may consist of three parts: induction, consolidation, and maintenance. Induction therapy reduces tumor mass quickly, often with minimal toxicity. Consolidation continues for multiple cycles to ensure maximum tumor cytoreduction. Maintenance reduces relapse risk using low doses of one or more agents over months to years (Figure 2).


Table 2. Criteria for Measuring Response to Myeloma Treatment

Response category

Response criteria

Stringent complete response

CR + normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry

Complete response

Negative immunofixation in the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in marrow

Very good partial response

Serum and urine M-protein detectable by immunofixation (not on electrophoresis) or 90% + greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hours

Partial response

≥ 50% reduction of serum M-protein and reduction in 24-hour urine M-protein by ≥ 90% or to < 200 mg per 24 hours. If soft-tissue plasmacytomas were present at baseline, then ≥ baseline reduction is also required

Stable disease

Criteria for CR, VGPR, PR, or PD are not met

Progressive disease

Requires any one or more of the following: increase of ≥ 25% from baseline for serum M-component (≥ 0.5 g/dL) and/or urine M-component (≥ 200 mg/24 h) and/or > 10% absolute increase in FLC levels in patients without measurable M-protein levels; ≥ 10% absolute increase in plasma cell % in bone marrow; definite development of new bone or soft-tissue lesions or increase in size of existing lesions; development of hypercalcemia attributed solely to MM

Abbreviations: CR = Complete response, FLC = Free light chain, MM = Multiple myeloma, PD = Progressive disease, PR = Partial response, SD = Stable disease, VGPR = Very good partial response. Source: Reference 6.

Classic Oldies Conventional chemotherapy consists of alkylating agents, corticosteroids, anthracyclines, and vinca alkaloids. Given in various combinations, these classes affect a broad range of cell types. They are often associated with myelosuppression, vomiting, and hair loss. Used since the 1960s, melphalan plus prednisone (MP) combination has no overall survival benefit compared with other chemotherapy. Recent studies show three-year overall survival rate around 54%.10 Because of relative tolerability, low-dose MP is appropriate for newly diagnosed patients who are ASCT ineligible, i.e., patients older than 65 years of age.6 Toxicity compares favorably to newer

regimens. Oral MP is convenient outpatient therapy and forms the backbone of treatment regimens using novel agents. Melphalan, a stem-cell poison, should be avoided prior to stem-cell harvest in anyone who may be suitable for ASCT.6 Cyclophosphamide, another alkylating agent, is used in combination therapy. Unlike melphalan, cyclophosphamide is not a stem-cell poison and is appropriate induction therapy prior to stem-cell mobilization and as salvage therapy. Hydration and complete blood count monitoring are required.


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Figure 2. Management and Treatment Schema for Patients with Multiple Myeloma

MGUS or Asymptomatic Disease

Symptomatic Disease

No treatment until symptomatic or clinical trial Eligible for Autologous Transplant

MelphalanPrednisone

Not Eligible for Autologous Transplant

LenalidomideMelphalanPrednisone

ThalidomideMelphalanPrednisone

BortezomibMelphalanPrednisone

+/- maintenance therapy +/- bisphosphonates Figure 2 Management and Treatment Schema for Patients with Multiple Myeloma

MGUS=monoclonal gammopathygammopathy of unknown of significance Abbreviation: MGUS = Monoclonal unknown significance.

Combination doxorubicin plus vincristine plus highdose dexamethasone (VAD) has been replaced by potent successors. At least half of patients who receive VAD as second-line or salvage therapy respond rapidly with acute symptom resolution. Doxorubicin and its relative, pegylated liposomal doxorubicin (PLD), are anthracyclines effective when combined with other agents, such as dexamethasone and/or bortezomib. The Food and Drug Administration (FDA) approved PLD in 2007 for significantly improved time-to-progression when combined with bortezomib in a large phase III study of relapsed patients.11 Patients older than 65 years of age had similar response as younger patients. Hand-foot syndrome incidence was higher in the combination, but cardiac events were similar.12 PLD causes less cardiotoxicity than doxorubicin.

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Dexamethasone is a potent corticosteroid used to treat lymphocytic malignancies, given alone or combined with other agents. As monotherapy, high-dose dexamethasone induces reasonable response rates and may be a suitable second-line choice for transplant-eligible patients. However, high-dose dexamethasone use in elderly patients should be avoided.2,3,6

Novel Agents Immunomodulatory Agents It is not clear how oral immunomodulatory agents (IMiDs) work; however, when they bind to cereblon, the proposed target of IMiDs, downstream effects include antiproliferative effects and inhibition of T-cell stimulation, cytokines, and angiogenesis.13 Because IMiDs have multiple mechanisms of action and atypical toxicities, they are often combined with other agent classes.



