US Pharm. 2014;39(1)(Specialty&Oncology suppl):7-11.
ABSTRACT: Multiple myeloma (MM) is a hematologic malignancy of the plasma cell. While its pathogenesis has not been fully elucidated, the treatment of MM has significantly changed over the past 15 years. Today, triple therapy is most often used, with an immunomodulatory drug and/or proteasome inhibitor included in the regimen. Although not curative, these therapies have significantly increased survival and bring us one step closer to a curable disease. Autologous stem cell transplantation (aSCT) continues to play a role in selected patients with MM; however, controversy surrounds the timing for transplantation and who should be considered for a transplant. It is essential that pharmacists have an understanding of myeloma since many of the drugs utilized are oral and the treatment regimens are complex.
Multiple myeloma (MM) is the second most common hematologic malignancy diagnosed in the United States. The disease accounts for an estimated 22,350 new cases and 10,710 deaths annually, making up 1% to 2% of all cancers in 2012.1 The etiology of myeloma is unknown. The incidence is slightly greater in men than women, highest in African Americans, and lowest in the Asian/Pacific Islander population.1 The median age at diagnosis is 69 years.2
The first well-documented case of myeloma was in 1844, in which a 39-year-old woman was reported to have fatigue and bone pain from multiple fractures.3 Her bone marrow upon autopsy reportedly contained an abnormal red substance, and the disease also affected her urine. Today, we know that MM arises from a monoclonal plasma cell.4
The pathogenesis of myeloma is complex and not well understood; however, genetic abnormalities and molecular changes are thought to contribute to cell cycle dysregulation, leading to the malignancy of plasma cells. Myeloma commonly evolves from a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with approximately 1% of cases progressing to myeloma each year.5 Some patients will progress to an intermediate, asymptomatic phase known as smoldering myeloma.6 Approximately 73% of patients will progress from smoldering myeloma to active myeloma within 15 years, and this progression is related to the degree of involvement of plasma cells in the bone marrow.6
Myeloma is a heterogeneous disease based on various genetic aberrations. It can be divided into categories based on diploidy, as either hyperdiploid or nonhyperdiploid MM.7 Translocations in the immunoglobulin heavy chain of chromosome 14 and aberrations in chromosomes 1, 5, 13, and 17 appear to be involved.4,7,8 The development of MM is affected by changes in adhesion molecule expression and subsequent interactions within the complex microenvironment of the bone marrow, which induces cytokine and growth factor secretion.4 Interleukin-6, interleukin-10, vascular endothelial growth factor, tumor necrosis factor, transforming growth factor β1, and insulin-like growth factor are produced and secreted by myeloma and other cells within the bone marrow, and they promote proliferation of malignant cells.4 Although MM is not currently considered curable, a growing understanding of the role of cytokines is leading to novel targets for drug therapy, new treatment strategies, and significantly improved survival.9
Signs and Symptoms
The major symptoms of MM are easily remembered with the acronym CRAB. The symptoms include hyperCalcemia, Renal dysfunction, Anemia, and Bone disease (TABLE 1).10 It is not uncommon for patients with MM to complain of fatigue and/or bone pain, as nearly 75% of cases will present with anemia and almost 80% with bone lesions, which can be identified on x-ray or MRI.10,11 Patients may also experience recurrent infections or weight loss. Plasma cell tumors, known as extramedullary plasmacytomas (EMPs), may be found outside the bone marrow, but only occur in approximately 7% of cases.12 While EMPs can occur in any organ, the upper respiratory tract is the most common site. Rarely, patients may present with hyperviscosity syndrome, including headache, blurred vision, epistaxis, oral bleeding, and altered mental status or confusion. This syndrome is most common in patients with immunoglobulin A (IgA) disease and can be alleviated with plasmapheresis.10
