Multiple myeloma (MM) is a malignancy of the plasma cells, which are a type of white blood cell arising from B-cells or B-lymphocytes. Healthy plasma cells are produced in the bone marrow and play an important role in the immune system. Multiple myeloma is a plasma cell dyscrasia, which is a disorder that causes an overproduction of abnormal plasma cells. Also referred to as Kahler disease, myelomatosis, and plasma cell myeloma, MM occurs when plasma cells differentiate to produce abnormally high levels of monoclonal immunoglobulins. Although a solitary plasmacytoma can occur, multiple myeloma is considered a systemic disease (Grossman & Porth, 2014; Ignatavicius, Workman, & Rebar, 2018; Multiple Myeloma Research Foundation [MMRF], n.d.g; Soh, Taria, & Wallace, 2017).
Multiple myeloma is rare, though it is still the second most common type of blood cancer. In the US, approximately 27,000 to 32,000 new cases are diagnosed each year, and there is an average of 12,960 deaths annually. Multiple myeloma is more commonly diagnosed in patients who are over 60 years of age, African American, and male. While MM is not considered a curable disease, treatment for the condition has evolved and contributed to significant improvements in overall survival. Historically, survival was limited to less than one year, but the median overall survival has now increased to seven to eight years, with enhanced quality of life and some patients achieving long-term survival (Michels & Petersen, 2017). With advancements in chemotherapeutic agents and other treatment modalities, the average survival is 45 to 60 months or more (Grossman & Porth, 2014; Ignatavicius et al., 2018; MMRF, n.d.g; National Cancer Institute [NCI], 2019; Soh et al., 2017).
Etiology and Pathophysiology
The etiology of multiple myeloma remains largely unknown. Research indicates that most cancers are caused by genetic mutations which occur during cell division as the 23 pairs of chromosomes in the human body are copied. Approximately 50% of patients diagnosed with multiple myeloma will lack chromosome 13, while others will have a translocation of other chromosomes. Some proposed etiologies of MM include hereditary factors, environmental exposure to ionizing radiation, exposure to low-level radiation, and exposure to metals, agricultural chemicals, petroleum products, and silicone (Itano, 2016).
Healthy bone marrow produces immature, non-differentiated blood stem cells which undergo a series of steps and changes until they fully mature into erythrocytes (red blood cells), leukocytes (white blood cells), and platelets. Figure 1 demonstrates the process by which blood stem cells differentiate into committed myeloid or lymphoid stem cells before they mature into one specific cell type. Lymphoid stem cells mature into T-lymphocytes, B-lymphocytes, and natural killer cells, whereas B-lymphocytes are stimulated by chemicals released from the helper T-cells, which causes them to divide and generate plasma cells (Ignatavicius et al., 2018).
Plasma cells are a critical component of the body’s immune system. They assist with fighting infection by producing antibodies, referred to as immunoglobulins, when the immune system recognizes a foreign object, or antigen. When antigens invade the body, they are targeted as foreign intruders and plasma cells respond by generating antibodies (MMRF, n.d.g). Healthy plasma cells produce a variety of antibodies that include immunoglobulin M (IgM), IgG, IgA, IgD, and IgE which exist in equal proportions within the body (Grossman & Porth, 2014; Ignatavicius et al., 2018).
In multiple myeloma, the body’s bone marrow produces excess abnormal plasma cells which have undergone malignant transformation from damage to the DNA in the B-cell. As the bone marrow produces excess plasma cells, the number of healthy plasma cells, erythrocytes, leukocytes, and platelets are crowded out and thereby reduced in peripheral circulation. This complex process results in the production of excessive amounts of a single abnormal antibody referred to as monoclonal, myeloma protein, or M protein. M protein is typically composed of an excess of IgG in about 60% of cases or IgA in about 20% of the cases. The remaining 15 to 20% is attributed to a protein known as Bence Jones. This protein has a lower molecular weight and is considered a light chain immunoglobulin. Patients with this protein are likely to secrete it in their urine. Bence Jones proteins are likely to cause damage to the renal tubular structures, which can lead to renal failure if untreated (Grossman & Porth, 2014; MMRF, n.d.g). M protein lacks the ability to fight infection and accumulates in the blood and urine. It has the potential to cause damage to vital organs such as the kidneys, and reduces the immune system’s ability to carry out necessary activities. These abnormal cells also produce increased amounts of cytokines which can lead to bone destruction (Grossman & Porth, 2014; Ignatavicius et al., 2018; MMRF, n.d.g; Soh et al., 2017).
As the excess M protein accumulates in the hematologic and renal systems, damage may occur to the kidneys and other essential organs. During myeloma cell proliferation, there is also increased activation of the osteoclasts, which leads to an increase in bone breakdown and resorption (Grossman & Porth, 2014; Ignatavicius et al., 2018). As patient’s plasma cells convert to myeloma cells, they can form what is known as plasmacytomas in the bone and soft tissue. These plasmacytomas frequently occur in the gastrointestinal tract or in the bone, causing the destruction of the bone and producing pain. These painful tumors in the weakened bones can eventually lead to a spontaneous fracture. Approximately 90% of all multiple myeloma patients will have multiple bone lesions upon diagnosis or during the disease. The trauma and bone resorption can also lead to potentially life-threatening hypercalcemia. Hypercalcemia means less available calcium in the bones to provide density and strength, as well as significant cardiac and central nervous system dysfunction. Hypercalcemia, which is defined as a serum calcium level of more than 2.75 mmol/L, can also contribute to the development of renal calculi (MMRF, n.d.g).
