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In the United States, multiple myeloma (myeloma, plasma cell myeloma) is the third most common hematologic malignancy after lymphoma and leukemia[1] but the 14th most common malignancy overall.[2] This cancer affects plasma cells—frequently involving multiple sites, typically within the bone marrow—which demonstrate aberrant secretion of monoclonal antibodies.[3,4] Thus, myeloma is characterized by neoplastic proliferation of plasma cells in the bone marrow.
Myeloma is considered treatable but rarely curable with current treatment approaches.[3,5] Evidence exists that the bone marrow microenvironment of tumor cells may play a pivotal role in the pathogenesis of myeloma,[4,6] thus allowing for the expansion of treatment options.[6]
The radiograph shows a frontal view of the shoulder in a patient with multiple myeloma. The solid arrow indicates a chronic pathologic humeral fracture at the surgical neck across a large lytic lesion with a "moth-eaten" appearance down the humeral shaft. The clavicle and ribs are also affected. The open arrows reveal a missing fifth rib, which was destroyed by a plasmacytoma (plasma cell tumor) (open arrows).
Image courtesy of Sexton C, Crichlow C. J Community Hosp Intern Med Perspect. 2013;3(2). [Open access.] PMID: 23882402, PMCID: PMC3716026.
The overall US incidence of myeloma has increased about 0.8% each year in the last decade, but overall mortality rates have fallen approximately 0.9% annually over 2003-2012.[2] In 2015, the Surveillance, Epidemiology, and End Results (SEER) Program and the American Cancer Society (ASC) estimate there will be approximately 26,850 new US cases of myeloma—representing approximately 1.6% of all new US cancer cases—with about 11,240 deaths (1.9% of all cancer deaths) from this disease.[2,4] Data from 2010 to 2012 indicate about 0.7% of men and women will be diagnosed with myeloma in their lifetime.[2]
After adjusting for age, males are more commonly affected than women, and black individuals are disproportionately affected (about two- to three-fold) compared to other races/ethnicities.[2] This disease also predominantly occurs in older people (ages 65-74 years [28.2%], followed by those aged 75-84 years [24.3%] and 55-64 years [23.2%]). The median age at diagnosis is 69 years.[2]
Adapted image courtesy of the National Cancer Institute (NCI)/SEER Program.[2]
The precise etiology of myeloma remains unclear.[4] This malignancy affects the skeletal, hematologic, renal, and neurologic systems, as follows[7]:
The image shows a potential mechanism for myeloma-driven bone destruction. CSL = CBF1, suppressor of hairless, lag-1 transcription factor; RANK = receptor for the osteogenic factor RANKL.
Image of osteoclastogenesis via Notch signal activation on tumor cells and osteoclasts through abnormal expression of Jagged Notch ligands courtesy of Colombo M, Thummler K, Mirandola L, et al. Oncotarget. 2014;5(21):10393-406. [Open access.] PMID: 25257302, PMCID: PMC4279381.
As noted earlier, myeloma occurs more commonly in males, older persons, and black individuals.
Inherited susceptibility may also play a role in myeloma[4,8]; this malignancy has been reported to be four times more likely in two or more first-degree relatives.[4] Chromosomal anomalies have been identified, including deletion (del) of chromosome 13 and del 17p13; translocations (t) (4;14), t(11;14), and t(14;16); as well as 1q21 amplification.[5] Overweight/obesity has also been associated with an increased risk of developing myeloma.[4,9] However, no conclusive evidence of occupational causes has been found: There are conflicting reports regarding workplace exposure to radiation and to chemicals such as benzene and ethylene oxide.[4,9,10]
Two conditions are considered myeloma precursor diseases: monoclonal gammopathy of undetermined significance (MGUS) (asymptomatic; serum monoclonal M protein [M-protein] <3 g/dL and bone marrow plasma cell concentration <10%[10]) and "smoldering myeloma" (asymptomatic; excess serum and urinary M protein ≥3 g/dL and/or bone marrow plasma concentration ≥10%[5,10]).[2-4,11] Solitary plasmacytomas of the bone may also eventually develop into symptomatic myeloma.[4]
The magnetic resonance image (MRI) reveals diffuse bone marrow replacement throughout the pelvis and proximal femora in a middle-aged male patient with extensive myeloma. Only small areas of residual fatty marrow are seen in the greater trochanters and femoral heads bilaterally.