The International Myeloma Working Group (IMWG) has developed guidelines for the classification of MM and other plasma disorders such as light chain amyloidosis.7,13,14 These guidelines have been incorporated into the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.15 MM is diagnosed based on the following criteria: ≥10% clonal plasma cells in the bone marrow and the presence of monoclonal protein (usually IgG or IgA) in the urine or serum (≥30 g/dL).14 The myeloma is classified as asymptomatic or symptomatic depending on the absence or presence of organ or tissue impairment, respectively, as defined by CRAB. A detailed medical history and physical examination, bone marrow biopsy, radiography, and laboratory testing are important components for diagnostic evaluation.4,10
Staging and Prognosis
Two staging systems have been utilized in myeloma. The International Staging System (ISS) is most often used to stage MM, which correlates with prognosis and survival. The criteria for the three stages are based on levels of serum β2-microglobulin and albumin (TABLE 2).16
The Durie-Salmon staging is an older, more complex system that is mentioned for historical context. The Durie-Salmon system has largely been replaced due to ISS’s simplicity and validation with the use of newer agents.11
Although not mentioned in the ISS, chromosomal abnormalities have also been shown to impact survival. The Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) has been developed to classify risk based on cytogenetic abnormalities (TABLE 3).17 Regardless of which staging system is used, the 5-year survival in myeloma is 43.2%.2
The IMWG Uniform Response Criteria are most often utilized to assess response to drug therapy. These responses include a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), and stable disease (SD).18,19 The response criteria incorporate the degree of reduction of serum and urine M-protein by electrophoresis and immunofixation, plasmacytomas, and plasma cells in bone marrow.
The treatment of myeloma depends on whether the patient has smoldering myeloma or symptomatic myeloma. Patients with smoldering myeloma are usually observed, with treatment initiated upon disease progression to active MM. There is no evidence that early treatment of asymptomatic myeloma prolongs overall survival.20 Patients with symptomatic, active myeloma require treatment. This treatment is patient-specific and depends on numerous factors including age, comorbidities, and performance status. Myeloma remains an incurable disease for patients; thus, treatment goals are to provide disease control, improve quality of life, and prolong survival.9
The treatment of MM includes induction therapy, transplantation, and maintenance therapy (FIGURE 1). High-dose chemotherapy with autologous stem cell transplantation (aSCT) has been shown to improve survival, and treatment recommendations are based on this modality.17 Thus, transplant-eligible patients should be identified at the start in order to determine the appropriate induction therapy. Induction therapy is used to reduce tumor burden prior to aSCT and usually entails a combination of chemotherapeutic and immunomodulatory agents. Any therapy that affects stem cell mobilization, such as melphalan, should be avoided.8 Following a response to induction therapy, transplant-eligible patients then undergo aSCT and may follow up with maintenance therapy. Transplant-ineligible patients are placed on a combination of chemotherapeutic and immunomodulatory agents that may include alkylating agents and lenalidomide. This regimen will be continued until there is disease progression, and then another regimen for relapsed disease will be initiated. There are numerous regimens that have been used in relapsed/refractory myeloma.11
There are five main classes of agents used in the treatment of MM: alkylating agents, anthracyclines, corticosteroids, immunomodulatory agents, and proteasome inhibitors. There are dozens of combination regimens used in the treatment of MM. For ease of discussion, these agents will be briefly discussed in order to highlight key points of the medication. The combinations of these drugs will be mentioned and are listed in TABLE 4.8,11,17
Alkylating Agents: The alkylating agents melphalan and cyclophosphamide are used in the treatment of MM. Melphalan has been used in the treatment of myeloma since the 1950s and is often given in combination with a corticosteroid.3 Today, melphalan remains highly utilized in the transplant-ineligible patient.11,17 Melphalan is usually avoided in transplant-eligible patients due to its toxicity to progenitor cells, thus decreasing the efficacy of stem cell mobilization.11 One of the largest advantages is that it can be given orally. Patients should be counseled that it must be taken on an empty stomach, as food can affect absorption. The IV formulation is often used as the conditioning regimen for aSCT (200 mg/m2). IV melphalan is often dose-adjusted to 140 mg/m2 for renal insufficiency.21