Thalidomide Thalidomide’s reputation from the late 1950s is infamous; every practicing pharmacist has seen pictures of malformed babies whose mothers took thalidomide for sleep or morning sickness.12 Although thalidomide was never marketed in the United States and caused no birth defects here, Congress passed the 1962 Kefauver-Harris Amendment to the Food and Cosmetic Act that requires drugs demonstrate both efficacy and safety before FDA approval. Despite its storied past, thalidomide found new life as myeloma treatment, approved by FDA in 2006 in combination with high-dose dexamethasone for newly diagnosed patients.14 Based on teratogenicity risks, thalidomide and its analogues have stringent Risk Evaluation and Mitigation Strategies programs. Patients require pregnancy monitoring and monthly counseling.14-16 Thalidomide plus high-dose dexamethasone (TD) improved overall response rate compared with MP in ASCT-ineligible patients. Sixty-eight percent responded to TD, but median overall survival was statistically better with MP (41.5 months vs. 49.5 months for MP). Patients older than 75 years of age experienced shorter survival with TD (19.8 vs 41.3 months, respectively); poor performance status and low albumin predicted early death.17 High-dose dexamethasone is the likely culprit, as demonstrated in other trials, and is not recommended in older adults.2,3,6 Melphalan plus prednisone plus thalidomide (MPT) is preferred over MP. Several studies compared MP to MPT in elderly patients. Two of five MPT studies showed median survival benefit around 45 to 52 months compared with 28-32 months for MP, but three did not. A meta-analysis concluded that despite a high level of patient heterogeneity, MPT confers survival benefit by extending overall survival by 20% and significantly improving response rate and progression-free survival.17 MPT is suitable first-line therapy; however, use in patients having poor performance status or renal dysfunction requires caution. Specific toxicities include peripheral neuropathies, infections, cytopenias, and venous thromboembolism (VTE).2,3,18-20

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Venous Thromboembolism Prophylaxis DVT and PE are major manifestations of VTE. The relationship between cancer and VTE was well-established by Armand Trousseau in 1865.41 By most estimates, cancer patients are more likely to have VTE compared with the general population (4% to 7% vs. 1%).42,43 The MM hypercoagulable setting is marked by an inflammatory microenvironment involving coagulation pathway activation and anticoagulation factor dysfunction.42 MM trials reveal that dexamethasone, when combined with IMiDs or combination chemotherapy, independently increase risk six-fold.41 VTE patients have worse survival outcome and are several times more likely to experience VTE recurrence compared with noncancer patients (21% vs 7%).41 Based on this knowledge, screened patients with known risk factors benefit from VTE prophylaxis (Table 3). The American College of Chest Physicians cannot recommend routine prophylaxis of MM outpatients unless they have additional VTE risk factors and low bleeding risk. Validated risk scoring tools provide guidance when the risk/ benefit is unclear; however, the benefit is clear for nursing facility patients with active MM.44 The consultant pharmacist is positioned to assess risk factors, recommend primary prophylaxis, monitor therapy (including any ESA use), and educate patients. Preferred agents are LMWHs or unfractionated heparin for patients receiving IMiDs and high-dose dexamethasone. Vitamin K antagonists are not recommended because of increased bleeding risk, even in low doses.42 Low- to full-dose aspirin may be adequate for only one VTE risk factor or IMiD monotherapy.43 Since VTE risk is highest in newly diagnosed patients, prophylaxis should be continued four to six months into treatment and re-evaluated.2,3,35 Patients with recurring disease at high risk should receive prophylaxis. Patients and caregivers require education about DVT and PE symptoms, so any suspected VTE is reported immediately. Treatment with LMWH is preferred, and MM therapy should be held until anticoagulation is optimized.42 Re-evaluation of risk factors may necessitate change in MM therapy to reduce VTE risk (e.g., bortezomib, low-dose dexamethasone). Abbreviations: DVT = Deep vein thrombosis, ESAs = Erythropoietinstimulating agents, ImiDs = Immunomodulatory agents, LMWH = Low molecular-weight heparin, MM = Multiple myeloma, PE = Pulmonary embolism, VTE = Venous thromboembolism. Source: References 2, 3, 35, 41-44.