There is a spectrum of conditions that fall under the category of plasma cell malignancies and are either closely related to or considered precursors to multiple myeloma. These include:
- Solitary plasmacytoma
- Smoldering myeloma (asymptomatic),
- Monoclonal gammopathy of undetermined significant (MGUS), and
- Monoclonal gammopathy of renal significance (MGRS).
Solitary plasmacytoma occurs when a tumor composed of plasma cells develops in a single, localized area of the body. This is often in the bone but may also develop in soft tissue. The condition is exceedingly rare, accounting for about 2-5% of all plasma cell dyscrasias and can be subdivided into two types; solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP). The two types are distinguished by whether the lesion originates in a bone or in the soft tissues. The incidence of SBP is approximately 40% higher than SEP. Patients with a solitary plasmacytoma do not have systemic myeloma cells in the bone marrow or throughout the body. Unlike multiple myeloma, a solitary plasmacytoma can be cured with timely and appropriate treatment, however up to 70% of these will transform into multiple myeloma over time. The most common signs and symptoms of the condition include bone pain and bony destruction, which can progress to spinal cord or nerve root compression as the condition worsens (Grammatico, Scalzulli, & Petrucci, 2017).
Smoldering multiple myeloma (SMM) is considered a precancerous condition that is asymptomatic, meaning the patient does not have symptoms and the disease is often picked up as an incidental finding on laboratory results performed for other indications (Michels & Petersen, 2017). These patients may present with mild anemia that is not attributed to other causes, and further workup usually indicates elevated levels of serum M protein and a few small nonspecific bone lesions on imaging (MMRF, n.d.g). Patients with SMM generally progress to MM at a rate of 10% per year during the first five years, and then at a lower rate with subsequent years (Michels & Petersen, 2017). Treatment of SMM can delay or prevent the transformation of disease to MM (MMRF, n.d.g).
Defining criteria of smoldering myeloma according to the National Comprehensive Cancer Network (NCCN, 2019) guidelines includes the presence of the following:
- “Serum monoclonal protein at least 3 g/dL, OR
- Bence-Jones protein at least 500 mg/24 h, AND/OR
- Clonal bone marrow plasma cells 10%-59%, AND
- Absence of myeloma-defining events or amyloidosis” (NCCN, 2019, p. MYEL-C).
Monoclonal gammopathy of undetermined significance (MGUS) is another type of plasma cell neoplasm. MGUS indicates the presence of M protein in small amounts, but no other diagnostic criteria are present to indicate MM, specifically the percentage of plasma cells on bone marrow biopsy. In the US, approximately 1% of people have M protein in their blood. The presence of M protein usually does not cause symptoms, nor does it require medical treatment. Patients with MGUS should be monitored, as 1-2% of patients with MGUS will advance to MM (Grossman & Porth, 2014; MMRF, n.d.g). MGUS is similar to MM as it leads to the development of mutated or clonal plasma cells that produce monoclonal proteins. These monoclonal proteins cause an M-spike, or high levels of one of the free light chains (kappa or lambda), or both. MGUS does not lead to any damage within the body. MGUS does not require any interventional treatment other than monitoring; for the vast majority of people living with MGUS, the disease will continue to be benign for the rest of their lives (Michels & Petersen, 2017).
A 2019 study by Landgren et al. evaluated the correlation between changes in serum immune markers and disease progression. The results of the study indicate that patients with MGUS should be followed on an annual basis to monitor for any change in their condition. These patients should have annual blood work, a risk assessment, and a physical assessment to monitor for any changes. Even though the risk of conversion from MGUS to MM is extremely low, doing annual surveys proves to be beneficial (Landgren et al., 2019).
Monoclonal gammopathy of renal significance (MGRS) is a relatively newer diagnosis within the realm of MM. It is premalignancy preceding MM that is similar to MGUS. MGRS is characterized by a low level of monoclonal protein or free light-chains. However, unlike MGUS, the monoclonal proteins damage the kidney and the condition is associated with high morbidity and mortality (Steiner et al., 2018).
There are known genetic mutations in MM, but the mutations are often unique from patient to patient. These mutations may be inherited or can develop over time. Having a first-degree relative with MM is thought to increase the risk slightly, but it is not considered to be a hereditary disease. The research indicates that these risk factors only slightly increase the risk of developing MM. Most research at this time indicates that cancers, including MM, are caused by random mutations that occur during one’s life. Age is a significant risk factor for MM. Approximately 96% of persons diagnosed are over the age of 45, and 63% are over the age of 65 (MMRF, n.d.g).
Other risk factors include being of African American ethnicity and male. Environmental exposures that can increase the risk of MM include pesticides, benzene, asbestos, working with chemicals used in the manufacturing of rubber, and wood products. Because exposure to wood products is a risk factor, carpenters and others who work with wood have increased risk. There is an indication that exposure to herbicides, such as Agent Orange, is a risk factor. Disorders that decrease your immune system, exposure to radiation, and the presence of MGUS are considered risk factors (Grossman & Porth, 2014; MMRF, n.d.g).
