Continuing Education Activity

Multiple myeloma is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal paraprotein leading to evidence of specific end-organ damage. The consequences of undiagnosed disease are severe. This activity reviews the underlying cause, presentation, diagnosis, and treatment of multiple myeloma. The importance of early recognition, treatment, and an interprofessional approach is highlighted in this activity.

Objectives:

• Describe the pathophysiology of multiple myeloma.
• Review the appropriate steps in evaluating a patient suspected of having multiple myeloma.
• Summarize the first-line therapy options for multiple myeloma.
• Outline the adverse effects of the disease process as well as treatment-related side effects.

Access free multiple choice questions on this topic.

Introduction

Multiple myeloma is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal immunoglobulins. Unchecked, the excess production of these plasma cells can ultimately lead to specific end-organ damage. Most commonly, this is seen when at least 1 of the following clinical manifestations is present: hypercalcemia, renal dysfunction, anemia, or bone pain accompanied by lytic lesions. Obviously, the differential is broad with any of these symptoms and/or findings. Still, multiple myeloma must be considered in the differential, as management is unique and improved outcomes are available with timely intervention.[1][2]

Etiology

The exact etiology of multiple myeloma is unknown. However, frequent alterations and translocations of promoter genes, especially on chromosome 14, are commonly found in multiple myeloma and are likely to play a role in disease development.[3] In addition, other oncogenes, such as NRAS, KRAS, and BRAF, may contribute to plasma cell proliferation.[4] Other factors contributing to disease occurrence include obesity, alcohol consumption, environmental causes such as insecticides, organic solvents, Agent Orange, and radiation exposure.[5][6]

Epidemiology

Multiple myeloma is relatively uncommon and only represents about 1.8% of all new cancer cases diagnosed in the United States each year. It occurs predominantly in the geriatric population with a median age at diagnosis of about 70 years and is slightly more commonly seen in males than females (1.4:1). There seems to be an increased incidence in African American and black populations by as much as 2-fold compared to Whites.[7][8]

Pathophysiology

MM is essentially a stage in the spectrum of monoclonal gammopathy. It is thought to arise from a pre-malignant, asymptomatic phase of clonal plasma cell growth called monoclonal gammopathy of undetermined significance (MGUS). MGUS is defined as the detection of monoclonal immunoglobulins in the blood or urine without evidence of end-organ damage. This is quite common and detectable in over 3% of people aged 50 or older. It appears that the cell of origin is a post-germinal center plasma cell. This is typically a benign condition, although, as noted above, it has a risk of progression to multiple myeloma of about 1% per year.[9][10]

The exact causes of MGUS development and progression to multiple myeloma remain unknown. However, as noted above, genetic alterations may increase expression of promoter genes or confer resistance to apoptosis, both of which result in higher plasma cell proliferation and population. Under the "second hit" hypothesis, progression could also result from additional cytogenetic lesions acquired by the original plasma cell clone, driven by genetic instability or abnormalities in the hematopoietic microenvironment.[11]

Regardless of the molecular driver, once there is excess monoclonal immunoglobulins, hyperviscosity, platelet dysfunction, and renal tubular damage can occur, leading to neurologic derangements, bleeding, and renal failure, respectively. One marrow occupation by the expanding plasma cell clone usually manifests as anemia, thrombocytopenia, and leukopenia. In addition, the interaction between myeloma cells and the bone microenvironment ultimately leads to osteoclast activation and osteoblast suppression, resulting in bone loss. Several intracellular and intercellular signaling cascades, as well as numerous chemokines and interleukins, are implicated in this complex process.[12]

Histopathology

A bone marrow aspirate and biopsy are usually performed to estimate the percentage of abnormal plasma cells. This percentage is required in the diagnostic criteria for myeloma.

Plasma cells in multiple myeloma exhibit several morphological variants. Firstly, they could take the form of a mature, normal plasma cell (a large cell, 2 or 3 times the size of a lymphocyte, with a single eccentric nucleus and abundant, basophilic cytoplasm). The Golgi apparatus typically produces a light-colored area next to the nucleus, called a perinuclear halo. Secondly, they can have features of immaturity, such as a low nuclear-cytoplasmic ratio, a larger size, and loose chromatin (ie, a plasmablast). Other possible morphologies include bizarre, multinucleated cells, "flame cells" with fiery red cytoplasm, or Mott cells with multiple clustered cytoplasmic droplets. The bone marrow is usually hypercellular and diffusely infiltrated by plasma cells. Rarely, plasma cells can be seen in peripheral blood (plasma cell leukemia).