Lenalidomide MP plus lenalidomide (MPR), a first-line alternative in adults 65 to 75 years of age, is not an FDA-approved combination for this indication, but adding lenalidomide to MP improved progression-free survival for those younger than 75 years of age. Lenalidomide maintenance after MPR induction (MPR-R) had similar overall response rate as MPR (about 33%) and better median progression-free survival (31 months vs. 15 months). Myelosuppression was more frequent in the MPR arm.21 Lower, continuous doses of lenalidomide in untreated older individuals (median age 75 years) demonstrated safety and efficacy in a phase II study. Eighty percent achieved at least partial response, and median progression-free survival was 18.4 months. Serious adverse events were neutropenia and skin rash. Eighty-three percent entered consolidation, and of those, 60% entered maintenance therapy. Several patients had response improvement in either consolidation or maintenance phases, further supporting the recommendation for maintenance therapy.22 Lenalidomide plus high-dose dexamethasone (LD) was FDA-approved in 2006 for second-line therapy. LD improved time to progression compared with high-dose dexamethasone in two studies. Elderly adults experienced similar efficacy, but were more likely to have VTE, renal failure, and atrial fibrillation with LD.15 Lenalidomide plus low-dose dexamethasone (Ld) is preferred to LD because of reduced toxicity and better one-year overall survival in patients older than 65 years of age (94% vs. 83%) despite a significantly lower overall response rate compared with LD (68.3% vs. 79%).23 Lenalidomide alone is also acceptable for steroid-intolerant patients.6 Pomalidomide The newest IMiD, pomalidomide, was approved in 2013 for patients who received at least two prior therapies including bortezomib and lenalidomide and progressed within 60 days of completing the last therapy.16 Pomalidomide plus low-dose dexamethasone (Pd) compared with pomalidomide alone in refractory patients significantly improved partial response (28.3% versus 7.4%). Although Pd does not improve overall survival,

it appears to overcome resistance mechanisms to other agents, including lenalidomide. Age subgroup analysis shows median progression-free survival of 3.7 months and median overall survival of 11.8 months in the older than 65 years of age cohort.24

Proteasome Inhibitors Proteasome inhibition increases apoptosis in malignant cells resulting in antitumor activity. Both marketed agents are approved for intravenous use, but subcutaneous bortezomib shows equal efficacy and less incidence of peripheral neuropathy.25 Thrombocytopenia, peripheral neuropathy, and viral reactivation are frequent toxicities. Bortezomib is distinguished by its utility in renal dysfunction patients. Carfilzomib, a more selective inhibitor of the proteasome active site, shows fewer off-target class effects, such as neurotoxicity.26 Bortezomib FDA approval in 2008 for first-line bortezomib was based on VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial results. Several important findings surfaced: bortezomib plus MP (VMP) increased response rate to 71%; patients older than 75 years of age, those with creatinine clearance less than 60 mL/min, or those with high-risk cytogenetics experienced similar benefit as normal patients; VMP delayed time to next treatment; efficacy of second-line therapy was not decreased.27 Treatment guidelines recommend VMP as another first-line therapy option for older adults.6 Additionally, bortezomib-prednisone or bortezomibthalidomide (VT) maintenance both increased complete response rate from 24% to 42% regardless of induction regimen, either VMP or bortezomib-thalidomide-prednisone (VTP).28 Thalidomide or bortezomib maintenance is recommended after induction therapy for suitable elderly patients based on these trial results.6 Following a familiar theme in a subsequent study, VMP was compared with VMP plus thalidomide (VMPT) with VT maintenance added to each arm. Partial response rate was about 80% for each, three-year progression-free survival was significantly better for VMPT, but overall


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survival was not.29 Post-hoc analysis showed reducedfrequency (weekly) bortezomib did not diminish efficacy.30 Subgroup analysis suggests elderly patients may not derive progression-free survival benefit with VMPT.29 Progression-free survival benefit with VMP is better for renally impaired patients over VMPT, thus strengthening the general recommendation for VMP in older adults.31 In 2003, FDA approved bortezomib monotherapy in relapsed disease. Weekly bortezomib plus MP demonstrated 57% overall response rate and 30-month median overall survival in a phase I/II study of relapsed elderly. Severe neuropathies decreased when twice-weekly bortezomib was reduced to a weekly schedule.32 Bortezomib, proven effective in multiple disease settings, should remain an option for relapsed elderly even after progression on bortezomib-based regimens.

