Abstract and Introduction
Abstract
Multiple myeloma (MM) accounts for approximately 1% of all cancers and 10% of all hematologic malignant disorders. MM occurs slightly more often in men than in women, and it is twice as common in African American persons compared with white persons. The median age at diagnosis is approximately 65 years. Although MM is incurable, several treatments are available, and the last two decades have seen great progress in understanding the biology and treatment of MM. Pharmacologic agents approved over the last 15 years for the treatment of MM have markedly improved patient outcomes. In 2015, the FDA approved four novel agents—panobinostat, ixazomib, elotuzumab, and daratumumab—for the treatment of relapsed MM, potentially offering the hope of improved survival.
Introduction
Multiple myeloma (MM) is a malignant neoplasm that affects the plasma cells in the bone marrow, resulting in bone destruction and marrow failure.[1] The characteristic clinical manifestations of MM include bone pain from lytic lesions or osteoporosis, skeletal destruction, anemia, renal insufficiency, hypercalcemia, immunodeficiency, and increased vulnerability to infection.[1–3] As MM progresses, the cancer cells accumulate in the bone marrow, causing painful bone lesions and preventing normal blood cell production.[4–6] MM accounts for an estimated 1% of all cancers and 10% of all hematologic malignant disorders.[1,7,8] The American Cancer Society has estimated that 30,330 new cases of MM would be diagnosed and 12,650 deaths from MM would occur in 2016.[9,10] MM is slightly more prevalent in men than in women, and its occurrence is twice as common in African American persons compared with white persons. The median age at diagnosis is approximately 65 years, and about 2% of MM cases are diagnosed in persons aged <40 years.[11–13]
Etiology and Risk Factors
Although the exact etiology of MM is unknown, research has identified various factors that may be linked to the disease, including genetic causes, occupational or environmental causes, monoclonal gammopathy of undetermined significance (MGUS), radiation exposure, infections, and chronic inflammation.[6,14–16] Moreover, research has found an increased risk in persons in agricultural and petrochemical occupations with substantial exposure to chemicals.[6] Some studies indicate that exposure to herbicides, insecticides, plastics, heavy metals, and petroleum products may be linked to MM development; however, the majority of people diagnosed with MM have no risk factors.[6,9,17] EPILYMPH, a large study whose results were published in 2012, concluded that there seems to be a correlation between MM and farm work, as well as printing and cleaning materials.[18]
Symptoms
Presenting symptoms of MM tend to vary from patient to patient; however, the majority of patients are asymptomatic in the early stages of MM, and approximately 20% of patients present with mild symptoms or no symptoms upon diagnosis.[19,20] The most common symptoms are fatigue and bone pain.[7,8,21]
For the past decade, diagnoses of MGUS and smoldering MM have been based on the absence of classic symptoms of end-organ or tissue impairment, which include hypercalcemia, renal insufficiency, anemia, and osteolytic bone lesions (CRAB).[7,8,22] In October 2014, the International Myeloma Working Group released updated MM diagnostic criteria that added to the classic CRAB features three markers considered to be myeloma-defining events: clonal bone marrow percentage ≥60%, involved/uninvolved serum free light chain ratio ≥100, and >1 focal lesion that is ≥5 mm in size.[7,8,22] Anemia, which occurs in about 75% of patients, likely contributes to episodes of fatigue.[21] Osteolytic skeletal lesions are detected in approximately 80% of patients, and other common clinical findings at diagnosis include hypercalcemia and elevated serum creatinine level.[21,23,24] The diagnosis of MM is incidental in approximately 30% of cases, and MM is often discovered via routine blood screening when the patient is being evaluated for an unrelated health issue.[9]
Advances in Treatment and Management
In the past two decades, great strides have been made in gaining deeper insight into the biology and treatment of MM. Although MM has no cure, it is highly treatable. Recent advances in therapy leading to the development and approval of new drugs, as well as the exploration of different approaches to treatment, have resulted in increased rates of improved overall survival and complete remission.[24]
Current strategies for the treatment of MM involve consecutive stages of therapy administered as an induction phase followed by consolidation and maintenance therapy.[24] The induction phase aims to eradicate MM by reducing the size of the cancer as much as possible.[24] Consolidation therapy further diminishes tumor bulk, and maintenance therapy is prescribed as long-term treatment with the goal of keeping residual disease under control and potentially leading to a cure.[24]
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PSIs) are considered the mainstays of MM treatment, along with other recently approved novel agents, but newer and more highly targeted treatments are being investigated in clinical trials.[24] IMiDs are a group of compounds that are functionally and structurally related to thalidomide.[25] These agents were formulated with increased anticancer and immunologic properties, and their biologic effects include the inhibition of angiogenesis and proinflammatory cytokines, the stimulation of cellular immunity, and the ability to precisely inhibit the growth of tumor cells and induce apoptosis.[25]
In the last 15 years, overall survival rates in MM patients have improved significantly with the approval of pharmacologic agents such as bortezomib, thalidomide, and lenalidomide.[26,27] Other novel agents include Pomalyst (pomalidomide), a potent oral IMiD that was approved in 2013, and Kyprolis (carfilzomib), a PSI approved in 2012. However, these therapies are not curative, and nearly all MM patients eventually relapse and require further therapy.[28] In 2015, the FDA approved four agents—panobinostat, ixazomib, elotuzumab, and daratumumab—for the treatment of relapsed MM, which may offer hope for improved patient outcomes.