Immunohistochemistry can detect plasma cells that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are typically CD56, CD38, CD138, and CD319-positive and CD19 and CD45-negative. Clonality is confirmed by kappa or lambda light chain restriction.

History and Physical

The presentation of multiple myeloma is quite variable. It is typically more subacute and insidious in onset, but certainly can present with severe symptoms. With that said, it is often seen in an older adult with some variation of constitutional symptoms or CRAB (hypercalcemia, renal dysfunction, anemia, and/or bone pain with lytic lesions). In a retrospective single-institution study, it was found that in newly diagnosed multiple myeloma, the following symptoms were most common: anemia (73%), bone pain (58%), elevated creatinine (48%), fatigue (32%), hypercalcemia (28%), and weight loss (24%).[13]

More specifically, hypercalcemia caused by bone demineralization can result in increased thirst and urination, bone pain, abdominal pain, nausea or vomiting, and/or altered mental status. Renal failure resulting from light chain cast nephropathy and/or hypercalcemia can lead to edema, acidosis, and electrolyte disturbances. Anemia develops likely secondary to bone marrow replacement, or decreased erythropoietin levels, which can result in fatigue, pallor, palpitation, and worsening previous heart failure or angina. Bone pain resulting from the osteolytic lesions often results in pathologic fractures and vertebral collapse, reducing height, spinal cord compression, radicular pain, or kyphosis.

Although rare, peripheral neuropathy and carpal tunnel syndrome may be present. If identified, further workup should be undertaken, as this is typically more related to an underlying component of amyloidosis. Also uncommon, hyperviscosity symptoms may be present, including bleeding, confusion, neurologic symptoms, vision changes, or heart failure. Despite being rare, it is crucial to identify these findings as it is a medical emergency. Finally, multiple myeloma patients seem to be more prone to infections, mostly pneumonia and pyelonephritis, so assessing for recurrent illness is important.

Evaluation

Multiple myeloma is simply a part of the spectrum of plasma cell proliferative disorders. This concept is restated in the National Comprehensive Cancer Network (NCCN) guidelines, where the disease is divided into MGUS, smoldering myeloma (asymptomatic), and multiple myeloma (symptomatic), and is reiterated elsewhere.[14] Because the treatment and management of each category differ widely, the correct identification and diagnosis of multiple myeloma are paramount.

When concern for multiple myeloma arises, several approaches to screening and diagnosis are available.

The NCCN guidelines recommend the following diagnostic studies:

• Complete blood count (CBC) with differential, platelet count
• BUN, creatinine, electrolytes, albumin, and calcium levels
• Serum LDH and beta-2 microglobulin
• Serum immunoglobulins, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE)
• 24-hour proteinuria, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE)
• Serum-free light chain (FLC) assay
• Whole Body low dose CT or PET CT
• Unilateral bone marrow aspirate and biopsy, including immunohistochemistry and/or flow cytometry, and cytogenetics
• Plasma cell FISH [del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q21 amplification, 1p abnormality]

Historically, we have diagnosed multiple myeloma if clonal bone marrow plasma cells were greater than or equal to 10% on bone marrow biopsy (or if a biopsy-proven plasmacytoma was present), in addition to at least 1 of the following CRAB criteria:

• Serum calcium level greater than 0.25 mmol/L (greater than 1 mg/dL), higher than the upper limit of normal, or greater than 2.75 mmol/L (greater than 11 mg/dL)
• Renal insufficiency (creatinine greater than 2 mg/dL [greater than 177 micromol/L] or creatinine clearance less than 40 mL per minute)
• Anemia (hemoglobin less than 10 g/dL or hemoglobin greater than 2 g/dL below the lower limit of normal)
• One or more osteolytic bone lesions on skeletal radiography, CT, or PET-CT are often described as punched-out, round, radiolucent lesions