Carfilzomib FDA approved carfilzomib in 2012 for refractory patients who received bortezomib and an IMiD and progressed within 60 days of last treatment.26,33 Although carfilzomib, a second-generation proteasome inhibitor, demonstrated clinical benefit in younger patients (median age 63 years of age), it is not recommended for elderly patients.6 Robust patients who require salvage therapy may benefit, but experience in older adults is not as extensive as bortezomib. Peripheral neuropathy incidence is lower despite patients having a high proportion of baseline neuropathy.26 Autologous Stem Cell Transplant ASCT is not standard MM treatment for patients older than 65 years of age because of unacceptable treatment-related mortality, e.g., 16% in one report using preparative high-dose melphalan.34 Select elderly with good performance status and few comorbidities may benefit, but little data exist to define a transplanteligible patient.2 A transplant physician should evaluate any transplant-eligible elder soon after diagnosis to determine reasonable approaches. Newer regimens in elderly patients include intermediate-dose melphalan

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plus bortezomib induction plus lenalidomide-based consolidation/maintenance (associated with 7% treatment-related mortality in one study) and MPT instead of ASCT (better median progression-free survival and overall survival).2,3

Disease Complications and Supportive Care Plasma cell migration and M-protein deposition in organs cause severe complications, manifesting as renal impairment, osteolytic bone lesions, and bone-marrow dysfunction. Management of complications oftentimes necessitates treating the patient’s MM. For example, renal failure is best managed with hydration, urine alkalinization, treatment of hyperuricemia and hypercalcemia, plus rapid MM treatment to decrease proteinuria and slow renal deterioration. In particular, bortezomib reduces disease rapidly in those with advanced renal failure.35 Neither bortezomib nor thalidomide requires renal dosing. Skeletal-related events (SREs) increase morbidity and reduce life expectancy. Comprehensive geriatric assessment predicts future fall risk and guides interventions for preventing disability related to SREs.9 In addition, pharmacists are equipped to identify concomitant medications that increase fall risk.8 Should a patient experience an SRE, acute management consists of systemic analgesia and radiotherapy or surgical intervention for local control.2,3 Bisphosphonates, in particular zoledronic acid and pamidronate, effectively delay the first SRE. Bisphosphonates are initiated as adjunctive therapy when patients show detectable osteolytic bone lesions on radiography. Expert consensus recommends provider discretion when initiating bisphosphonates in symptomatic patients without detectable lesions and in high-risk asymptomatic patients, especially with osteoporosis. Zoledronic acid significantly reduces SRE risk at disease progression compared with oral clodronate in newly diagnosed patients. It also reduces risk of death by 16%.36 Both zoledronic acid and pamidronate are FDA-approved for myeloma-induced osteolytic


Table 3. VTE Risk Factors to Consider for Patients in Nursing Facilities Individual factors Previous VTE Reduced mobility Age ≥ 70 years Body mass index ≥ 30 Cardiovascular or renal disease Central venous catheter placement Inherited thrombophilic condition such as protein C or S deficiency Disease-related factors Active malignancy Hyperviscosity or other blood-clotting disorder Recent trauma, surgery, or hospital admission Therapy-related factors High-dose dexamethasone Erythropoietin-stimulating agents Thalidomide, lenalidomide Multi-agent chemotherapy Hormonal treatment Smoking Abbreviations: VTE = Venous thromboembolism. Source: References 2,3,35, 41-44.

lesions.37,38 Experts recommend administration every three to four weeks until disease progression in those who still have active disease (not achieved a complete response). An ideal treatment duration is unclear. Intravenous bisphosphonates are preferred to oral formulations, but oral bisphosphonates may be considered for those unable to receive parenteral infusions. Renal and electrolyte monitoring are crucial and should be performed prior to each dose.36 Bone-marrow impairment increases infection risk, especially with comorbid diabetes and heart disease.