In November 2015, the FDA approved two first-inclass injectable agents for MM: Darzalex (daratumumab), a human CD38-directed monoclonal antibody (Mab), and Empliciti (elotuzumab), a Signaling Lymphocytic Activation Molecule Family member 7 (SLAMF7)–directed immunostimulatory antibody.[28] Also approved was Ninlaro (ixazomib), joining the previously approved PSIs Velcade (bortezomib) and Kyprolis.[28] Earlier that year, the FDA approved Farydak (panobinostat), the first oral histone deacetylase (HDAC) inhibitor approved to treat MM.[29]
A number of strategies exist for the management of MM, and the treatment plan is individualized for each patient.[30] Treatment options include chemotherapy, immunosuppression, radiation, autologous stem-cell transplantation, and adjunctive therapy when warranted.[9] Adjunctive therapy for MM may include radiation that targets areas of pain, impending pathologic fracture, or existing pathologic fracture.[9] Bisphosphonates may be used as prophylactic therapy (i.e., primary, secondary) against skeletal events (i.e., hypercalcemia, spinal cord compression, pathologic fracture, need for surgery or radiation).[9] Evidence suggests that bisphosphonates may be effective in treating bone pain and reducing the likelihood of lesion recurrence.[9,31–33] Other adjunctive therapies include erythropoietin, corticosteroids, surgical intervention, and plasmapheresis.[9] There is no one standard of therapy for MM, and treatment is generally selected based on the patient’s age, general health, prior MM treatment, laboratory and cytogenetic test results, symptoms, and extent of disease.[30,34]
Panobinostat
In February 2015, the FDA approved panobinostat, the first agent in a new class of drugs with promising clinical activity against MM, in nearly 15 years.[29] Panobinostat, the first oral HDAC inhibitor approved for the treatment of relapsed MM, is indicated for patients with MM who have received at least two prior regimens, including bortezomib and an IMiD; it should be used in combination with bortezomib and dexamethasone (DXM).[35,36] Accelerated approval was granted based on progression-free survival (PFS).[36]Deacetylase overexpression, which has been observed in MM, is associated with poor outcomes, so the availability of a novel agent such as panobinostat is encouraging for the treatment of MM.[37] Panobinostat is rapidly absorbed following a single 20 mg oral dose, and the time to maximum absorption is 2 hours.[36] Both CYP450 enzymes and non-CYP enzymes may play a vital role in panobinostat metabolism, with CYP2D6 and CYP2C19 making minor contributions.[36,37] The primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes.[36,37] The terminal elimination half-life of panobinostat is about 30 hours.[36,37]
The approval of panobinostat was based on the phase III PANORAMA 1 trial, which showed that panobinostat plus bortezomib and DXM significantly extended PFS (median, 12.0 months) compared with placebo plus bortezomib and DXM (median, 8.1 months; P <.0001) in patients with relapsed or relapsed/refractory MM.[38] Research conducted thus far has demonstrated that panobinostat is a valuable addition to the current treatment options for relapsed MM and that it provides opportunities for the further development of agents in this class with comparable mechanisms of action.[38] Moreover, clinical trials evaluating additional rationally designed combinations incorporating panobinostat in the up-front, relapsed/refractory, and maintenance MM settings are ongoing.[38] Other trials are investigating the use of panobinostat in combination with other agents in the relapsed/refractory and newly diagnosed treatment settings.[38]
The most common adverse reactions reported in clinical studies include diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.[35,36] The most common nonhematologic laboratory abnormalities reported are hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine.[35,36] The most common hematologic laboratory abnormalities reported are thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.[35,36]
Panobinostat is available as a capsule for oral administration, and the recommended dosage is 20 mg taken orally once every other day for three doses per week (on days 1, 3, 5, 8, 10, and 12) in weeks 1 and 2 of each 21-day cycle, for up to eight cycles.[35,36] Panobinostat has a black box warning alerting patients and healthcare providers to the occurrence of severe diarrhea and severe and fatal cardiac events, arrhythmias, and ECG changes in patients taking this agent and stating that the patient should be closely monitored and panobinostat discontinued, if warranted.[35,36]
