Multidisciplinary Management of Multiple Myeloma in Older Adults

Submitted on 08/17/17
Citation

Journal of Clinical Pathways. 2017;3(6):45-48.

Affiliation

Department of Family Medicine, Prince George’s Hospital, Cheverly, MD; The Access Group, Berkeley Heights, NJ.

Correspondence

Dr Richard G Stefanacci

400 Connell Drive, 2nd Floor

Berkeley Heights, NJ 07922

Phone: (908) 508-6714

Email: rstefanacci@theaccessgp.com

Disclosures

Drs Tavakoli, Khan, and Knowles report no relevant financial relationships. Dr Stefanacci is the chief medical officer for The Access Group, a managed markets agency for pharmaceutical companies.

Abstract: Multiple myeloma (MM) is a progressive and fatal disease, primarily affecting men aged 66 years or older. Because MM is primarily a disease of the elderly, it is incumbent on geriatricians and primary care providers to understand the best course of management for their patients with this disease. Although the acute management of MM is driven by specialists, the identification of MM and management outside of the oncologist’s office will fall to geriatric care providers. In this article, the authors review information to guide the appropriate management of older adults with MM and discuss issues that may arise from the multidisciplinary management of this patient population.  

Received April 2, 2017

Accepted July 14, 2017

Multiple myeloma (MM) accounts for roughly 1% of all cancers in the United States and affects all races and geographics, although a greater incidence has been seen in individuals of African descent.1-3 The disease occurs more frequently in men, especially those aged 66 years or older. It is also seen in those with a higher body mass index.4

Because MM occurs most commonly in older adults, primary care providers (PCPs) and geriatric specialists need to be well versed in its management. In this article, we review the current information about diagnosing and caring for older adults with MM in order to guide multidisciplinary care for this patient population, many of whom might be frail.

Pathophysiology Overview 

MM is a fatal disease characterized by the proliferation of plasma cells that turn malignant and produce lytic lesions at multiple bony sites, including skull, ribs, vertebrae, and long bones of extremities, with concomitant IgM or IgG antibody production.5 The overexpression of light chains can then deposit in the kidneys, causing renal failure; deposits also occur in the bone marrow, causing bone pain, hypercalcemia, anemia, and increased susceptibility to infections.5 As such, it is important that these patients receive vaccines yearly pneumococcal pneumonia and influenza vaccines from their PCPs.6

Most cases of MM tend to start as monoclonal gammopathy of undetermined significance (MGUS). Although this is stipulated, the steps of this transformation process remain unknown, and there are postulations of several events that may take place for MGUS to change into MM.5 The formation of MGUS is thought to occur when antigens are presented to B cells, from which cell formation abnormalities follow. About half arise from B-cell immunoglobulin heavy locus translocation, while half are seen to be a cause of hyperploidy; less likely, it is a combination of both.7

It is believed that multiple random events occur when MM forms from MGUS, including secondary translocations, Ras mutations, p16 methylation, p53 mutations, increased cell production due to abnormal cell cycle, avoidance of apoptosis, increased angiogenesis, or IL-6 in bone marrow.8 Depending on which translocation is picked up, the disease can be categorized into different risk groups, and treatment is tailored to the specific risk group.9

Risk Factors

Epidemiological data suggest a genetic predisposition to MM in addition to other potential risk factors, such as older age, immunosuppression, and environmental exposures.10-14 Exposure to radiation, organic solvents, herbicides, and insecticides are also thought to play a role; however, the number of cases reported for each risk factor is small. It is shown that radiologists exposed to large doses of long-term radiation have an increased risk of MM.13 There is not enough research in this area to make a firm cause-and-effect relationship, but physicians should be aware of this potential relationship when gathering a social history. PCPs should obtain a history of patient hobbies as well as work history, as some might be relevant to MM. Even though this direct causal relationship between radiation, organic solvents, herbicides, insecticides, and MM has not been confirmed, physicians should consider patients with these exposures as high risk, and should consider a lower threshold for screening them for MM with initial diagnostic testing.