MRI courtesy of Robin J, Fintel B, Pikovskaya O, Davidson C, Cilley J, Flaherty J. J Med Case Rep. 2008;2:229. [Open access.] PMID: 18627621, PMCID: PMC2500028.
The annual risk of MGUS progression to a lymphoid or plasma cell malignancy is 0.5%-1.0% in population-based cohorts; this risk increases to between 2% and more than 20% in higher-risk patients.[3] For smoldering myeloma, the annual risk of progression to myeloma is about 10% for the first 5 years after the diagnosis is made, 3% per year for the next 5 years, and then 1% each year thereafter.[11]
Risk factors that appear to predict disease progression include the following[3]:
Adapted image of protein electrophoresis showing monoclonal gammopathy (paraprotein, M-peak) from a patient with multiple myeloma courtesy of Wikimedia Commons/Steven Fruitsmaak.
Patients with multiple myeloma can present asymptomatically or with varying degrees of symptomatic severity, and different areas of the body may be involved.
In general, signs/symptoms do not appear until the disease is already advanced. They may include the following[4,9,10]:
Image of bone marrow involvement of the lumbar spine in myeloma courtesy of Blausen Medical Communications, Inc, via Wikimedia Commons.
Myeloma can involve other anatomic sites. For example, ophthalmologic evaluation may reveal pallor from anemia and/or ecchymoses or purpura from thrombocytopenia. Exudative macular detachment, retinal hemorrhage, or cotton-wool spots may be present.
Myeloma may also cause light-chain amyloidosis which can result in severe organ dysfunction, particularly affecting the kidneys, heart, and peripheral nerves.[3,4] Signs/symptoms include fatigue, purpura, cutaneous changes, paresthesias of the hands or lower extremities, edema/congestive heart failure, enlarged tongue, hepatosplenomegaly, and diarrhea.[3,4]
The left image shows extramedullary myeloma involving the left maxillary and zygomatic regions, resulting in a midline shift of the nose and chin. The right image demonstrates exophytic, irregular lesions protruding from the palate and left nostril in the same patient.
Images courtesy of Feller L, White J, Wood NH, Bouckaert M, Lemmer J, Raubenheimer EJ. Head Face Med. 2009;5:4. [Open access.] PMID: 19152712, PMCID: PMC2649913.
The computed tomography (CT) scans are from the same patient as in the previous slide. The left image is sagittal scan showing extensive destruction of the left maxilla and revealing the left paranasal tissues. The left orbit is filled with tumorous tissue. The right image is an axial scan demonstrating tumor invasion of the left orbit, resulting in ptosis, as well as tumor extension to the left ethmoidal sinus and temporal and infratemporal fossae.
Images courtesy of Feller L, White J, Wood NH, Bouckaert M, Lemmer J, Raubenheimer EJ. Head Face Med. 2009;5:4. [Open access.] PMID: 19152712, PMCID: PMC2649913.
These images are from another patient with ocular multiple myeloma. The photograph shows the right eye on initial presentation. The MRI reveals involvement of the right greater wing of the sphenoid as well as right orbital extension. The lateral rectus muscle and the lateral wall of the orbit are affected, and a right-sided preseptal soft-tissue swelling and thickening can be seen.
Images courtesy of Hassan M, Alirhayim Z, Sroujieh L, Hassan S. Case Rep Ophthalmol Med. 2012;2012:252310. [Open access.] PMID: 23198203, PMCID: PMC3502777.