Daratumumab
In November 2015, the FDA issued an accelerated approval for daratumumab to treat patients with MM who have received at least three prior treatments, including a PSI and an ImiD, or are double-refractory to a PI and an IMiD.[39,40] Daratumumab, the first Mab approved to treat MM, is classified as a human CD38-directed Mab.[39,41] The safety and efficacy of daratumumab were demonstrated in two open-label studies. In one study, 29% of 106 patients receiving daratumumab experienced a complete or partial reduction in tumor burden that lasted for an average of 7.4 months.[41]In the other study, 36% of 42 patients receiving daratumumab had a complete or partial reduction in tumor burden.[39,41,42]
Patients should be advised that, prior to IV infusion of this agent, they will be premedicated with a corticosteroid, an antipyretic, and an antihistamine to prevent infusion-related reactions. Typical dosing is 16 mg/kg IV once weekly (weeks 1–8), with the frequency reduced to every 2 weeks (weeks 9–24) and then to every 4 weeks (week 25 and thereafter) until disease progression.[40,41] Adverse events include infusion-related reactions, fatigue, nausea, back pain, fever, and cough.[40,41] Daratumumab may also cause lymphopenia, neutropenia, leukopenia, anemia, or thrombocytopenia.[40,41]This agent should not be used during pregnancy, and women who want to conceive should use effective contraception during therapy and for 3 months after stopping the drug.[40,41] Patients should be advised that daratumumab may interfere with certain tests carried out by blood banks, such as antibody screening in patients needing a blood transfusion.[40–42]During counseling, the pharmacist should inform patients that postinfusion medications will be administered to prevent infusion reactions and potential herpes zoster reactivation.[40–42] To prevent herpes zoster reactivation, antiviral prophylaxis is given within 1 week of starting daratumumab and for 3 months after therapy has ended.[40–42] Patients should be counseled regarding the symptoms of infusion-related reactions and should be instructed to contact their healthcare provider immediately if symptoms develop. Infusion reactions generally occur within the first 4 hours post infusion, and patients with obstructive pulmonary disorder may benefit from postinfusion treatment with bronchodilators and inhaled corticosteroids following the first four infusions.[40–42]
In June 2016, at the annual meeting of the American Society of Clinical Oncology, a three-drug regimen including daratumumab, bortezomib, and DXM was declared a new standard of care in relapsed MM.[43] The drug combination reduced the risk of cancer progression by 70% and noticeably improved patient outcomes in patients with recurrent or refractory MM.[43]
Elotuzumab
Also in November 2015, the FDA approved elotuzumab for administration in combination with lenalidomide and DXM in patients with MM who have received one to three prior medications.[44,45] Elotuzumab is classified as a humanized immunoglobulin G1 Mab that specifically targets the protein SLAMF7.[44–47] SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities, and it is also expressed on natural killer (NK) cells, plasma cells, and, at lower levels, specific immune-cell subsets of differentiated cells within the hematopoietic lineage.[44–47] Elotuzumab directly activates NK cells via both the SLAMF7 pathway and Fc receptors, and it also targets SLAMF7 on MM cells and facilitates the interaction with NK cells to mediate the killing of MM cells through antibody-dependent cellular cytotoxicity.[46,47]
Approval of elotuzumab was based on the results of ELOQUENT-2, a randomized, open-label study with a minimum follow-up of 2 years.[44–47]Subjects received either elotuzumab in combination with lenalidomide and low-dose DXM (ERd) or lenalidomide and low-dose DXM (Rd).[46,47] ERd delivered a benefit in PFS that was maintained over time, with PFS rates of 68% versus 57% at 1 year and 41% versus 27% at 2 years in the ERd and Rd arms, respectively. The ERd regimen also demonstrated a significant improvement in overall response rate (ORR), achieving an ORR of 78.5% versus 65.5% in the Rd arm.[46,47]
Elotuzumab is administered via IV infusion, and patients should be premedicated with DXM, antihistamines, and acetaminophen because this agent can cause infusion reactions.[45–47] The recommended dosage of elotuzumab is 10 mg/kg IV every week for the first two cycles, and then every 2 weeks as directed.[45–47] The most common adverse reactions include fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia.[45–47] Patients should be monitored for fever, other signs of infection, and hepatotoxicity during therapy.[45–47]Elotuzumab is contraindicated during pregnancy and in women who are breastfeeding.[45–47]