Clinical Presentation

The majority of patients with MM present with bone pain, commonly in the back area.2,5 Bone pain is secondary to the myeloma cells stimulating osteoclasts to resort bony matrix and by the cells inhibiting osteoblasts.15

Other common presenting symptoms are fatigue secondary to anemia, pathological fractures, or weight loss. Less common presenting symptoms are fever, paresthesias, infection, cardiomegaly, or altered mental status.2,5,10,16-18 The most common features of MM can be remembered by the popular mnemonic CRAB: calcium elevation, renal failure, anemia, and bone pain. As PCPs, our threshold for MM screening in a black or African American male patient aged older than 60 years, who presents with a symptom such as back pain, should be low. A patient may present with no symptoms; with one of the common symptoms mentioned above, such as back pain; or with multiple common symptoms, which makes a differential diagnosis easier. It is the responsibility of PCPs to recognize the population most affected by MM, and to test accordingly. Due to the vagaries of certain symptoms, MM should be part of a differential diagnosis for black or African American men older than 60 years, so that we may screen these patients, diagnose MM in earlier stages, and refer these patients to appropriate specialized care from hematologists and oncologists.

Diagnostic Testing

Initial diagnostic testing must be ordered upon clinical suspicion of MM. These tests include complete blood count (CBC) with peripheral blood smear; serum calcium; basic metabolic panel, to evaluate creatinine; liver function test, to evaluate albumin; lactate dehydrogenase test (LDH); beta-2 microglobulin; and C-reactive protein, to determine prognosis of the disorder. At the same time, serum protein electrophoresis and immunofixation, serum free light chain assay, and a 24-hour urine protein for electrophoresis and immunofixation should be performed.19-22 Beta-2 microglobulin levels, along with albumin, are used for staging and prognosis of MM.3

Should the blood work be suggestive of MM, the next step is imaging to evaluate for lytic bone lesions. A metastatic bone survey, including humerus and femur, using plan radiography is imperative to the diagnosis of MM.23 Most patients presenting with bone pain will have signs of MM such as puched-out lesions, which are detected in 80% of patients undergoing skeletal bone survey at the time of diagnosis.19,24-29 If the skeletal survey via X-ray is normal in patients who are presenting with bone pain or in patients who are asymptomatic, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography scan should then be ordered before diagnosis is made for solitary plasmocytoma or smoldering MM, respectively.19,27-29 CT scans are also useful in identifying suitable locations for bone biopsies to be directed.30 MRI is shown to be superior for detecting focalization diffuse lesions of the axial skeleton, while the metastatic bone survey using plain radiography better identifies bone lesions of the appendicular skeleton.31 In one study, with all patients receiving both MRI of the axial skeleton and X-ray of the axial and appendicular skeleton, MRI was able to detect 52% of focal lesions negative on skeletal survey, whereas X-ray detected only 20% of focal bone lesions that was negative on MRI. This study showed that MRI was better able to detect lesions of the pelvis, sternum, and spine, whereas the skeletal survey was better able to detect lesions on the humerus, femur, and ribs.31 Of note, technitium-99 scan is inferior to above imaging and should not be performed.32

The diagnosis of MM in asymptomatic patients is called smoldering MM.11 If patients are asymptomatic, the diagnostic criteria will be: a serum M protein spike(>3 g/dL), elevated plasma cells in the bone marrow (>10%), with no organ damage symptoms such as renal failure, bone pain, or anemia.11

Patients who present with symptoms such as bone pain or anemia will require a M protein spike measure via serum or urine (>3g/dL), elevated plasma cells in the bone marrow (>10%), with indications of organ damage such as renal failure or anemia.11 For confirmation of diagnosis of MM, a bone marrow aspiration and biopsy should be performed.

Diagnosis of MM, according to the revised International Myeloma Working Group,27 is made when there is either:

  • > 10% clonal plasma cells in bone marrow, OR
  • Biopsy proven BONY or SOFT TISSUE plasmocytoma
  • PLUS 1 of:
  • Damage to organs which is shown by the mnemonic CRAB: 
  • Hypercalcemia (serum calcium >11 mg/dL) 
  • Renal impairment (serum creatinine > 2mg/dL)
  • Anemia (hemoglobin <12 g/dL)
  • Bone lesions
  • OR, with presence of marker suggestive of progression to end organ damage:
  • Large amount of plasma cells in bone marrow, >60%
  • Free light chain ratio >100
  • MRI with multiple bone lesions 

PCPs should work to coordinate care with experienced oncologic subspecialists for patients with positive initial diagnostic testing and lytic lesions. Further evaluation, such as bone marrow biopsy, should be arranged to confirm diagnosis and initiate treatment. PCPs should still continue to follow the patient and monitor for psychosocial support, disease progression and/or complications, and adverse events associated with medications used to treat MM.