Typically, the diagnosis of myeloma is suspected on the basis of the patients signs/symptoms, of which bone pain is often the chief complaint. On rare occasions, multiple myeloma is found when a routine blood test shows abnormally elevated levels of serum protein,[4] or when end-organ damage is present (as evidenced by hypercalcemia, renal dysfunction, anemia, and lytic bone lesion ["CRAB" criteria]).[12]
The International Myeloma Working Group (IMWG) recently updated their diagnostic criteria for myeloma to include the presence of one of three biomarkers ("myeloma-defining events") as being sufficient for the diagnosis, whether the CRAB features are present or not.[12] They are (1) plasma cell bone marrow involvement of 60% or more; (2) serum FLC ratio of at least 100, as long as the absolute level of the involved light chain is at least 100 mg/L; and/or (3) the presence of more than one focal lesion that is 5 mm or larger on MRI.[12]
The diagnosis of light-chain amyloidosis is made on the basis of clinical findings as well as laboratory tests that include positive amyloid staining by Congo red on any tissue specimens, and the presence of elevated serum or urinary light chains or abnormal plasma cells in the bone marrow.[4,12]
Image of plasma cells from a patient with myeloma courtesy of Wikimedia Commons/Dr Erhabor Osaro.
Laboratory tests
Initial laboratory studies include the following[4,5,8,9,12]:
Histologic image of a plasmacytoma under hematoxylin phloxine saffron (HPS) stain courtesy of Wikimedia Commons/Nephron. Abundant malignant plasma cells with the occasional Mott cell (a plasma cell with abundant Russell bodies [an eosinophilic uniformly staining membrane bound body which contains immunoglobulin]) are present.
Imaging studies
To evaluate lytic bone lesions, guidelines from the National Comprehensive Cancer Network (NCCN) and the IMWG recommend a full radiographic skeletal survey (including the skull, humeri, pelvis, and femurs).[5,12]
The lateral skull radiograph in image a shows multiple lytic lesions with a "punched out" appearance that is classic for myeloma. A closer view of the craniocervical junction (image b) reveals a destructive lesion of C2 that has caused compression (open arrow), abnormal flexion (blue arrow), and translation (solid red arrow), with potential instability.
Image courtesy of Sexton C, Crichlow C. J Community Hosp Intern Med Perspect. 2013;3(2). [Open access.] PMID: 23882402, PMCID: PMC3716026.
This lateral thoracic spine radiograph is from the same patient as in the previous slide. Multiple severe vertebral body compression fractures (solid arrows) and vertebra plana (or "pancake" vertebra), which are also characteristic of multiple myeloma, can be seen. The open arrows at T11 and T12 show mild vertebral sclerosis as a result of treatment and healing.
Image courtesy of Sexton C, Crichlow C. J Community Hosp Intern Med Perspect. 2013;3(2). [Open access.] PMID: 23882402, PMCID: PMC3716026.
CT scanning, MRI, and combined positron-emission tomography-CT scanning are more sensitive at detecting bone disease than plain radiographs. These imaging modalities are typically used to further evaluate symptomatic areas that appear normal on plain radiographs.[5]
The MRIs of the lumbar spine demonstrate five different infiltration patterns of multiple myeloma. Fat-signal fraction appears to show potential as a biomarker to differentiate between symptomatic and asymptomatic disease in lumbar bone marrow without visible focal lesions.[13]
Image courtesy of Takasu M, Kaichi Y, Tani C, et al. PLoS One. 2015;10(2):e0116842. [Open access.] PMID: 25706753, PMCID: PMC4338220.
These images show coronal views of a patient with myeloma using three imaging modalities. The combined PET/MRI in image A was obtained using a novel CXCR4 probe, gallium-68 [68Ga]Pentixafor (high CXCR4 expression generally portends tumor metastasis and poor prognosis).[14] The increased [68Ga]Pentixafor uptake shows bone marrow infiltration and correlates with the increased T2 short-tau inversion recovery (STIR) signal on the MRI in image B that indicates intramedullary infiltration. The corresponding CT scan in image C does not demonstrate a similar sensitivity at detecting myeloma as the other two images.[14]
Image courtesy of Philipp-Abbrederis K, Herrmann K, Knop S, et al. In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma. EMBO Mol Med. 2015;7(4):477-87. [Open access.] PMID: 25736399, PMCID: PMC4403048.