Cyclophosphamide is another alkylating agent less frequently used, but can be used in combination regimens with bortezomib and dexamethasone. Unlike melphalan, cyclophosphamide may be used in the induction therapy for transplant-eligible patients.17
Anthracyclines: Doxorubicin and liposomal doxorubicin are also used in the treatment of MM. These two drugs are often given in combination with vincristine and dexamethasone to constitute the older regimen known as VAD (vincristine-doxorubicin [Adriamycin]-dexamethasone).11 This regimen has not been used for initial therapy since the introduction of the newer agents and is often reserved for patients who cannot tolerate other combinations. A newer combination of bortezomib, doxorubicin, and dexamethasone may be utilized based on results showing increased response rates compared to VAD. Pharmacists should recall that doxorubicin is myelosuppressive and cardiotoxic. It is also a vesicant, and this is the only class of drugs that has an FDA-approved antidote, dexrazoxane. Patients should be counseled that doxorubicin IV solution is red, and patients should understand that their urine may be discolored red following treatment.21
Corticosteroids: Dexamethasone and prednisone are found in many regimens used for the treatment of myeloma. The doses of corticosteroids are often quite high compared to the treatment of other diseases and given on a pulse basis (i.e., dexamethasone 40 mg po days 1-4, 9-12, 17-20).11 Pharmacists should be aware of the multitude of adverse effects corticosteroids can cause. Appropriate counseling as well as intervention may be necessary (i.e., glucose control).
Immunomodulatory Drugs: Thalidomide, lenalidomide, and pomalidomide are three immunomodulatory drugs used in the treatment of myeloma. The mechanism of action is unknown, but these drugs are believed to inhibit proinflammatory cytokines and angiogenesis and to stimulate natural killer cells.21 There are numerous regimens utilized, with some of the most common being lenalidomide with low-dose dexamethasone and thalidomide with dexamethasone. Lenalidomide may impair stem cell mobilization. This may be overcome by using cyclophosphamide in combination with a growth factor prior to collection or by collecting stem cells for transplantation in early cycles of use.11
Compared to many chemotherapeutic agents, immunomodulatory drugs are much more convenient for patient use as they are available in oral formulations and dosed once daily. However, these drugs are not without risks. All three carry black box warnings for thromboembolism, while thalidomide and lenalidomide are labeled as contraindicated in pregnancy because of the potential for severe birth defects and fetal death.21 These agents can increase the risk of venous thrombo-embolism, and proper prophylactic anticoagulation is warranted (refer to Supportive Care section). Lenalidomide is also known to cause secondary malignancies, including hematologic and solid tumors. Because of these risks, enrollment in the respective Risk Evaluation and Mitigation Strategy (REMS) programs is required of physicians, pharmacies, and patients.21 For pharmacies, this consists of completing an enrollment form, which must be signed by the pharmacist-in-charge or director of pharmacy, and agreement for strict compliance with all of the program conditions to obtain and dispense the drug.
Proteasome Inhibitors: The proteasome inhibitors, bortezomib and carfilzomib, are another mainstay in the treatment of myeloma. These novel agents inhibit the 26S proteasome, leading to cell cycle arrest and apoptosis.21 Originally approved for relapsed and refractory MM, bortezomib-based combinations are now used as first-line therapy in newly diagnosed patients.8 The toxicity profile includes neurotoxicity, such as peripheral neuropathy, and an increased risk of herpes zoster infection. The neurotoxicity may be reduced by giving bortezomib weekly or by subcutaneous injection.11 Prophylaxis with acyclovir is recommended to reduce the incidence of herpes zoster.8 Unlike with thalidomide, the risk of thromboembolism is low. Carfilzomib was FDA-approved in 2012 for patients with progressive myeloma who have failed at least bortezomib and an immuno-modulatory agent. Serious adverse effects include cardiac arrest, pulmonary hypertension, and shortness of breath. Close monitoring is warranted in patients receiving carfilzomib.21 Ongoing studies will determine the role of carfilzomib in combination therapy and in earlier disease.