Ixazomib
In November 2015, the FDA approved ixazomib, a PSI indicated in combination with lenalidomide and DXM for the treatment of patients with MM who have received at least one prior therapy.[48–50] It should be noted that although ixazomib joins other PSIs (e.g., bortezomib and carfilzomib) in the treatment of MM, it is the only oral formulation that is considered to be advantageous for patients who prefer an all-oral regimen or do not live near an infusion center.[48–50] Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta-5 subunit of the 20S proteasome.[48–50] Ixazomib induced apoptosis of MM cell lines in vitro, and it demonstrated in vitro cytotoxicity against MM cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and DXM.[48–50] The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in MM cell lines.[48–50]
The recommended starting dosage of ixazomib is 4 mg administered orally once weekly on days 1, 8, and 15 of a 28-day treatment cycle.[49,50] Dose reductions (starting dose of 3 mg) is recommended in patients with moderate-to-severe hepatic impairment, severe renal impairment, or end-stage renal disease and who are on dialysis.[49,50] Ixazomib should be taken once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle.[49,50] Ixazomib should be taken at least 1 hour before or at least 2 hours after food, and the capsule should be taken with water and swallowed whole.[49,50] During counseling, patients should be advised that the capsule should not be crushed, chewed, or opened, and that if a dose is delayed or missed, it should be taken only if the next scheduled dose is in ≥72 hours.[49,50] If vomiting occurs after a dose is taken, the patient should not repeat the dose; dosing should resume at the time of the next scheduled dose.[50,51] The most common adverse reactions include diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain.[49,50]
The concurrent use of ixazomib with strong CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) should be avoided, and patients should be monitored for thrombocytopenia, severe gastrointestinal effects, peripheral neuropathy, peripheral edema, rash, and hepatotoxicity.[49,50]Patients should be reminded to report any possible adverse effects to their healthcare provider; they also should be advised to avoid contact with the contents of the ixazomib capsules and to wash the skin thoroughly if contact occurs.[49,50] Ixazomib and DXM should be taken separately, since DXM (unlike ixazomib) should be taken with food.[49,50] Patients should be advised to use an effective form of contraception during ixazomib treatment and for 3 months after completing treatment because of the potential for birth defects.[49,50]
Ongoing Research and Other Emerging Therapies
Clinical trials are investigating several other promising agents in the fight against MM, and each of these drugs has shown single-agent activity in relapsed MM.[51,52] These agents are isatuximab (a CD38 Mab); marizomib (a new PSI); oprozomib (an oral PSI related to carfilzomib); selinexor (a selective inhibitor of nuclear export compound); filanesib (a kinesin spindle protein inhibitor); dinaciclib (a cyclin-dependent kinase inhibitor); venetoclax (a selective B-cell lymphoma 2 inhibitor); and LGH-447 (a pan-PIM kinase inhibitor).
Conclusion
Knowledge about MM, its management, and possible treatments ( Table 1 ) is the best ammunition in the fight against MM. Although the diagnosis of MM is challenging, approval of new treatments and greater insight into this form of cancer provide hope for better treatments and positive outcomes. Although there is no cure for MM, numerous clinical studies report that patients may benefit from the various treatment options available; indeed, many of these therapies are improving remission and survival rates, decreasing pain and complications, and generally providing patients with more options. Great strides have been made in the last decade with the introduction of autologous stem-cell transplants and novel agents such as IMiDs and PSIs.[52] A host of clinical trials on MM are currently being conducted; the Multiple Myeloma Research Foundation has a searchable database that provides information about these trials.[53] Additionally, the National Comprehensive Cancer Network has an excellent patient-education resource for MM patients.[54]
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