Treatment

MM treatment consists of several options, such as chemotherapy, bisphosphonates, radiation, surgery, stem cell transplantation, and/or plasmapheresis.33 The treatment of MM is tailored to the disease grade, and this depends on which specific type of translocation is present. A technique called fluorescence in situ hybridization (FISH) will look for specific translocations and/or deletions, and the treatment differs for each risk group. There are different classifications of MM: high risk, intermediate risk, and standard risk. The classification depends on which specific translocation is present using the FISH technique in addition to abnormal lab values, which include LDH and CBC.9,34 Once this is established, prognosis continues to remain uncertain as it depends on age, comorbidities, stage, and response to treatment. The risk vs benefit needs to be weighed when evaluating whether to pursue treatment or not. Chemotherapy can be aggressive and produce harmful adverse events, particularly in the elderly population.9,34

Once the classification of the MM is identified, the next step includes determining whether the patient is eligible for autologous hematopoietic cell transplantation (HCT).9 In general, patients in overall good physical condition are eligible for high-dose chemotherapy and stem cell transplantation.35 Chemotherapy followed by HCT appears to improve survival. All patients typically receive induction therapy. There are newer agents available including thalidomide, lenalidomide, bortezomib, and carfilzomib, and because of these, the role of HCT may change.9 It appears that patients are just as responsive to these newer agents as to HCT. Other studies have shown that a procedure termed double (tandem)-autologous HCT, consisting of chemotherapy followed by an additional HCT, may offer even better outcomes. Multiple studies have looked into how successful this is. In particular, one study evaluated event-free survival and overall survival after induction regimens, followed by a double autotransplant procedure. The researchers found that event-free survival was 49 months, and overall survival exceeded 62 months.36

One of the complications of HCT is that there might be residual malignant cells. If a patient cannot tolerate high-dose chemotherapy and HCT, the only option is chemotherapy alone. Chemotherapy continues until the level of M-protein is stable in the serum and urine, and the patient becomes less symptomatic.9 If the protein cannot be measured in the serum or urine, the next step is to measure the free light chain assay to evaluate for response.

Risk Stratification

Of note, survival depends on which risk group the MM falls under. For instance, high-risk MM accounts for approximately 15% of patients, and is associated with a median survival of approximately 2 to 3 years.9,34,37 These patients tend to do poorly with conventional treatment options and should be considered for novel therapeutic strategies (eg, early use of bortezomib-containing regimens).9

Adverse Events

MM treatment options are associated with adverse events, including blood clots, neuropathy, anemia, fatigue, infections, gastrointestinal issues, problems with bleeding, and easy bruising.37 Treatment might even be halted if these adverse events are causing a significant amount of distress. These conditions require specific treatments, in addition to chemotherapy, and a multidisciplinary care approach is required. The PCP should actively manage the patient, in conjunction with treating specialists. Once diagnosed, treatment is initiated by the medical oncologist and radiation oncologist, but patients will often bring their concerns regarding adverse events to PCPs. If a patient becomes symptomatic for anemia, it is important for the PCP to address this issue, for a possible blood transfusion. Likewise, if a patient experiences bleeding due to thrombocytopenia, it is the role of the PCP to address this and take appropriate action. If the patient becomes pancytopenic and febrile during chemotherapy, the PCP should consult with an infectious disease specialist for further treatment and work-up. PCPs should play a crucial role in coordinating patient care across the treatment spectrum.

Conclusion

MM is a systemic disease which affects multiple organ systems. Patients typically present with bone pain, especially in the back. Diagnostic tests used to confirm MM include CBC, comprehensive metabolic panel, albumin, and beta-2 microglobulin, which are used to check for hypercalcemia, anemia, and elevated creatinine, all of which are suggestive of MM. Patients with MM have an abundance of malignant plasma cells in the bone marrow that needs to be eliminated. These clones take over the function of the good functioning plasma cells and in doing so, they produce antibodies that impair multiple systems in the body. Because the disease is systemic, it is treated systemically, usually with chemotherapy and/or autologous HCT. Treatment options depend on patient risk categorization. It is important to monitor the level of M-protein, both in the serum and in the urine, to make sure that the response is appropriate when treatment is started.

Patients with MM frequently develop complications related to their disease, including hypercalcemia, renal insufficiency, infection, and skeletal lesions, as mentioned earlier. These conditions require specific treatments in addition to chemotherapy. As such, there needs to be close discussion between PCPs and oncologists to manage the patient appropriately. As with many conditions affecting older adults, geriatric specialists and PCPs will play a key role in the overall care of these patients. 

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