Multiple Myeloma

By Manni Mohyuddin, MD, Assistant Professor of Medicine at Huntsman Cancer Institute 

Practice Essentials

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of malignant plasma cells that produce monoclonal immunoglobulin. These neoplastic cells result in characteristic clinical features that include bone lytic lesions/pathological fractures, hypercalcemia, renal insufficiency, and anemia. Contemporary treatments for MM have resulted in dramatic improvements in outcomes. However, most patients continue to experience relapse, and the disease currently remains incurable for the majority of afflicted patients. Furthermore, significant heterogeneity exists within the disease, and outcomes for certain high-risk subtypes remain poor. ¹

In addition to complete blood count and metabolic panels, the diagnostic workup for MM includes serum and urine assessment via electrophoresis and immunofixation for measurement of monoclonal protein. Serum-free light chain assays are also an integral part of diagnosis and measurement of response. Serum beta2-microglobulin, albumin, and lactate dehydrogenase are essential to allow for adequate staging of disease. Bone marrow aspiration and biopsy are necessary for diagnosis, and standard metaphase cytogenetics and fluorescence in-situ hybridization (FISH) looking for characteristic cytogenetic abnormalities is integral for risk stratification.  FISH panels should assess for del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14;20), 1q21 amplification and 1p deletion. Advanced imaging (as opposed to just a skeletal survey) is recommended for all newly diagnosed patients and can comprise of a PET/CT, a low dose whole body CT scan, or a whole-body myeloma MRI scan.²

For fit, eligible patients, the current standard of care remains as follows:

1. Induction with novel three or four drug regimens
2. Consolidation with high-dose chemotherapy and autologous stem cell transplantation
3. Maintenance therapy

For patients who are ineligible for autologous stem cell transplant, current paradigms include continuous therapy with novel regimens. After relapse, new treatment regimens are incorporated. Recent advances have led to the availability of numerous treatment options across various classes of drugs for patients with MM.

Although the current paradigm of treatment for relapsed and refractory MM usually involves indefinite, continuous treatment, new approaches are being investigated that allow for therapy adapted for response, including discontinuation for patients with no measurable residual disease (MRD), as well as further escalation for those with evidence of MRD.

Pathophysiology

MM is a disease in which malignant plasma cells proliferate. Invariably, MM is preceded by a state known as monoclonal gammopathy of undetermined significance (MGUS). Although various risk factors for MGUS have been identified, the precise reason why MGUS occurs remains unknown. The progression of MGUS to MM is characterized by the accumulation of adverse genetic changes in the plasma cell clone, as well as changes in the microenvironment that lend to tumor proliferation. In some cases, patients are diagnosed with smoldering multiple myeloma (SMM), an intermediate condition between MGUS and MM, in which the tumor burden is greater than what is seen with MGUS, but the disease has not yet caused end-organ damage.

Because not all cases of SMM progress to MM, it is very likely that SMM represents two different heterogeneous populations. Some patients with SMM will have a disease that behaves like MGUS and is destined not to progress, despite the greater volume of disease. The other subtype of SMM represents patients with a plasma cell clone that is destined to progress to MM but has not yet caused organ damage. Although progress is ongoing in recognizing genomic hallmarks that can differentiate between these two types of SMM, current risk models reflect disease volume rather than genomic features. ³

The exact inciting event that leads to a normal plasma cell changing into a pre-malignant MGUS clone remains poorly defined. As most cases of MGUS have characteristic cytogenetic abnormalities, it is thought that most cases are initiated either by conjunction with characteristic translocation events that involve immunoglobulin heavy chain (IgH) locus, ⁴ trisomies, or a combination of both of these events. The IgH locus is on chromosome 14q32, and the hallmark translocations seen in MGUS and MM result in the juxtaposition of an oncogene next to the IgH locus. Oncogenes commonly involved in this process include Cyclin D1, Cyclin D3, musculoaponeurotic fibrosarcoma (C-MAF), and MM set domain (MMSET/WHSC1).^5,6

The subsequent progression of MGUS to MM occurs as a result of additional adverse genetic changes that enhance the proliferation and survival of the malignant plasma cell clone within the bone marrow microenvironment. Various genetic changes can contribute to evolution of the clone. Mechanisms implicated include MYC activation, deletion of TP53, dysregulation of apoptosis, activating mutations in the NFkB pathway, and activation of the RAS/MAPK pathway.^7,8 During this evolution, structural changes that may be seen include shattering of entire chromosomes with subsequent random reassembly (chromothripsis) and multiple double stranded DNA breaks with incorrect joining (chromoplexy).⁹ Furthermore, the bone marrow microenvironment also changes during progression from MGUS to MM, allowing for proliferation of the malignant clones. These include dysregulation of the immune system, increased angiogenesis, and cell signaling pathways that foster malignant cell growth.^10,11

The mechanisms of organ damage attributable to MM are as follows:

Osteolytic Bone Lesions and Hypercalcemia

Central to the pathophysiology of bone disease in MM is increased osteoclastic activity and reduced osteoblastic activity.¹² This imbalance is mediated by increased receptor activator of nuclear factor kappa-B ligand (RANKL) activity as well as increased levels of inflammatory proteins that activate osteoclasts.¹³ The same pathways that activate osteoclasts also result in hypercalcemia.