While this set of criteria identified the majority of cases requiring treatment, many were missed. In November 2014, the International Myeloma Working Group (IMWG) identified additional factors associated with an 80% higher risk of myeloma-related organ damage within 2 years.[15] As a result, the following were added to the CRAB criteria as diagnostic alternatives to myeloma-defining events:

• Bone marrow plasma cells (BMPCs) equal to 60%
• Involved/uninvolved serum free light chain ratio greater than or equal to 100
• Abnormal MRI with more than 1 focal lesion, with each lesion greater than 5 mm, that were often missed on previous skeletal surveys

Now, the presence of any CRAB criteria or any of these 3 additional criteria justifies diagnosis and therapy. It is certainly more sensitive and identifies more cases needing treatment. This new set of diagnostic criteria is often referred to as SLiM CRAB.

Treatment / Management

Initial management of multiple myeloma should include evaluation for acute issues that require immediate stabilization. Some of these may include administration of isotonic saline for volume expansion, calcitonin, and/or bisphosphonates to address severe hypercalcemia. If significant renal dysfunction is noted, medical optimization should be undertaken, including a nephrology consultation, to address fluid status, avoid nephrotoxic agents, adjust renal dosing of necessary medications, and, if severe dysfunction is noted, discuss hemodialysis. Spinal cord compression resulting from vertebral fracture or plasmacytoma can also be seen and is a medical emergency that should be managed aggressively by neurosurgery or orthopedic consultation and possible radiation therapy. In the rare instance that hyperviscosity is diagnosed, plasmapheresis should be completed.

Once stabilized, the patient's treatment plan is driven by risk stratification and transplant eligibility. A patient's disease can fall into 1 of 2 categories: high or standard-risk multiple myeloma. High risk is defined as any of the following as seen on FISH: t(14:16), t(14:20), del17p13, t(4:14), or 1q gain. Standard risk demonstrates either trisomies, t(11:14) or t(6:14). Transplant eligibility is made on a case-by-case basis, but typically, patients who are over 77 years old, have cirrhosis, have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, or have New York Heart Association class III or IV heart failure are typically deemed transplant ineligible. 

Patients who are fit for transplant typically receive induction therapy over 3 or 4 months to decrease the tumor burden. This is followed by peripheral blood stem cell mobilization and harvesting, and then an autologous stem cell transplant (ASCT), which improves overall and progression-free survival.[16] The ASCT can be performed early after recovery from stem cell collection or delayed at the time of the first relapse. After completing ASCT, the patient is placed back on maintenance therapy until disease progression or until tolerability limits. 

The ideal induction regimen is a nuanced decision, and many individual factors must be considered. In general, based on the Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) consensus opinion, for patients deemed high risk and transplant eligible, induction therapy would typically be initiated with 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone, followed by an early ASCT. Although debatable, long-term survival seems to favor an early transplant approach in high-risk disease.[17] After completion of ASCT, proteasome inhibitor-based maintenance therapy should be initiated and continued until disease progression.

In those patients with standard-risk disease who are transplant eligible, a similar algorithm is followed, with a different drug regimen being used. Typically, induction therapy with 4 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) is completed, followed by ASCT, and then maintenance therapy with lenalidomide until disease progression, as tolerated. 

For high-risk transplant-ineligible patients, there are several options. One approach would be to employ the VRd regimen for 8 to 12 cycles followed by maintenance bortezomib-based therapy. Another option could include daratumumab, lenalidomide, and dexamethasone (DRd), continued until disease progression, based on the MAIA trial, which showed improved progression-free survival and overall survival compared with Lenalidomide and Dexamethasone.[18] This may be particularly helpful in patients ineligible for bortezomib-based therapy. 

For standard risk transplant-ineligible patients, options include VRd for 8 to 12 cycles followed by lenalidomide maintenance, or DRd continued until disease progression.[19][20]

Differential Diagnosis

The differential diagnosis for many of the vague symptoms accompanying multiple myeloma is broad.[21] However, several entities must be considered and ruled out before diagnosis and treatment. The following is a list of important diseases to consider and how to differentiate them from multiple myeloma:

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Serum monoclonal protein less than 3 g/dl
• Clonal bone marrow plasma cells are less than 10%
• No end-organ damage

Smoldering Multiple Myeloma

• Monoclonal protein is greater than or equal to 3 g/dl
• Clonal bone marrow plasma cells between 10% to 59%
• No end-organ damage [22]

Solitary Plasmacytoma

• Solitary lesion made up of clonal plasma cells
• Normal bone marrow
• Negative imaging outside of the single lesion
• No end-organ damage

Waldenstrom Macroglobulinemia

• Lymphoplasmacytic lymphoma noted in the bone marrow
• The type of M protein is IgM, which is very unusual in multiple myeloma.
• Presence of MYD88 L265P
• Symptoms include hyperviscosity, peripheral neuropathy, anemia, lymphadenopathy, and hepatosplenomegaly [23]

AL Amyloidosis

• Caused by deposition of amyloid fibrils or non-fibrillar material, resulting in heart failure, hepatomegaly, and/or nephrotic syndrome
• Less than 20% plasma cells in the bone marrow and a lack of lytic lesions
• Congo-red staining on bone marrow or affected tissue [24]

Staging

There are several staging systems for multiple myeloma. The 2 main systems used today are the Durie-Salmon Staging System and the Revised International Staging System (R-ISS). 

For many years, the Durie-Salmon staging system was the standard for risk stratification. It is based on the tumor cell mass, hemoglobin, calcium, IgA and IgG levels, urine monoclonal protein levels, and the extent of bone damage on X-rays. It divides patients into 3 stages (I, II, and III) and further sub-classifies them into groups A and B based on serum creatinine levels.[25] Given the subjectivity, accuracy, and reproducibility are challenging to achieve. With this in mind, the R-ISS is most often used. In addition, the R-ISS is simple and provides more robust prognostic information.[26] Staging for the R-ISS is as follows:

• Stage 1: B2M less than 3.5 mg/L, albumin greater than or equal to 3.5 g/dL, normal LDH, and standard-risk cytogenetics
• Stage 2: Neither stage 1 nor stage 3
• Stage 3: B2M greater than 5.5 mg/L and high-risk cytogenetics [del(17p), and/or t(4:14), and/or t(14,16)] or elevated LDH

Prognosis

The prognosis for multiple myeloma is quite variable, and many factors can affect outcomes. However, the 2 main drivers of prognosis are likely stage and disease biology. 

The R-ISS staging system was developed by combining data from 11 international trials to evaluate newly diagnosed multiple myeloma. When stratified by stage, they found that in R-ISS I, the 5-year overall survival was 82% and progression-free survival (PFS) was 55%. In stage II disease, the 5-year overall survival was 62% and the PFS was 36%. Stage III demonstrated a 5-year overall survival of 40% and PFS of 24%.[26]

High-risk cytogenetic abnormalities can adversely affect outcomes. 4:14), t(14:16), and f(14:20) are all considered high risk and have been shown to decrease overall survival. In a study, the presence of t(14:16) was associated with a PFS of 2.1 years and an overall survival of 4.1 years.[27] 17p deletions also portend worse outcomes, with a small study demonstrating median PFS of 18.1 months and median overall survival of 36 months when del(17p) was paired with TP53 mutation.[28]

These factors help understand the general prognosis and can guide discussions with patients. However, it is important to note that significant therapeutic progress has been made over the last several years, with overall survival changes yet to reflect these advances.

Complications

Common manifestations and complications of multiple myeloma can include hypercalcemia, renal insufficiency, infection, skeletal lesions, and anemia. Less common complications include venous thromboembolism and hyperviscosity syndrome.[29]

Hypercalcemia is caused by bone demineralization and may be asymptomatic or cause anorexia, fatigue, constipation, polydipsia, polyuria, confusion, or stupor. Treatment depends on clinical severity and the rapidity of onset of hypercalcemia. As noted previously, it can include hydration, glucocorticoids, bisphosphonates, calcitonin, and/or hemodialysis.

Renal insufficiency can develop acutely or chronically. A variety of etiologic mechanisms may be involved, including excess production of monoclonal light chains (light-chain cast nephropathy), deposition of intact light chains causing nephrotic syndrome, light-chain amyloidosis, hypercalcemia, hyperuricemia, or dehydration.

Myeloma bone disease is thought to result from overexpression of RANKL by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. Bone breakdown leads to calcium release into the blood, leading to hypercalcemia and symptoms of kidney failure that may develop acutely or chronically. It can manifest as severe bone pain, pathological fractures, and even spinal cord compression.

Another important complication is an increased risk of infection. Infection risk seems to be highest over the first 3 to 4 months of induction therapy. Factors contributing to increased infection risk include impaired lymphocyte function, suppression of normal plasma cell function, hypogammaglobulinemia, and chemotherapy-induced neutropenia. The most common infections are pneumonia and urinary tract infections, most often caused by organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Escherichia coli. Early identification is important to ensure timely treatment and resolution of the infection.

Neuropathy is also commonly seen. It can be secondary to the plasma cell dyscrasia itself, to direct compression, or to light-chain deposition. However, it can also be worsened or even caused by treatment regimens including thalidomide, bortezomib, or vincristine.[30]

Also significant is the increased risk for thrombosis. This can be secondary to the patient's comorbidities, tumor/disease-related factors, and immunomodulatory drugs, including thalidomide or lenalidomide. Practitioners should have a low threshold for workup or evaluation for any signs or symptoms of venous or arterial thrombus.[31]

A rare side effect is hyperviscosity, which can have severe complications. It typically presents as oronasal bleeding, blurred vision, retinal hemorrhage, seizure, other neurologic symptoms, confusion, dyspnea, and heart failure. This is considered an emergency, and plasmapheresis should be initiated immediately to relieve symptoms promptly.

Deterrence and Patient Education

Patient education is crucial in the management of multiple myeloma. The disease itself is complex, and outcomes can be improved if early and appropriate intervention is undertaken. That said, a patient must be an active participant in shared decision-making to ensure improved compliance with therapy.

Another deterrent to positive outcomes seems to be racial disparities. Compared with Whites, African Americans have a higher mortality rate and have not seen the same gains in survival. Although a specific cause has not been identified, there does seem to be less utilization and access to appropriate healthcare and treatment.[32] With this in mind, community outreach and education are imperative to build trust and improve access for those in this demographic.

Enhancing Healthcare Team Outcomes

Multiple myeloma is a complex disease that often involves numerous systems. Given this, treating multiple myeloma often requires an interdisciplinary approach. While the oncologist is certainly involved, the aid and expertise of several other individuals are needed. 

From a diagnostic standpoint, pathology provides critical information and interpretation of serum protein electrophoresis, bone marrow biopsy, and quantification of plasma cell involvement. Radiology helps determine whether lytic lesions are present. Nephrologists may be required to aid in the management of any new or worsening renal dysfunction. Radiation oncology input may be necessary to address any symptomatic bony lesions. Orthopedic or neurosurgery can help address pathologic fractures or lesions that are causing impending progression. In addition, many orthopedists see patients before an actual diagnosis of multiple myeloma for pain, so ensuring this is in their differential diagnosis is critical for earlier diagnosis.[33] Another important team member often involved much too late in the disease process is palliative care. Palliative care is a service that focuses on symptom management. Palliative care involvement improves not only the patient experience but also tangible outcomes. A decrease in discontinuation due to adverse reactions can be seen by involving palliative care early and improving symptom management.[34][35] In addition, and perhaps by extension, survival is longer among those with palliative care.[36]

Finally, another consideration for improving outcomes is that of a second opinion. Studies have demonstrated decreased mortality risk when a patient is evaluated and treated at a National Cancer Institute Comprehensive Cancer Center (NCI CCC).[37] With this in mind, although not always possible, an initial evaluation or review by a designated NCI-CCC is reasonable and may improve outcomes. 

While every case is unique in its presentation and progression, a multidisciplinary approach undoubtedly improves outcomes. 

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Disclosure: Sara Albagoush declares no relevant financial relationships with ineligible companies.

Disclosure: Cameron Shumway declares no relevant financial relationships with ineligible companies.

Disclosure: Alexandre Azevedo declares no relevant financial relationships with ineligible companies.