Chemotherapy, such as bortezomib and dexamethasone, increases bone-marrow suppression. Trimethoprimsulfamethoxazole is recommended during the first three months of therapy when infection risk is highest.2,3 Prophylactic antiviral therapy reduces risk of varicella-zoster viral reactivation specifically during bortezomib therapy.25 Although MM treatment manages complications, it also increases adverse effects. Agent and dose selection are important if older adults have decreased physiologic reserve and age-related decline in organ function. Published recommendations suggest dosing strategies based on underlying risk factors for clinical vulnerability—factors identified during a comprehensive geriatric assessment. Doses should be held for severe toxicities and resumed at lower dose levels when toxicities resolve. In the absence of risk factors or drug toxicity, patients should be given the benefit of full doses (Table 4).39 Frequent drug toxicities are neutropenia, anemia, thrombocytopenia, thrombosis, and peripheral neuropathy. Besides dose reductions, neutropenia management employs growth factors, and thrombocytopenia is managed with transfusions. Anemia is managed with blood transfusions or erythropoietin-stimulating agents (ESAs). The ESA Apprise Oncology Program outlines prescribing and administration parameters.40 ESAs increase thrombosis risk and should be carefully considered in this population.2,3 Preexisting peripheral neuropathy is an independent risk factor for treatment-related neuropathy. Functional assessment is crucial before choosing thalidomide and/ or bortezomib therapy. Typical onset is 10 months for thalidomide and 2 to 4 months for bortezomib.35 Frequent symptom monitoring detects peripheral sensory neuropathies and neuropathic pain, especially paresthesia, which may be irreversible. Switching bortezomib’s administration route to subcutaneous and dose-reducing or discontinuing is recommended general management—otherwise there are no effective pharmacologic interventions. Alternative agent choices—lenalidomide and carfilzomib—may produce fewer neuropathies compared with thalidomide and bortezomib, respectively.26,35


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Table 4. Drug Classes Used to Treat Multiple Myeloma Generic Drug Name (brand name)

MM-Related FDA-Approved Indication

Specific Adverse Events Related to the Elderly (incidence)

Monitoring and Precautions for Older Adults

Myelosuppression (> 10%)

Monitor CBC weekly

Vomiting (< 10%)

Expect low incidence of vomiting using low-dose oral melphalan; ensure adequate hydration

Myelosuppression

Monitor CBC weekly

Moderate nausea/vomiting

Use antiemetics as needed

Hemorrhagic cystitis

Hydrate adequately; do not administer tablets at bedtime

Acute infusion reactions (10%)

Infuse cycle 1 at 1 mg/min; slow infusion and premedicate for future cycles if required

Hand-foot syndrome (19%)

Monitor hands and feet each cycle; delay dosing and dose reduce if needed

Myelosuppression

Monitor CBC and institute growth factors if necessary; risk increased with concomitant anticancer therapies; monitor for infection

Cardiac toxicity

Obtain baseline LVEF; monitor for symptoms; risk increased with underlying cardiovascular disease, previous anthracycline exposure, mediastinal radiotherapy, or concomitant use of cardiotoxic agents

Mucositis/stomatitis (20%)

Discontinue and start topical oral rinses

Neurotoxicity

Monitor for loss of deep tendon reflexes, paralytic ileus, and constipation

Conventional Chemotherapy

Melphalan oral tablets (Alkeran)

Palliative treatment

Cyclophosphamide for injection (Cytoxan)

Hematologic diseases

Doxorubicin liposome for injection (Doxil)

Vincristine for injection (Oncovin)

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In combination with bortezomib in patients who have received at least one prior therapy and not a bortezomibcontaining regimen

Hematologic diseases



Table 4. Drug Classes Used to Treat Multiple Myeloma (continued) Generic Drug Name (brand name)




Corticosteroids

Dexamethasone oral tablets (Decadron)

Hematologic diseases Cardiovascular: CHF, VTE, hypertension CNS: depression, insomnia Endocrine: hyperglycemia, adrenal suppression GI: increased appetite, hemorrhage

Prednisone oral tablets

Hematologic diseases CNS: insomnia, nervousness (both > 10%) GI: indigestion, increased appetite (both > 10%)

Avoid use of high-dose dexamethasone

Proteasome Inhibitors

Bortezomib for injection (Velcade)

In patients with MM

Thrombocytopenia (32%)

Monitor platelet count prior to each dose; dose and/or reduce or modify dosing schedule

Peripheral neuropathies (38%)

Assess baseline risk for neuropathies; dose reduce or modify dosing schedule as needed or switch to SQ administration

Hypotension (8%)

Use caution in patients who are dehydrated, have syncope history, or are taking concomitant antihypertensives

HZV reactivation (11%)

Use HZV prophylaxis

Substrate of CYP3A4, Avoid strong inhibitors/inducers of CYP2C19, CYP1A2 enzymes CYP3A4, CYP2C19, CYP1A2 enzymes; dose according to hepatic function Carfilzomib for injection (Kyprolis)

In patients who Cardiac failure events (7%) received at least two prior therapies (an IMiD and bortezomib) and have disease progression on or within 60 days of last therapy