Approach to Therapy
Treatment of newly diagnosed MM consists of combination-based therapy. The treatment contains various doublet and triplet drug combinations (TABLE 4). There are currently no data to suggest that quadruplet drug regimens provide any benefit compared to current therapy.11 In patients who are transplant-eligible, the initial combinations often include bortezomib, thalidomide, or lenalidomide along with a corticosteroid. As mentioned earlier, melphalan is avoided in transplant-eligible patients due to the effects of reducing stem cell mobilization. In the transplant-ineligible patient, combination therapy often utilizes melphalan. There are similar outcomes between these various regimens; thus, drug regimen selection should be based on other factors including patient preference, quality of life, and toxicity profile.
Hematopoietic Stem Cell Transplantation
In patients with myeloma, aSCT has been shown to improve overall survival compared to conventional therapy.17 For this reason, it is recommended that all patients be evaluated for transplant eligibility, with initial therapy selection based accordingly. It is important to note that many of these transplant studies were completed prior to the advent of the newer agents such as bortezomib and lenalidomide. Therefore, the timing of a transplant (early vs. late) as well as the value of transplantation compared to newer agents remains controversial. There is a subset of patients who will not achieve a good response (CR or VGPR) after a single transplant. In those patients a tandem (second) transplant may be recommended immediately following recovery from the first transplant to improve overall survival.11
Maintenance therapy following a transplant has been shown to improve progression-free survival with limited overall survival benefit.17 Single-agent thalidomide or lenalidomide has been used as maintenance therapy following aSCT as well as after primary treatment in the nontransplant patient. As discussed earlier, lenalidomide increases the risk of secondary malignancies by almost three-fold.11 Clinicians should discuss this risk with patients and consider limiting therapy to 2 years.22 Bortezomib may also be used as maintenance therapy in both the transplant and nontransplant patient, as studies show improvement in response rates.11
All chemotherapy patients require supportive care, but some particularly important components must be remembered in myeloma. Due to the skeletal-related events, the use of IV bisphosphonates has been recommended by the American Society of Clinical Oncology (ASCO) for some patients, with careful monitoring.23 If used, bisphosphonate therapy is usually limited to use for 2 years, and then resumed at the onset of a new skeletal event because of the risk of osteonecrosis of the jaw. In addition to prevention of skeletal lesions, the other complications of CRAB should be managed as well (TABLE 1). Although most patients with myeloma are anemic, certain therapies may increase the risk of thromboembolism. Deep venous thrombosis (DVT) prophylaxis should be considered when patients are on an immunomodulatory agent such as thalidomide or lenalidomide.4 Medications used in the prevention of thromboembolism include low-molecular-weight heparin, warfarin, and, in selected patients, aspirin. Clinicians should refer to the NCCN Clinical Practice Guidelines for deep or superficial venous thrombosis to provide direction for the appropriate management of DVT prevention.24
Role of the Pharmacist
Pharmacists can play a critical role in the management of MM. They can be involved in providing patient counseling and supportive care recommendations. Keep in mind that the immunomodulatory agents and corticosteroids are oral formulations, so community pharmacists are essential in providing the consultation. Risks that should be discussed are specific to the individual medications but may include the risk of neurotoxicity, secondary malignancies, thromboembolism, and birth defects. In patients who are receiving care in the hospital or at an outpatient infusion center, appropriate laboratory work should be evaluated. Many patients have poor renal function, anemia, and hypercalcemia; thus, supportive care measures as well as dose adjustments may be necessary. By understanding the complex disease process of myeloma, pharmacists will have a better understanding of the treatment goals and be able to provide the necessary care to their patients.
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