Renal Insufficiency

In patients with MM, kidney disease is a result of the production of monoclonal immunoglobulin and its fragments, the light, and heavy chains. Under normal conditions, light chains cross the glomerulus and are reabsorbed by proximal tubular cells. However, an excess of light chains combines with uromodulin, and the resulting precipitation creates casts that obstruct the tubules and incur fibrosis.¹⁴

Etiology

The etiology of MGUS and MM remains unknown. A small fraction of cases is associated with exposure to radiation or chemicals such as herbicides, rubber manufacturing, benzene, and pesticides. Professional firefighters also have been shown to have a higher risk of progression from MGUS to MM. Although radiation has been suggested as a potential risk factor as well, there was no increased risk of MM observed in survivors of exposure to atomic radiation resulting from the Hiroshima and Nagasaki bombings.¹⁵ It must be stated that most patients who do develop MGUS or MM have no such exposure to these risk factors. Hence, a clear inciting etiology cannot be ascertained for most patients.

As MM is predominantly a disease of older people and is more common in men than women, both age and male gender are risk factors associated with MM. Although obesity has not been shown to impact the risk of developing MGUS, it can increase the risk of progression of MM in patients with MGUS.¹⁶ However, most patients have no such exposure to these risk factors.

Although the mutations causing MM are generally acquired and not inherited, family history is a well-known risk factor for MM, with first-degree relatives having a higher risk of developing the disease. However, the vast majority of patients have no clear identifiable exposure to the above or a family history of MM. As such, the cause of MM remains unknown.

Epidemiology

MM is the second most common hematologic malignancy, and there are approximately 35,000 new cases diagnosed annually in the United States. Given advances in treatment that are increasing survival, the prevalence of this disease is expected to rise. As such, the lifetime risk of getting MM is approximately one in 125 (0.8%).¹⁷

Incidences of MM vary between races/ethnicities, with the highest incidence seen in African Americans (12.1 cases per 100,000 women, 16.1 cases per 100,000 men) and the lowest incidence seen in Asian/Pacific Islanders (3.1 cases per 100,000 women, 4.8 per 100,000 men).¹⁷

Additionally, the median age at diagnosis is 69 in the United States. Only 15% of patients are under the age of 55 at diagnosis.¹⁷

Presumably due to increased recognition, and therefore more detection, of this disease, the incidence of MM has increased in the United States over the last few decades. As median survival increases and more patients live longer, the prevalence of MM has also been increasing.¹⁸

Prognosis

MM is a tremendously heterogeneous disease, with significant differences in outcomes between different subtypes of the disease. Dramatic advances in treatment have led to improved survival outcomes, with median life expectancy increasing from 2-3 years in the 1990s to 8-10 years according to the latest available data. This number is expected to rise further as it does not reflect newer advances in the last few years.¹⁹ Although certain subsets, such as patients with high-risk cytogenetics, have not had such a marked improvement in outcomes,²⁰ they too have experienced improvements in outcomes.

Risk Stratification Models

There are various models of risk stratification for MM. The most commonly used and well-known model – albeit still not encompassing all potential risk factors – is the Revised International Staging System (R-ISS).²¹

The R-ISS system incorporates cytogenetic/FISH risk factors, as well as B-2 microglobulin lactate dehydrogenase and albumin. Classical high risk cytogenetic abnormalities include t(4;14), t(14;16), 17p deletion, and are associated with higher risk of progression.²²

Other prognostic risk factors not accounted for in this model include chromothripsis (broken chromosomes), presence of extra-medullary disease, and presence/number of circulating plasma cells.²² Although not accounted for as a high-risk cytogenetic abnormality in the R-ISS system, gain1q chromosome abnormalities, are also increasingly recognized as an independent risk factor for poor outcomes in MM.²³

Patient Education

Patients with MM have access to a robust patient network known for its advocacy and involvement in research.

An important but not comprehensive list of questions for newly diagnosed patients should include inquiries about the causes of MM, the organs that are (and could be) affected, the treatment options available, any clinical trials available, adverse effects of the medicine prescribed, and prognosis based on patient’s individual risk factors.

International Myeloma Foundation (IMF)

The International Myeloma Foundation (IMF) offers resources and can be easily contacted by (800) 452-CURE (800-452-2873) in the United States and Canada or reached online.

Multiple Myeloma Research Foundation

The Multiple Myeloma Research Foundation also offers patient education programs.

Multiple Myeloma Patient Support Groups

Societies such as MyelomaCrowd also allow patients to connect with peer groups and other patients who have common interests. Myeloma Coach programs are also available that help facilitate one on one connections between patients and caregivers.

 

References

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3. Maura, F., et al., Moving From Cancer Burden to Cancer Genomics for Smoldering Myeloma: A Review. JAMA Oncol, 2020. 6(3): p. 425-432.
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