Monitor for cardiac complications and assess benefit/risk of continuing therapy

Abbreviations: ADLs = Activities of daily living, CBC = Complete blood count, CHF = Congestive heart failure, Clcr = Creatinine clearance, CNS = Central nervous system, CYP = Cytochrome P450 enzymes, DVT = Deep venous thrombosis, FDA = Food and Drug Administration,

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Pulmonary complications (35%) and pulmonary hypertension (2%)

Monitor and manage immediately by holding therapy; assess benefit/risk of continuing therapy

Infusion reactions

Premedicate with dexamethasone prior to all cycle 1 doses and when future doses are escalated

Thrombocytopenia (32%)

Monitor platelet count prior to each dose; hold and/or dose reduce

Renal failure (9%) and increased serum creatinine (24%)

Hold drug and/or dose reduce

Proteasome Inhibitors (continued)

Carfilzomib for injection (Kyprolis)

Peripheral neuropathy (14%) Hold drug and/or dose reduce when symptomatic HZV reactivation (2%)

Use HZV prophylaxis

Potentially irreversible peripheral neuropathies (≥ 50%)

Examine monthly for first 3 months of therapy, then periodically; discontinue immediately if symptomatic

Somnolence (> 35%) and fatigue (79%)

Use caution in patients with impaired ADLs and those taking other sedating medications

Constipation (≥ 50%)

Consider concomitant stool softener

VTE (≥ 10%)

22.5% occurrence reported in patients also taking dexamethasone; recommend VTE prophylaxis

Neutropenia (> 40%) and thrombocytopenia (> 20%)

Monitor CBC every two weeks for first 12 weeks, then monthly; dose reduce as needed

Fatigue (> 40%)


Constipation (> 40%)


DVT (> 5%)

Recommend VTE prophylaxis

Immunomodulatory Drugs

Thalidomide oral capsules (Thalomid)

Lenalidomide oral capsules (Revlimid)

In combination with dexamethasone for newly diagnosed MM

In combination with dexamethasone for patients with MM who have received at least one prior therapy

GI = Gastrointestinal, HZV = Herpes zoster-varicella, IMiD = Immunomodulatory agent, LVEF = Left ventricular ejection fraction, MM = Multiple myeloma, ONJ = Osteonecrosis of the jaw, SQ = Subcutaneous, VTE = Venous thromboembolism.


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Skin rashes (> 20%)

Interrupt therapy for grade 2-3 skin rash; discontinue for angioedema, grade 4 rash, any exfoliative or bullous rash

Renal drug elimination

Dose according to renal function

Fatigue and asthenia (≥ 50%)


Constipation (≥ 35%)


Renal failure (> 10%)

Avoid using in patients with serum creatinine > 3 mg/dL

Immunomodulatory Drugs (continued)

Lenalidomide oral capsules (Revlimid)

Pomalidomide oral capsules (Pomalyst)

In patients who received at least two prior therapies (lenalidomide and bortezomib) and have disease progression on or within 60 days of last therapy

Peripheral neuropathies (10%) Monitor for neuropathies VTE (3% in patients receiving prophylaxis)

Recommend VTE prophylaxis

Substrate of CYP1A4, CYP3A Avoid use of CYP1A2, CYP3A and enzymes, and p-glycoprotein p-glycoprotein inhibitors/inducers transporter Bisphosphonates

Zoledronic acid for injection (Zometa)

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For treatment of Renal function deterioration patients with MM and patients with documented bone metastases from solid tumors, in conjunction Hypocalcemia with standard antineoplastic therapy Osteonecrosis of the jaw (ONJ)

Hold for serum creatinine increase of 0.5 mg/dL over normal baseline; dose reduce for Clcr < 60 mL/min Infuse over no fewer than 15 minutes Hydration and electrolyte monitoring Prior preventive dental exam and avoidance of invasive dental procedures during treatment






Renal function deterioration

Hold for serum creatinine increase of 0.5 mg/dL over normal baseline Start elderly at lower end of dosing range

Hypocalcemia

Hydration and electrolyte monitoring

ONJ

Prior preventive dental exam and avoidance of invasive dental procedures during treatment

Bisphosphonates (continued)

Pamidronate for injection (Aredia)

Treatment of osteolytic bone lesions associated with MM or metastatic breast cancer

Abbreviations: ADLs = Activities of daily living, CBC = Complete blood count, CHF = Congestive heart failure, Clcr = Creatinine clearance, CNS = Central nervous system, CYP = Cytochrome P450 enzymes, DVT = Deep venous thrombosis, FDA = Food and Drug Administration, GI = Gastrointestinal, HZV = Herpes zoster-varicella, IMiD = Immunomodulatory agent, LVEF = Left ventricular ejection fraction, MM = Multiple myeloma, ONJ = Osteonecrosis of the jaw, SQ = Subcutaneous, VTE = Venous thromboembolism. Source: References 14-16, 25, 33, 37, 38, 40.

Endnote Last decade’s advances moved MM treatment into the outpatient setting. Treatment’s goal is to maximize benefits using optimal drug, dose, and duration while minimizing treatment-related toxicities. Although studies show novel agents have efficacy in elderly cohorts, older adults are less able to tolerate toxicities compared with younger patients. Treatment choice is especially important. Comprehensive geriatric assessment tools help practitioners understand frailty’s impact on treatment outcomes. Together practitioners, patients, and caregivers make informed decisions about the best approach for MM management. n

Tali M. Johnson, PharmD, BCOP, is senior clinical research pharmacist, Pharmaceutical Management Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. For correspondence: Tali M. Johnson, PharmD, BCOP, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Room 5W236, MSC 9725, Bethesda, MD 20892; Phone: 240276-6575; Fax: 240-276-7893; E-mail: [email protected]. Disclosures: No funding was received for the development of this manuscript. The author has no potential conflicts of interest. Acknowledgment: The author would like to acknowledge Jeannette Y. Wick, RPh, MBA, for her editorial assistance. Consult Pharm 2014;29:434-51. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.434.


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Internet Resources on Multiple Myeloma for Health Care Professionals and Patients Internet Resources Patients Practitioners International Myeloma Foundation http://myeloma.org/IndexPage.action

Multiple Myeloma Research Foundation http://www.themmrf.org/living-with-multiple-myeloma/ additional-resources/

National Cancer Institute http://www.cancer.gov/cancertopics/pdq/treatment/ myeloma/healthprofessional

American Cancer Society http://www.cancer.org/cancer/multiplemyeloma/index

CancerCare http://www.cancercare.org/professionals

American Society of Clinical Oncology http://www.cancer.net/cancer-types/multiple-myeloma

National Comprehensive Cancer Network http://www.nccn.org/index.asp

Leukemia & Lymphoma Society http://www.lls.org/

MedlinePlus http://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v %3Aproject=medlineplus&query=multiple+myeloma&x=12 &y=17

National Cancer Institute http://www.cancer.gov/cancertopics/pdq/treatment/ myeloma/Patient National Comprehensive Cancer Network http://www.nccn.org/patients/default.aspx

References 1. Howlader N, Noone AM, Krapcho M et al. SEER cancer statistics review 1975-2007. National Cancer Institute. Available at http://seer. cancer.gov/statfacts/html/mulmy.html. Accessed September 8, 2013. 2. Wildes TM, Vij R, Petersdorf SH et al. New treatment approaches for older adults with multiple myeloma. J Geriatr Oncol 2010;3: 279-90. 3. Gay F, Palumbo A. Management of older patients with multiple myeloma. Blood Rev 2011;25:63-73. 4. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57. 5. National Cancer Institute. Plasma cell neoplasms treatment. Available at http://www.cancer.gov/cancertopics/pdq/treatment/ myeloma/healthprofessional. Accessed August 20, 2013. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. 2013. Available at http:// www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed September 2013. 7. Fonesca R, Bergsage PL, Drach J et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009;23:2210-21.

450

8. Hurria A, Lichtman SM, Gardes J et al. Identifying vulnerable older adults with cancer: integrating geriatric assessment into oncology practice. J Am Geriatr Soc 2007;55:1604-8. 9. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol 2001;56A:M146-M156. 10. Mateos MV, Richardson PG, Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 2010;28:2259-66. 11. Doxil (doxorubicin HCl liposome injection) prescribing information. Horsham, PA: Janssen Products, LP; August 2013. 12. Orlowski RZ, Nagler A, Sonneveld P et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improved time to progression. J Clin Oncol 2007;25:3892-901. 13. Lopez-Girona A, Mendy D, Ito T et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012;26:2326-35. 14. Thalomid (thalidomide) prescribing information. Summit, NJ: Celgene Corporation; February 2013.


