A Clinical Primer. for Managed Care Stakeholders

Transcription

1 reviews therapy Diagnosing, Staging, and Treating Multiple Myeloma: A Clinical Primer for Managed Care Stakeholders by Ralph V. Boccia, MD, FACP, Medical Director, Center for Cancer and Blood Disorders Multiple myeloma (MM) is among the most common hematologic malignancies second only to non-hodgkin lymphoma in terms of prevalence and the most common form of plasma cell cancer. 1 More than 20,000 cases of MM were diagnosed in 2010, with a greater incidence in men than in women (11,170 vs. 9,010, respectively). 2 In addition to being more prevalent in males, the disease is nearly twice as common among African-Americans as Caucasians. 2 As is the case with most cancers, the risk of MM increases with age, with less than 1% of cases diagnosed in individuals younger than age Despite these seemingly insignificant epidemiologic characteristics, recent data indicate increasing incidence and an earlier age of onset for the disease than previously reported. 1 An estimated 10,650 Americans died from MM in 2010, accounting for only 2% of cancer deaths. 1,2 Furthermore, with a five-year relative survival rate of approximately 35%, patients diagnosed with MM often benefit from years of drug therapy. 2 Recent therapeutic advances, including effective maintenance therapy, have additionally promoted prolonged survival among these patients, offering managed care hematologists and oncologists an opportunity for improved outcomes through judicious treatment selection and planning. However, prior to choosing the appropriate course of drug treatment, clinicians must carefully diagnose, assess, and stage a patient s MM. Pathophysiology To accurately diagnose and assess MM, the multifaceted pathophysiologic processes driving the development and progression of this complex hematologic cancer must 23

2 be fully understood. MM originates when plasma cells residing in the bone marrow become malignant and grow unchecked. This proliferation of cancerous plasma cells produces a tumor known as a plasmacytoma. While plasmacytomas generally develop in the bone marrow, these tumors are also found in other tissues in rare cases. The existence of a single plasma cell tumor is considered an isolated (or solitary) plasmacytoma, while evidence of more than one plasma cell tumor constitutes the development of multiple myeloma. This disease process has a number of interrelated ramifications. When the cancerous plasma cell operates independently of the immune system, it fails to recognize that the antibody it is forming is dysfunctional and manufactures large amounts of this M protein, a condition known as monoclonal gammopathy. Myeloma cells also eventually overcrowd the bone marrow space and displace healthy plasma cells, making functional antibodies with the ability to facilitate the fighting of infectious disease. As a result, patients with MM are approximately 15 times more susceptible to infection. 2 Beyond the immune-related implications of this process, the excess M protein produced is excreted through the kidneys, which may cause direct or indirect damage that results in renal failure. In some cases, the M protein deposits in other organs, resulting in a condition called secondary amyloidosis. In addition to the production of dysfunctional M protein antibodies, the infiltrating myeloma plasma cells occupying the bone marrow impair the manufacturing of red blood cells, white blood cells, and platelets, resulting in low blood counts. Further proliferation of malignant plasma cells eventually narrows the bone marrow, physically displacing and pathologically remodeling healthy bone structure. Further exacerbating this problem, myeloma cells produce a substance that signals accelerated osteoclast-mediated breakdown of the bone without promoting the generation of new bone by the osteoblasts. This MM-driven weakening of the bone may lead to bone pain, fractures, and increased calcium in the blood. Diagnosis, Assessment, and Staging While there are no specific signs indicating a potential diagnosis of MM, patients may present with the following symptoms: fatigue, flu-like symptoms, bone pain, back pain especially low back pain and recurring infections, most often pneumonia. If these symptoms are unexplained and unresolved after eight to 12 weeks, this may increase suspicion and prompt further testing. Furthermore, MM often causes very few symptoms, or symptoms easily mistaken for other conditions, until the disease has progressed to an advanced stage. In advanced disease, confusion, nausea, vomiting, and weakness may result from hypercalcemia or kidney failure. Pathologic fractures are another potential presenting symptom of advanced disease. Bruising easily, secondary to low platelets or amyloidosis, may also be a presenting symptom in rare cases. Patients with MM generally appear healthy upon physical examination, with the possible exception being sausage-string appearance of the blood vessels in the eyes or a palpable plasmacytoma. Tenderness in affected bones and hip ligaments may also occasionally be elicited, including tenderness or pain radiating around the chest or waist when plasmacytomas compromise the spine, spinal cord, and nerves. 24 managedcareoncology Quarter