Signs and Symptoms of Multiple Myeloma
Patients who have MM are symptomatic. Symptoms can be nonspecific and generalized, such as nausea, vomiting, weakness, fatigue, and weight loss. Nearly all patients present with anemia at some point in their disease (Michels & Petersen, 2017). In patients who present with symptoms at the time of diagnosis, it is likely that the MM has already caused musculoskeletal or renal damage (MMRF, n.d.g). Bone pain is one of the most commonly reported symptoms of MM, as approximately 75% of patients will have an initial symptom of bone pain. Bone destruction or plasmacytomas occurring in the vertebra can result in vertebral fractures and spinal cord compression. Spinal cord involvement can lead to neuropathy (Grossman & Porth, 2014; Ignatavicius et al., 2018; Mayo Clinic, 2019a).
A rise in the M protein can cause the patient’s blood to become viscous, resulting in possible heart failure and renal dysfunction (Grossman & Porth, 2014; Ignatavicius et al., 2018). As the kidneys attempt to filter the blood, the excess M protein and calcium may cause their filtration system to work harder than it should. When the kidneys are overworked for an extended period, renal insufficiency ensues, which has the potential to progress to renal failure. These patients may present with declining urinary output and fluid retention (MMRF, n.d.f).
Other symptoms the patient may experience are related to a decreased immune function, causing the patient to be more susceptible to infections, especially bacterial infections. Patients may experience gastrointestinal symptoms associated with plasmacytomas in the gastrointestinal tract or systemic hypercalcemia. Some of these symptoms would include nausea, constipation, anorexia, thirst, and weight loss (Grossman & Porth, 2014; Ignatavicius et al., 2018; Mayo Clinic, 2019a). Hypercalcemia results from bone destruction causing excess calcium to be released into the bloodstream. The symptoms of hypercalcemia are similar to the symptoms found in plasmacytomas of the gastrointestinal tract. Besides the gastrointestinal symptoms listed above, the patient may experience fatigue, excessive urination, restlessness, difficulty concentrating, and confusion (MMRF, n.d.f).
Anemia symptoms include pallor, weakness, weight loss, fatigue, shortness of breath, and vertigo. These may occur as the patient’s erythrocyte counts decline. A normal hemoglobin level is 12 to 16 g/dL in a female patient and 14 to 18 g/dL in a male patient. Some resources describe anemia in levels of severity based on the hemoglobin level:
- Mild anemia is a hemoglobin level lower than the normal range but above 10 g/dL.
- Moderate anemia is a hemoglobin level from 8.0- 9.9 g/dL.
- Severe anemia is a hemoglobin level from 6.5- 7.9 g/dL.
It is important to note that anemia can become life-threatening when the hemoglobin is less than 6.5 g/dL. It is estimated that at least 60% of all patients diagnosed with multiple myeloma have anemia when diagnosed, and the other 40% will develop it (Grossman & Porth, 2014; Ignatavicius et al., 2018; MMRF, n.d.f).
The collection of symptoms seen in symptomatic multiple myeloma is often referred to using the acronym CRAB, which stands for:
- Calcium- indicating serum hypercalcemia,
- Renal dysfunction- indicating elevated creatine (greater than 173 mmol/L)
- Anemia- indicating a hemoglobin at least 2 g/dL below the lower limit of normal, or less than 10 g/dL.
- Bone pain or lesions- indicating symptomatic evidence of plasmacytomas, evidence of osteoporosis, or vertebral fracture on imaging (International Myeloma Foundation, 2014).
The NCCN is an alliance of leading cancer centers and world-renowned experts devoted to cancer care, research, and education. Through rigorous clinical trial research, data compiled across institutions, and annual expert panel review, the NCCN provides evidence-based clinical practice guidelines in oncology according to cancer cell type, pathology, staging, inheritance patterns as well as several other specific features. The guidelines are widely utilized in cancer care and guide the diagnostic work up and medical decision-making throughout the patient’s disease trajectory. According to the MM guidelines, the initial diagnostic work-up for patients presenting with symptoms and clinical findings concerning for multiple myeloma include the following:
- History and physical exam,
- CBC, differential, platelet count,
- Peripheral blood smear,
- Serum BUN/creatinine, electrolytes, albumin, calcium, serum uric acid, serum LDH, and beta-2 microglobulin,
- Creatinine clearance (calculated or measured directly),
- Serum quantitative immunoglobulins, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE),
- 24-hour urine for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE),
- Serum free light chain (FLC) assay,
- Whole-body low-dose CT scan or FDG PET/CT,
- Unilateral bone marrow aspirate and biopsy, including immunohistochemistry (IHC) and/or multi-parameter flow cytometry,
- Plasma cell FISH panel on bone marrow (NCCN, 2019)
The diagnostic criteria for multiple myeloma were last updated by the International Myeloma Working Group in 2014 (International Myeloma Foundation, 2014). The new criteria include bone marrow plasmacytosis indicating more than 10% plasma cells, or plasmacytoma on tissue biopsy. In addition, at least one of the following must be present:
- presence of end-organ damage as evidenced by CRAB features,
- more than 60% plasma cells on bone marrow examination
- bone lesion(s) present on MRI that is at least 5mm in size,
- elevated involved serum free light chains and involved/uninvolved ratio (light chains are proteins produced by plasma cells and typically combined with heavy chains to form immunoglobulins, the excess of which enter the bloodstream) (Grossman & Porth, 2014; Ignatavicius et al., 2018; International Myeloma Foundation, 2014).