15. Revlimid (lenalidomide) prescribing information. Summit, NJ: Celgene Corporation; June 2013. 16. Pomalyst (pomalidomide) prescribing information. Summit, NJ: Celgene Corporation; February 2013. 17. Ludwig H, Hajek R, Tothova E et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009;113:3435-42. 18. Fayers PM, Palumbo A, Hulin C et al. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood 2011;118:1239-47. 19. Palumbo A, Bringhen S, Liberati AM et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008;112:3107-14. 20. Hulin C, Facon T, Rodon P et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664-70. 21. Palumbo A, Hajek R, Delforge M et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759-69. 22. Falco P, Cavallo F, Larocca A et al. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia 2013;27: 695-701. 23. Rajkumar SV, Greipp PR, Jacobus S et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomized controlled trial. Lancet Oncol 2010;11:29-37. 24. Jagannath S, Hofmeister CC, Siegel DS et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Blood 2012;120:Abstract 450. 25. Velcade (bortezomib) prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; January 2012. 26. Siegel DS, Martin T, Wang M et al. A phase 2 study of singleagent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120:2817-25. 27. San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906-17. 28. Mateos MV, Oriol A, Martinez-Lopez J et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012;120:2581-8.

29. Palumbo A, Bringhen S, Rossi D et al. Bortezomib-melphalanprednisone-thalidomide followed by maintenance with bortezomibmelphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28:5101-9. 30. Bringhen S, Larocca A, Rossi D et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010;116:4745-53. 31. Morabito F, Gentile M, Mazzone C et al. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood 2011;118:5759-66. 32. Petrucci MT, Levi A, Bringhen S et al. Bortezomib, melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma. Cancer 2013;119:971-7. 33. Krypolis (carfilzomib) prescribing information. South San Francisco, CA: Onyx Pharmaceuticals; 2012. 34. Badros A, Barlogie B, Siegel E et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 2001;114:600-7. 35. Palumbo A, Mateos MV, Bringhen S et al. Practical management of adverse events in multiple myeloma: can therapy be attenuated in older patients? Blood Rev 2011;25:181-91. 36. Terpos E, Morgan G, Dimopoulos MA et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol 2013;31: 2347-57. 37. Zometa (zoledronic acid) prescribing information. East Hanover, NJ: Novartis Pharma Stein AG; September 2013. 38. Dana WJ, Fuller MA, Goldman MP, Golembiewski JA, Gonzales JP, Lowe JF, Snoke J. Drug Information Handbook. 21st ed. Hudson, Ohio: LexiComp; 2012. 39. Palumbo A, Bringhen S, Ludwig H et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood 2011;118:4519-29. 40. Procrit (epoetin alfa) prescribing information. Horsham, PA: Janssen Products, LP; July 2012. 41. Thaler J, Ay C, Pabinger I. Venous thromboembolism in cancer patients—risk scores and recent randomized controlled trials. Thromb Haemost 2012;108:1042-8. 42. Niesvizky R, Badros AZ. Complications of multiple myeloma therapy, part 2: risk reduction and management of venous thromboembolism, osteonecrosis of the jaw, renal complications, and anemia. JNCCN 2010;8 (suppl 1:S13-S20). 43. Palumbo A, Rajkumar SV, Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-23. 44. Kahn SR, Lim W, Dunn AS et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians evidencebased clinical practice guidelines. Chest 2012;141 (Suppl:e195S-e226S).


451

Multiple myeloma in the very elderly patient: challenges and solutions.

Multiple Myeloma: Diagnosis and Treatment.

Letter: Management of multiple myeloma.

The Diagnosis and Treatment of Multiple Myeloma.

Management of bone disease in multiple myeloma.

Optimal management of elderly patients with myeloma.

Challenges in multiple myeloma diagnosis and treatment.

The role of radiotherapy in the management of multiple myeloma.

Multiple myeloma. New treatment options.

Bortezomib for the treatment of multiple myeloma.

Elotuzumab for the treatment of multiple myeloma.

Treatment of relapsed multiple myeloma.

Treatment of relapsed multiple myeloma.

Treatment of smoldering multiple myeloma.

Primary hyperparathyroidism in an elderly patient with multiple myeloma.

New approaches to management of multiple myeloma.

[Clincal features and treatment of multiple myeloma].

Treatment of relapsed and refractory multiple myeloma.

Bone disease in multiple myeloma: pathophysiology and management.

Pomalidomide for the management of refractory multiple myeloma.

Treatment-related symptom management in patients with multiple myeloma: a review.

[New drugs in the treatment of multiple myeloma].

The Singapore Myeloma Study Group Consensus Guidelines for the management of patients with multiple myeloma.

Management of tumor lysis syndrome in patients with multiple myeloma during bortezomib treatment.