3 The bruising, secondary to low platelet count or amyloidosis, may likewise be noted upon physical examination. Rather than suspicion generated from presenting symptoms or physical examination, MM is more frequently detected through routine laboratory/ imaging abnormalities. The most common of these abnormalities, and the one that should drastically increase a clinician s suspicion of MM, is elevated levels of M protein in both the blood and urine. This may be suspected when routine chemistry profiles demonstrate an elevated protein level or urinalysis reveals protein in the urine. In 25% of cases, most often in those with advanced disease, hypercalcemia may be detected in the blood. 3 Likewise, high levels of uric acid and blood urea nitrogen (BUN)/creatinine or coagulation dysfunction should be investigated further. In approximately 10% of MM patients, serum vitamin B12 and red blood cell folic acid may register below normal levels. 3 In terms of hematology, counts of red blood cells (anemia), white blood cells, and platelets may be low depending on the amount of bone marrow involvement and the presence or absence of vitamin B12 or folate deficiency. Imaging may also indicate a potential diagnosis of MM if an X-ray shows distinct bone damage. Often noted are apparent holes (i.e., lytic lesions), unexplained osteoporosis, or fractures of the spine. Building upon these laboratory/ imaging abnormalities, a definitive diagnosis of MM is established by the detection of the specific M protein in the serum and/or the urine, the presence of abnormal plasma cells in the bone marrow, low levels of otherwise normal antibodies, bone lesions, or the existence of plasmacytoma. Several components comprise a complete workup for MM: protein electrophoresis and myeloma typing of serum and urine by immunofixation, as well as an evaluation of kidney function, serum calcium, uric acid levels, and all antibody levels, including functional antibodies. A complete bone survey via X-ray of the arms, legs, back, pelvis, and skull is advisable to rule out any significant damage that needs immediate attention. Finally, a bone marrow biopsy is necessary to evaluate the extent of myeloma cell proliferation, their activity in the bone marrow, and the extent of damage they have caused the normal bone marrow structure. A bone marrow biopsy is also necessary to perform cytogenetic testing, which has prognostic value. Monoclonal gammopathies are a spectrum of disorders that may be benign or malignant. Specifically, monoclonal gammopathy may start as benign and remain as such or evolve to a symptomatic and malignant form. On the more benign end of this spectrum, monoclonal gammopathy of unknown significance (MGUS) is the least aggressive subclass of plasma cell dyscrasia, affecting 2% of the American population ages 65 and older. 3 Patients with MGUS have only a small abnormal M protein spike (< 3.0 g/dl and < 2.0 g/dl for IgG, IgA, and IgM, respectively), insignificant or no bone marrow involvement (< 10% plasma cells), no bony involvement, normal blood counts, and typically normal levels of unaffected antibodies. 3 The urine is also usually free of monoclonal protein. Individuals with this form of plasma cell dyscrasia have a 20% to 25% chance of developing MM or a related hematologic disorder at an incidence of 1% annually. 3 Next, smoldering multiple myeloma (SMM) has some characteristics similar 25

4 (ISS), originally published by the International Myeloma Working Group in The Durie-Salmon staging system originally published in 1975 is still in use, but the ISS has achieved more widespread credibility since its introduction. ISS staging divides cases of MM into three stages and is based simply on ß2-microglobulin and serum albumin alone. The criteria for this staging system, which guides the course of treatment and is predictive of likely survival, can be found in the table below. 4 to MGUS, except that the serum M spike is > 3.0 g/dl, the percentage of plasma cells in the bone marrow is higher (10% to 20%), and there is a greater likelihood that normal antibodies will be suppressed. 3 Patients with SMM do not have anemia, renal failure, or bone disease. Generally considered more severe than MGUS, approximately half of individuals with SMM will progress to MM. 3 At this stage, since no consequences of myeloma exist, it is generally observed without early treatment. The presence of a plasmacytoma may indicate active MM, and the following criteria may be used to confirm: (1) the monoclonal protein level is > 3.0 g/dl or > 2.0 g/dl for IgG or IgA and IgM, respectively; (2) the bone marrow contains > 20% plasma cells; (3) the patient has abnormally low quantitative immunoglobulins; and (4) the patient demonstrates the presence of destructive bone changes. Otherwise, plasmacytoma may exist as a freestanding, true disease. While solitary plasmacytoma of the soft tissue or the bone can potentially be cured by local treatment (i.e., radiation therapy), multiple plasmacytomas or plasmacytomas that are part of MM must be treated with systemic therapy. When a definitive diagnosis of active MM (i.e., not MGUS or SMM) is made, the disease is staged according to the International Staging System Pharmacologic Treatment Several treatment options are available for patients diagnosed with MM, including both pharmacologic and nonpharmacologic therapy. In general, initial treatment should be based on a patient s age and comorbidities as well as prognostic factors at the time of diagnosis. In recent years, high-dose chemotherapy followed by hematopoietic stem cell transplantation has become a standard of care for patients ages 65 and older who can tolerate this course of treatment. Prior to stem cell transplant, patients typically receive an induction chemotherapy regimen, such as thalidomide-dexamethasone, bortezomib-based regimens, or lenalidomide-dexamethasone. While induction chemotherapy and hematopoietic stem cell transplantation have proven relatively effective in achieving disease containment and suppression, in recent years, similar progression-free survival (PFS) has been achieved in initial treatment with The International Staging System for Multiple Myeloma and Associated Median Survival by Stage 2,4 Stage ß2-microglobulin Serum Albumin Median Survival I < 3.5 mg/l 3.5 g/dl 62 months II < 3.5 mg/l < 3.5 g/dl 3.5 mg/l to 5.5 mg/l Any 44 months III 5.5 mg/l Any 29 months 26 managedcareoncology Quarter