Traditionally, two staging systems have been used for multiple myeloma.[4,5,15] The Durie-Salmon system is good for evaluating disease extent and tumor size.[10] It consists of three stages based on the serum and urinary levels of abnormal M proteins, the serum calcium levels, the severity of lytic bone lesions on plain radiography, and the hemoglobin level.
The more commonly used International Staging System (ISS) also consists of three stages, but staging is based only on two factors: the serum levels of beta-2 microglobulin and albumin.
More recently, the IMWG has proposed a revised ISS (R-ISS) system that uses ISS stage, chromosomal abnormalities, and serum LDH levels to stratify patients with newly diagnosed myeloma, as follows[15]:
Using this revised system in 3060 patients, the IMWG found overall 5-year survival rates of 82% in those staged as R-ISS I; 62%, R-ISS II, and 40%, R-ISS III.[15] The respective progression-free survival rates were 55%, 36%, and 24%.
Image courtesy of NCI/Linda Bartlett.
Treatment selection is made on the basis of whether the patient is symptomatic or not, their age and general health, whether they've previously received therapy, whether they are candidates for high-dose chemotherapy or stem cell transplantation (SCT), and whether there are disease complications.[10]
In general, patients with smoldering myeloma or MGUS are asymptomatic and monitored with laboratory testing at 3- to 6-month intervals and with periodic bone surveys, unless or until they become symptomatic.[5] Solitary plasmacytoma of bone (radiotherapy) or extramedullary plasmacytoma (radiotherapy and/or surgery) are potentially curable.[3]
Therapeutic options for symptomatic myeloma include the following[3-5,9,10]:
Adjunct therapy includes the following[3-5,9,10]:
CT scan of the brain in a myeloma patient courtesy of Wikimedia Commons/Dr Laughlin Dawes.
Chemotherapy and other agents
Treatment for symptomatic disease includes monotherapy or combination therapy with agents such as the following[3-5]:
On November 16, 2015, the US Food and Drug Administration (FDA) granted accelerated approval for daratumumab for the treatment of multiple myeloma.[16] This agent is the first monoclonal antibody approved for treating myeloma. Daratumumab is administered as an injection, given as an infusion, to patients who have received at least three prior treatments for myeloma.[16]
On November 20, 2015, the FDA approved ixazomib, the first oral proteasome inhibitor, for the treatment of myeloma.[17] This agent is administered in combination with lenalidomide and dexamethasone to patients who have received at least one prior therapy for myeloma.[17]
Image of bortezomib bound to an assembled yeast proteasome core courtesy of Wikimedia Commons/Opabinia regalis.
Stem cell transplantation
Candidates for SCT receive high-dose chemotherapy with or without whole-body irradiation, followed by stem cell transfusion.[3-5,9,10]
Single autologous SCT is considered the standard of care. High response rates can be achieved.[5]
Tandem SCT involves two sequential courses of high-dose chemotherapy and SCT within a 6-month period. The NCCN guidelines recommend collecting stem cells for two transplants in all eligible patients,[5] and they indicate that tandem transplants with or without maintenance therapy may be a consideration for all SCT-eligible patients as well as an option for those who do not achieve a very good partial response following the first autologous SCT.[5]
Alllogeneic SCT with or without myeloblative or nonmyeloablative transplants (differentiated by the chemotherapy regimens used) attempts to use the associated graft-versus-tumor effect to destroy the malignant cells.[4,5] The NCCN guidelines indicate myeloablative allogeneic SCT may be considered, preferably in a clinical trial, for disease that is responsive to primary therapy, for primary progressive disease, or for progressive disease following an initial autologous SCT.[5]
Image courtesy of Flickr/Larry Graff.
Favorable prognostic features include the following[3]:
Overall, almost 47% of patients diagnosed with myeloma survive 5 years or more.[2] The majority of deaths from this disease are among patients with metastatic disease. The 5-year relative survival for those with localized disease is nearly 69% compared to 45% in patients with metastatic disease.[2]
Adapted image courtesy of the NCI/SEER Program.[2]
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