There are multiple tests that can be ordered to assist in establishing a definitive diagnosis of MM. Below is a list of frequently ordered diagnostic tests.
Blood chemistry is a collection of various lab values that measure substances released by organs and tissues in the body. All the values are important, but some of the specific values the provider will want to evaluate include albumin, calcium, L-lactate dehydrogenase, blood urea nitrogen (BUN), and creatinine (Mayo Clinic, 2019b; MMRF n.d.b).
A bone marrow biopsy is a procedure that requires the patient to sign an informed consent before being scheduled. Bone marrow testing is typically done using local anesthesia or conscious sedation at the provider’s discretion. A sample of bone marrow will be taken from the sternum or iliac crest using a long needle to access the bone marrow. This will provide a sample of bone marrow, bone, and blood to be analyzed by the laboratory. Tests that can be done on these samples include cytogenetic analysis or fluorescence in situ hybridization [FISH] looking for chromosomal/genetic abnormalities. A bone marrow biopsy will also evaluate for malignant cells and an abnormal-appearing chromosome 11, which indicates a more favorable prognosis, whereas the absence of chromosome 13 represents a poor prognosis. The myeloma cells will also be evaluated to determine how quickly they are dividing, which helps the provider establish prognosis (Grossman & Porth, 2014; Ignatavicius et al., 2018; Mayo Clinic, 2019b; MMRF, n.d.b, n.d.c).
Complete blood count with differential is a serum blood test that will evaluate how many total erythrocytes, leukocytes, and platelets are present, as well as determining hemoglobin, hematocrit and the differential, which is a breakdown of the different types of white blood cells (i.e., neutrophils, basophils, eosinophils, lymphocytes, and monocytes). This determines the presence of anemia, the patient’s ability to fight infection, and their potential for bleeding risk (Mayo Clinic, 2019b; MMRF, n.d.b).
Serum protein electrophoresis is a specialized test that can be conducted on either serum, urine, or both. M protein produced by the myeloma cells is typically present in the multiple myeloma patient’s serum or urine. In addition to M protein, the patient may have a second abnormal protein in their blood known as beta-2-microglobulin. If there is a positive presence of this protein, it can help providers assess the aggressiveness of the disorder and determine treatment options. (Mayo Clinic, 2019b; MMRF, n.d.b).
During a 24-hour urine, the patient will be asked to collect their urine for 24 hours. If this is done as an inpatient, nursing is responsible for collecting the urine. A urinalysis should also be ordered to assess for levels of M protein known in urine as Bence Jones. An elevated level of total protein in the 24-hour urine or Bence Jones in the urinalysis may indicate multiple myeloma. (Mayo Clinic, 2019a; MMRF, n.d.b).
Imaging studies are important when establishing a diagnosis of MM. The NCCN (2019) guidelines recommend a whole body lose-dose computed tomography (CT) scan or a fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan. Alternatively, a skeletal survey, which is a series of x-rays of all or most of the bones in the body, may be acceptable in certain circumstances but skeletal surveys are significantly less sensitive. These imaging studies are useful for evaluating the level of change in the bones, determine how many lesions are present, as well as their size and location. When imaging studies detect multiple bone lesions, it indicates a potential case of multiple myeloma (Mayo Clinic, 2019b; MMRF, n.d.b; NCI, 2019).
The provider will evaluate all the diagnostic studies and previous assessment data collected to formulate or rule out the diagnosis of multiple myeloma. Once diagnosed, additional imaging studies may need to be done to determine the extent and placement of bone lesions (Grossman & Porth, 2014; Ignatavicius et al., 2018). According to the NCCN (2019), a diagnosis of multiple myeloma includes the following:
- “Clonal bone marrow plasma cells of at least 10% or biopsy-proven bony or extramedullary plasmacytoma, AND
- Any one or more of the following myeloma-defining events:
o Calcium level that is more than 0.25 mmol/L (1 mg/dL) higher than the upper limit of normal, or greater than 2.75 mmol/L (11 mg/dL)
o Renal insufficiency (creatinine above 2 mg/dL or 177 μmol/L; or creatinine clearance less than 40 mL/min)
o Anemia (hemoglobin below 10 g/dL, or more than 2 g/dL below the lower limit of normal)
o One or more osteolytic bone lesion on skeletal radiography, CT, or FDG PET/CT
o Clonal bone marrow plasma cells of at least 60%
o Involved: uninvolved serum FLC ratio of at least 100 and involved FLC concentration 10 mg/dL or higher
o More than one focal lesion on MRI studies that measures at least 5mm
o Other examples of active disease include “recurrent infections, amyloidosis, light chain deposition disease, or hyperviscosity” (NCCN, 2019, p. MYEL-C).
Staging of Multiple Myeloma
Staging for MM is premised on the International Staging System (ISS) as devised by the IMWG. The stage and prognosis are based on the patient’s serum level of beta 2- microglobulin, serum total albumin level, age, overall physical capacity, and a variety of other serum, urine, and imaging diagnostics. Treatment is usually indicated to help slow the progression of the disease, treat any symptoms the patient is experiencing, and prevent both short- and long-term complications. The staging includes an estimation of the tumor cell mass using the level of the M protein as well as a variety of lab results, bone lesions, and impaired renal function. The more evidence of renal disease, the worse the prognosis (Grossman & Porth, 2014; Ignatavicius et al., 2018; Mayo Clinic, 2019b).
1. Stage I disease is less aggressive. It is defined by a beta-2-microglobulin that is less than 3.5 mg/L and an albumin greater than 3.5 g/dL. No median survival is established for stage I.
2. Stage II is defined by a beta-2-microglobulin that is between 3.5-5 mg/L. The median survival rate is approximately 83 months.
3. Stage III implies the disease is more aggressive and likely involves the bone, kidneys, and other organs. It is defined by a beta-2-microglobulin that is greater than 5.5 mg/L, elevated LDH, or the presence of chromosomal abnormalities. The median survival rate for a patient in stage III is approximately 43 months (Grossman & Porth, 2014; Ignatavicius et al., 2018; NCI, 2019).
Radiation therapy is the treatment of choice for solitary plasmacytoma. Some solitary plasmacytoma also benefit from certain types of surgical intervention. Surgery is indicated for patients with lesions that have caused structural instability of the spine, or if there is neurologic compromised secondary to mass effect. These patients must undergo routine follow up and surveillance, usually every three to six months, with monitoring of laboratory values and urine testing. Repeat imaging is recommended once annually for at least five years following initial diagnosis to monitor for transformation to MM (NCCN, 2019).
SMM does not require treatment, but follow-up and surveillance are advised every three to six months, with laboratory and urine testing. Radiology imaging is recommended annually, or as clinically indicated to monitor for progression to symptomatic MM (NCCN, 2019).
Management of MGUS and MRGS also include routine follow-up and surveillance. Surveillance for MGUS is not outlined or defined by the NCCN guidelines, however MGRS surveillance was recently added to version 2.2020 of MM guidelines due to heightened morbidity and mortality associated with the condition. When MGRS is suspected, NCCN recommends a comprehensive evaluation for kidney disease including kidney function, estimated glomerular filtration rate (GFR), and metabolic urinary testing. Renal biopsy is indicated for patients who meet select criteria indicative of advanced kidney disease. The follow up and surveillance recommendations include monitoring every three to six months with laboratory values, urinary testing, and radiology imaging annually, or as clinically indicated. The goal is to detect the early progression to symptomatic MM to reduce the morbidity and mortality (NCCN, 2019).
Past treatment of MM consisted of the chemotherapeutic agent melphalan (Alkeran) and prednisone (Deltasone). These drugs have been used for many years and are still widely used today. Treatment options may also include stem cell transplant, targeted therapy, biologic therapy, and others. If a patient has mild symptoms, the management plan may be to monitor the patient closely instead of subjecting the patient to chemotherapy and its associated adverse effects (Grossman & Porth, 2014; Ignatavicius et al., 2018).
As the provider establishes a treatment plan, the patient is evaluated for the possibility of a transplant as a treatment option. Otherwise healthy patients under the age of 65 are evaluated for transplant eligibility, while patients over 75 are typically not transplant-eligible secondary to other comorbid conditions or age. Patients between 65 and 75 are evaluated for comorbid conditions and overall health for consideration of transplant (NCI, 2019). The best outcomes are usually from autologous stem cell transplant (MMRF, n.d.e).
Stem cell transplants have largely replaced bone marrow transplants for MM treatment. When the provider and the patient agree on transplant as an option, it is usually used in combination with high doses of chemotherapy. The chemotherapy kills the MM cells but also the healthy cells in the bone marrow. After the destruction of both healthy and unhealthy cells from chemotherapy, the transplant infuses the patient with new and healthy cells. These medications are often administered intravenously, and some can be administered orally. Stem cell transplant can be either autologous, allogeneic, or syngeneic (Mayo Clinic, 2019b; MMRF, n.d.e).
An autologous stem cell transplant uses the patient’s own stem cells, and allogeneic uses cells from a donor. If possible, autologous carry less risk of rejection and other complications. If the patient chooses this option, they will have their own stem cells harvested and stored for a later date. Once the harvesting procedure is completed, the patient will undergo intense chemotherapy or radiation or a combination of both to destroy the myeloma cells. Once the patient has completed this step, the stem cells are reinfused into the patient (MMRF, n.d.e).
If the patient chooses allogeneic transplant (see Figure 2 below), or if an autologous transplant is not an option, the patient will receive stem cells from a compatible donor, usually a relative. The patient will still need to undergo chemotherapy, radiation, or a combination of both. Allogeneic transplantation is associated with additional risks and can result in life-threatening complications. The greatest risk is the complication of graft-versus-host disease (GVHD) when the patient’s immune system identifies the stem cells as foreign. This triggers an immune response to seek and destroy the transplanted stem cells. The last type of stem cell transplant would be a syngeneic transplant (from an identical twin). This reduces the risk for GVHD and is more desirable than an allogeneic transplant, albeit rare (MMRF, n.d.e).
If the patient is not a candidate for transplant, the provider usually reverts to an older and more standard approach using chemotherapy agents such as melphalan (Alkeran) combined with prednisone (Deltasone), vincristine (Oncovin), cyclophosphamide (Cytoxan), doxorubicin (Adriamycin) or carmustine (BiCNU). This type of treatment will not provide a cure for the patient but can control the MM. These chemotherapy combinations may cause adverse effects and toxicities such as myelosuppression, peripheral neuropathy, and decreased quality of life. Nausea, vomiting, diarrhea, or constipation can be severe, and even life-threatening (MMRF, n.d.d). The use of melphalan (Alkeran) can result in bone marrow toxicity, which can lead to the development of myelodysplasia, leukemia, and dysfunction in stem cell production (Grossman & Porth, 2014; Ignatavicius et al., 2018). Targeted therapy includes the use of proteasome inhibitors such as bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro). These medications work by blocking proteasome, a substance in myeloma cells that recycles proteins, eventually killing them. Proteasomes function to break down proteins in both healthy and cancerous cells, so these drugs work by blocking or slowing down the action of proteasomes inside cells. They are generally well tolerated and can slow the progression of the disease or increase the time interval from stem cell transplant to relapse (NCCN, 2019). Bortezomib (Velcade) is given intravenously and can be used as the first treatment of MM or can be used in a patient that has had a relapse of their disease. It can also be given as an adjunct with other medications to enhance their effect. Carfilzomib (Kyprolis) is also given intravenously and is indicated for use in a patient that has previously been treated for MM. It can be given alone or in combination with another medication. Ixazomib (Ninlaro) is a medication that is given orally and is most often given with another medication. It is not typically used as a first choice but is recommended for a patient who has previously been treated for MM with another drug (Mayo Clinic, 2019b; MMRF, n.d.c).
Biological therapy utilizes a class of medications known as immunotherapy drugs. This class of medications uses the body’s immune system to try and fight the myeloma cells by increasing the healthy immune cells’ ability to find and attack the cancer cells. Many of these medications can be administered orally. The medications in this class that are commonly prescribed include lenalidomide (Revlimid), pomalidomide (Pomalyst), and thalidomide (Thalomid) (Mayo Clinic, 2019b; MMRF, n.d.d).
Corticosteroids are commonly prescribed in combination with other medications in the treatment of MM. Corticosteroids reduce inflammation and suppress the immune system. If corticosteroids are used in high doses, they can kill myeloma cells. Commonly prescribed corticosteroids for MM treatment include dexamethasone (Decadron) and prednisone (Deltasone). Corticosteroids have many adverse effects, which include immunosuppression, hyperglycemia, weight gain, impaired skin integrity, or personality and mood changes (Mayo Clinic, 2019b; MMRF, n.d.d).
Panobinostat (Farydak) is the only FDA-approved histone deacetylase inhibitor for the treatment of MM. This medication inhibits the production of histone deacetylase, a protein that causes rapid growth and division of cancer cells. These medications are given with bortezomib (Velcade) and dexamethasone (Decadron) only for patients who have already been treated in the past at least twice for MM (MMRF, n.d.d).
While radiation therapy is the treatment of choice for solitary plasmacytoma, radiation is only used for palliation of symptoms in patients with MM and is generally low-dose. It is used to damage myeloma cells and decrease their ability to grow and divide. Radiation is successful in treating the disease in some cases. The patient may undergo local radiation focused on a specific area or generalized over a larger portion of the patient’s body. At times, radiation is used in combination with chemotherapy prior to transplants or used locally to help relieve bone pain and shrink tumors that are interfering with the spinal cord. Patients must be monitored for radiation burns and other adverse effects such as fatigue, anorexia, bone marrow suppression, or gastrointestinal symptoms (MMRF, n.d.d).
Maintenance therapy is another important piece of MM treatment for certain high-risk patients. After patients have completed primary therapy, particularly those who have undergone stem cell transplantation, they may be placed on maintenance therapy to prolong the response at minimal toxicity (Michels & Petersen, 2017). According to the NCCN (2019) guidelines, lenalidomide (Revlimid) is the preferred first-line maintenance therapy, followed by ixazomib (Ninlaro) or bortezomib (Velcade). As previously described, lenalidomide (Revlimid) is an immunomodulatory drug that works by supporting the function of the immune system. Ixazomib (Ninlaro) or bortezomib (Velcade) are proteasome inhibitors that target the proteasome inside cells (NCCN, 2019).
In addition to the above treatment options, many patients will require adjunctive treatment. This involves treatments for the damage and complications associated with the disease or some of the associated treatments. Many patients experience renal dysfunction, which may lead to fluid and electrolyte issues, requiring fluid management, dialysis, or education to avoid medications known to cause further kidney damage such as nonsteroidal anti-inflammatories. Patients may need to be treated for the bone damage with bisphosphonates or surgical intervention for fractures (MMRF, n.d.f). Bisphosphonates have been part of the treatment plan in patients who have MM for several years, and a recent studyconfirms that these medications should be continued. These medications should be used to lower the risk of pathological fracture and musculoskeletal concerns, although the study did not find that they lower the risk of mortality. It is important to prevent fractures and skeletal damage, as this decreases the incidence of pain, which is a significant concern in patients who have MM (Mhaskar & Djulbegovic, 2018).
Anemia is a common concern, which may require nutritional treatment with diet and vitamin/iron supplements. It may also require more advanced medications such as growth hormones or synthetic replacement of erythropoietin (Procrit or Epogen). Patients with MM need to promote immune health by staying current on vaccines and using antibiotics and antivirals as ordered when indicated. It is imperative that patients maintain good general health and take all necessary precautions to prevent infection. Patients with MM are also at risk for blood clots and may need to take daily aspirin products or other anticoagulants, stay hydrated, or use compression stockings as indicated (MMRF, n.d.f).
Alternative and complementary medicine are options for treating side effects, anxiety, or depression. While these treatments do not treat MM, they are used as adjunctive therapies. Art therapy, variations of spiritual care, exercise, meditation, distraction, music therapy, and a variety of relaxation techniques may help with coping and relaxation. Any of these options should be offered and encouraged after consulting with the healthcare provider if the patient is interested (Mayo Clinic, 2019b).
Providers will frequently screen for minimal residual disease to evaluate if treatment is working. The bone marrow is biopsied and evaluated for how many live malignant cells are present. If there are still malignant cells in the bone marrow, these cells have the potential to start growing and dividing, leading to relapse for the patient. This screen is typically done when a patient has partially or totally completed a treatment option to determine if the treatment is effective. If no malignant cells are found following treatment, the patient has an improved prognosis (MMRF, n.d.c).
Amyloidosis can be a complication associated with MM and other plasma cell dyscrasias. As abnormal antibody and protein levels rise, they may cause the nerves or organs to become stiff over time and unable to function normally. This causes significant organ dysfunction, affecting the renal, cardiac, and peripheral nervous systems. Symptoms often include fatigue, enlargement of the tongue, peripheral edema, diarrhea, as well as peripheral paresthesias. It is important that amyloidosis is diagnosed promptly by analyzing the deposits of amyloid. The treatment for amyloidosis involves the use of chemotherapeutic medications and possible stem cell transplant (NCI, 2019).
Refractory MM indicates that the patient had treatment, but the condition did not respond to the standard treatment options or relapsed later, and on second treatment attempts, the condition did not respond. The healthcare team may try other options to treat the disease or encourage the patient to enter a clinical trial that is focused on refractory MM (MMRF, n.d.c).
Nurses are involved in collecting the assessment data, including the patient’s health history, social history, family history, and physical assessment during the diagnostic period as well as continued assessment during treatment. The nurse should fully assess for pain, gathering subjective and objective data. The nurse should assess the type of pain, what makes it better or worse, and if the patient uses or desires to use alternative or complementary treatment for pain management (Ignatavicius et al., 2018).
One method that can be used to assess pain is PQRST pain assessment. Pain is a subjective and individual concept. The gold standard of measurement of pain is self- reporting by the patient. The PQRST method provides for accurate description, assessment, and documentation of pain. The information that is gathered also helps the provider and nursing staff to implement appropriate analgesics and document the outcome for the patient. Listed below in Table 1 is the PQRST description with some sample questions, but these are meant as examples and are not exhaustive (Crozer Keystone Health System, 2019).
Table 1: Pain Assessment
What do they stand for
Possible questions to ask
Are there things that make the pain better or worse?
What do you think cause the pain?
Quality and quantity
Can you describe how the pain feels?
(give the patient examples of terms that might describe the pain such as throbbing, stabbing, sharp, and others)
Region and radiation
Can you tell me or show me where the pain is?
Does the pain radiate or travel anywhere after it starts?
Severity of the pain
Use a pain scale to help the patient communicate how significant the pain is.
Has your pain impacted your ability to take care of yourself or others?
Has the pain caused you to miss work or to stop things you enjoy?
When did the pain start?
How often do you have pain?
When you have pain, how long does it last?
Did the pain come on suddenly?
Does it start as dull pain and become more severe over time?
(Crozer Keystone Health System, 2019)
The nurse may also want to ask about other possible symptoms that occur with the pain. It is important that the documentation is accurate and detailed as the nurse gathers the pain assessment information (Crozer Keystone Health System, 2019). The nurse may be involved in assisting the provider and the laboratory staff to collect specimens to assist in the diagnostic work-up. The nurse will work with the provider to schedule and plan for bone marrow biopsies, assist with the procedure, as well as monitor the patient following the procedure. The nurse may assist in the treatment phase of the disease by administering chemotherapy and providing extensive patient education throughout the diagnosis and treatment phases. This should include explaining to the patient and family about the treatment and symptoms the patient may experience. If the patient experiences adverse effects, the nurse should provide emotional and physical support and contact the provider for orders as needed to assist with nausea, vomiting, or pain. It is critical that the nurse provides education and written materials to the patient about monitoring for signs of infection and what symptoms should prompt the patient or family to call or return to the healthcare facility. The nurse plays an important role in assessing conditions that warrant follow-up by the provider as well as advocating for the patient (Ignatavicius et al., 2018). If the patient is not responding to treatment or chooses to stop treatment, they may be a candidate for hospice care. Nursing can provide services to the patient who is in the terminal phase of the disorder, such as pain management and nutritional support. Hospice strives to:
- empower the patient to make decisions about their own care,
- allow the patient to live out the rest of their life surrounded by family,
- achieve an acceptable level of pain control, optimize the quality of life for the patient (Ignatavicius et al., 2018).
There are many emerging therapies being tested in clinical trials. One of these is CAR-T therapy, which stands for chimeric antigen receptor T-cell. This involves harvesting T-cells from the patient and genetically changing their ability to recognize an antigen on the myeloma cells. When reinfused into the patient, these cells will find the antigen and seek to destroy the myeloma cells. While this is not meant to be a first-line treatment, clinical trials have shown some success in patients who have had a relapse or have developed refractory MM. There are also vaccines being developed to stimulate T-cells. It appears that MM often responds better to combined treatments, which has prompted studies in combining proteasome inhibitors and immunomodulatory drugs with other successful treatments (MMRF, n.d.a).
In conclusion, multiple myeloma can cause significant damage to the body and is usually not curable, but continued research brings more options for treatment. There is progress with extending the patient’s quality of life and life expectancy, providing remissions for many. Many clinical trials are in progress and continue to offer hope.
Crozer Keystone Health System (2019). PQRST pain assessment method. https://www.crozerkeystone.org/nurses/pqrst
Grammatico, S., Scalzulli, E., & Petrucci, M. (2017). Solitary plasmacytoma. Mediterranean Journal of Hematology and Infectious Diseases, 9(1), 1-26. https://doi.org/10.4084/MJHID.2017.052
Grossman, S., & Porth, C., (2014) Porth’s pathophysiology concepts of altered health states (9th ed.). Wolters Kluwer Lippincott Williams & Wilkins.
Häggström, M (2014). Hematopoiesis. [image] Medical gallery of Mikael Häggström 2014. WikiJournal of Medicine 1 (2). https://doi.org/10.15347/wjm/2014.008
Ignatavicius, D., Workman, M., & Rebar, C. (2018) Medical-surgical nursing concepts for interprofessional collaborative care (9th ed.). Elsevier.
International Myeloma Foundation. (2014). International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma. https://www.myeloma.org/international-myeloma-working-group-imwg-criteria-diagnosis-multiple-myeloma
Itano, J. K. (2016). Core curriculum for oncology nursing. (5th ed.). (J. Brant, F. Conde, & M.
Saria, Eds.). Elsevier.
Landgren, O., Hofmann, J., McShane, C., Santo, L., Hultcrantz, M. Korde, N.,…Turesson, I., (2019). Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma. JAMA Oncology, 5(9), 1293-1301. https://doi.org/10.1001/jamaoncol.2019.1568
Mayo Clinic (2019a). Multiple myeloma. https://www.mayoclinic.org/diseases-conditions/ Multiple-myeloma/symptoms-causes/syc-20353378?p=1
Mayo Clinic (2019b). Multiple myeloma diagnosis and treatment. https://www.mayoclinic.org/diseases-conditions/multiple-myeloma/diagnosis-treatment/drc20353383?p=1
Mhaskar, R., Djulbegovic. B. (2018). Bisphosphonates for patients diagnosed with multiple myeloma. JAMA, 320(14). https://doi.org/10.1001/jama.2018.13773.
Michels, T. C., & Petersen, K. E. (2017). Multiple myeloma: Diagnosis and treatment. American Family Physician, 95(6), 373-383A. https://www.aafp.org/afp/2017/0315/p373.pdf
Mugwump (2012). Allogeneic Transplant [image]. WikiMedia. https://commons.wikimedia.org/wiki/File:Bone_Marrow_Transplant.png
Multiple Myeloma Research Foundation (n.d.a). Clinical trials and experimental therapies. https://themmrf.org/multiple-myeloma/treatment-options/clinical-trials-and-experimental-therapies/
Multiple Myeloma Research Foundation (n.d.b). Diagnosis. https://themmrf.org/multiple-myeloma/diagnosis/
Multiple Myeloma Research Foundation (n.d.c). Prognosis. https://themmrf.org/multiple-myeloma/prognosis/
Multiple Myeloma Research Foundation (n.d.d). Standard Treatments. https://themmrf.org/multiple-myeloma/treatment-options/standard-treatments.
Multiple Myeloma Research Foundation (n.d.e). Stem cell transplants. https://themmrf.org/multiple-myeloma/treatment-options/stem-cell-transplants/
Multiple Myeloma Research Foundation (n.d.f). Symptoms, side effects, and complications. https://themmrf.org/multiple-myeloma/symptoms-side-effects-and-complications/
Multiple Myeloma Research Foundation (n.d.g). What is multiple myeloma? https://themmrf.org/multiple-myeloma/what- is -multiple-myeloma/
National Cancer Institute (2019). General information about plasma cell neoplasms. https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq
National Comprehensive Cancer Network. (2019). Multiple myeloma version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
Soh, K., Tario, J., Wallace, P. (2017). Diagnosis of plasma cell dyscrasias and monitoring of minimal residual disease by multiparametric flow cytometry. Clinics in Laboratory Medicine, 37(4), 821-853, https://doi.org/10.1016/j.cll.2017.08.001
Steiner, N., Gobel, G., Suchecki, P., Prokop, W., Neuwirt, H., & Gunsilius, E. (2018). Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: An observational study of 2935 MGUS patients. Oncotarget, 9(2), 2344-2356. https://doi.org/10.18632/oncotarget.23412