5 newer therapies, such as lenalidomide and bortezomib without stem cell transplant. Furthermore, recent transplant data suggest that transplant is a potentially viable option after relapse, if pharmacologic therapy is unsuccessful. Although some patients have been cured with allogenic stem cell transplantation, there is a 5% to 10% treatment-associated mortality rate associated with this line of therapy, and most patients are not candidates. The most common form of the hematopoietic stem cell transplantation autologous stem cell transplantation offers no cure, but it may prolong overall survival. However, it remains to be seen if this initial form of therapy is more effective than pharmacotherapy alone with the newer agents. For patients ages 65 and older and those with significant concurrent illness, stem cell transplantation is often intolerable. In these patients, the standard of care for initial treatment has previously been chemotherapy with melphalan and prednisone. However, once again, recent data in these populations suggest improved outcomes with the newer chemotherapy regimens mentioned previously. For example, treatment with bortezomib, melphalan, and prednisone elicited an estimated overall survival of 83% at 30 months, while lenalidomide plus low-dose dexamethasone elicited an 82% survival at two years. 5,6 Furthermore, the regimen of melphalan, prednisone, and lenalidomide yielded a 90% survival at two years. 6 After initial treatment with either induction chemotherapy/stem cell transplant or pharmacotherapy alone, maintenance therapy with thalidomide, bortezomib, or lenalidomide regimens may assist in further reducing tumor burden and prolonging PFS. Furthermore, recent data show an overall survival advantage in patients treated with maintenance lenalidomide after autotransplant. Intermittent treatment with corticosteroids is employed by some clinicians but with less robust data. In addition to these primary forms of maintenance therapy, additional forms of supportive care can be used for managing some of the collateral damage caused by MM. Bisphosphonates assist in stabilizing bone destruction and may strengthen weakened bones. Judicious use of radiation therapy can be employed for bone lesions and/or bone pain in applicable cases. Erythropoietin-stimulating agents are used as supportive care in some patients with anemia, but the complication rate with these agents is significantly higher in those with MM. In the event of relapse or recurrence, the next course of action is determined by prior treatment modalities and re-evaluation of the patient s functional status. In these cases, retreatment using the initial agent in combination with a new therapy may elicit an improved response, as may switching to a completely different class of therapy or agent with a different mechanism of action. Clinical trials at this stage should always be offered, considering the abundance of new drugs currently available in the pipeline. In general, as the disease progresses, other therapy is warranted. This includes regimens such as high-dose cyclophosphamide or liposomal doxorubicin, assuming the patient can tolerate such treatment. Managed Care Considerations Current clinical practice in the treatment of MM remains on the forefront of data from current research, with many hematologists and oncologists employing regimens that have demonstrated efficacy in the literature but have yet to achieve acceptance in clinical guidelines. Since effective regimens for MM are being discovered at a rate much faster than can be incorporated in consensus recommendations, clinical pathway initiatives and similar interventions must be liberal and flexible to be successful among hematologists and oncologists. Thankfully, most payors are willing to review the clinical data presented by their network physicians and grant approval when a treatment regimen meets evidence-based criteria. For example, while lenalidomide is only indicated for relapsed MM, coverage is frequently granted for initial and maintenance therapy based on available data from the literature. As the introduction of agents such as lenalidomide and bortezomib has dramatically changed the face of conventional treatment for MM, so will additional pipeline drugs as they receive approval. The proteasome inhibitor carfilzomib and the immunomodulator pomalidomide are currently showing promise in their capacities to build upon the success of bortezomib and lenalidomide, so the future is now. By staying on the leading edge of the research, managed care stakeholders can ensure the clinically appropriate and cost-effective utilization of these newer therapies while minimizing push back from the provider network. Of course, judicious use of these costly agents on the part of clinicians is imperative, and collaboration between payors and providers in the management of this complex disease will ultimately benefit the patient. References 1. Multiple myeloma/other plasma cell neoplasms. National Cancer Institute website. cancertopics/types/myeloma. Accessed June 29, Detailed guide: multiple myeloma. American Cancer Society website. DetailedGuide/index. Accessed June 29, Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111: Greipp PR, San Miguel J, Durie BG, et al. International Staging System for multiple myeloma. J Clin Oncol. 2005;23: 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: Durie BGM. Treatment of myeloma: are we making progress? N Engl J Med. 2008;359: