Multiple myeloma: An overview

Multiple myeloma (MM) is a monoclonal gammopathy, resulting from the abnormal proliferation of clonal plasma cells. This abnormality leads to an excess production of a single immunoglobulin and, in turn, high levels of monoclonal paraprotein M – also referred to as the M protein. MM is the second most common hematological malignancy diagnosed in adults, with the highest prevalence among older male patients from non-White backgrounds.¹

Etiology

The primary cause of MM is not fully understood, but it is believed to be the result of an acquired genetic mutation. Translocations in chromosome 14 are commonly observed in MM, and common oncogene mutations and their incidence in MM include.²

• KRAS: 36%
• NRAS: 20%
• TP53: 16%
• DIS3: 16%
• FAM46C: 12%

The main risk factors associated with the development of MM include³

• Older age (≥65 years)
• Male gender
  • Men are 1.5 times more likely to develop MM than women
• Race
  • Black patients are at a higher risk of developing MM compared with White patients
• A family history of MM
• Obesity
• Diagnosis of other plasma cell dyscrasias
  • Monoclonal gammopathy of undetermined significance
  • Solitary plasmacytoma
  • Smoldering MM

Epidemiology

The age-standardized rate (ASR) of MM globally is 1.78 people per 100,000, with the highest incidence recorded in Australia and New Zealand (ASR: 4.86) and the lowest in western Africa (ASR: 0.81).⁴

Across all regions, MM is most prevalent in males, particularly in those over 65 years⁵; see Figure 1 for more details.

*Data from Huang, et al.⁴ and Padala, et al.⁵

Pathophysiology^7,8

The pathophysiology of multiple myeloma is demonstrated in Figure 2.

BMSC, bone marrow-derived mesenchymal stem cell.
*Adapted from Lentzsch, et al.⁷ and Mukkamalla, et al.⁸
Created with BioRender.com.

• Hematopoietic stem cells in the bone marrow differentiate into a disproportionate volume of B cells and, subsequently, overproduce plasma cells (>10% plasma cells).
• These plasma cells produce abnormal antibodies and an excess of light-chain antibodies.
• MM cells secrete cytokines such as IL3, which inhibits the production of osteoblasts, limiting the production of bone cells.
• MM cells cause an increase in osteoclast production and subsequent breakdown of bone cells by:

• • Secreting DKK1, which inhibits OPG production by osteoblasts and, in turn, increases osteoclast activity
  • Stimulating osteoclasts through the expression of MIP1α and RANKL
  • Stimulating IL6, which is involved in the self-regulation of osteoclast cells.
• An increase in osteoclast activity results in the breakdown of bone cells, which then release calcium, and causes hypercalcemia.
• The paraproteins produced in excess cause renal damage and failure.
• Anemia can result from renal failure and the overproduction of plasma cells.

Signs and symptoms¹

The primary indicators for MM are often denoted using the acronym CRAB:
C: hypercalcemia
R: renal failure
A: anemia
B: lytic bone lesions

Other common signs and symptoms are shown in Figure 3.

*Data from Van de Donk, et al.¹

Diagnosis⁶

A diagnosis of MM requires at least one myeloma-defining event (MDE) to occur in addition to either ≥10% clonal plasma cells or an observed plasmacytoma.

MDEs may include any of the CRAB signs (listed above), as well as:

• Clonal plasma cells ≥60%
• Serum free light-chain ratio ≥100
• ≥1 focal bone lesion.

The high abundance of the M protein associated with MM can be used as a diagnostic indicator through serum protein electrophoresis. Further investigation with immunofixation can be used to determine MM subtype by identifying the particular immunoglobulin in excess.

Disease staging can then be determined using a number of tools, most commonly the Revised International Staging System (R-ISS), as shown in Table 1.

Table 1. Revised International Staging System for multiple myeloma*

CA, cytogenetic abnormalities; iFISH, interphase fluorescence in situ hybridization; LDH, lactate dehydrogenase; R-ISS, Revised International Staging System. *Adapted from Van de Donk, et al.1
Stage	Criteria
I	Sβ2M < 3.5 mg/L Serum albumin ≥ 3.5 g/dL Standard-risk chromosomal abnormalities by iFISH Normal LDH
II	Not R-ISS stage I or III
III	Sβ2M ≥ 5.5 mg/L and either High-risk CA by FISH or High LDH

Risk stratification in MM is determined by the presence of following indicators for high-risk disease status:

• High risk genetic abnormalities:
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • Del 17p or p53 mutation
  • Gain 1q (amplification of duplication)
• High-risk plasma cell S-phase
• R-ISS stage 3

However, it is important to note that the individual criteria for diagnosis, risk stratification, and staging may vary by region. A variety of international guidelines can be found at the end of this document.

Management^6,9

The only potentially curative treatment for MM is stem cell transplantation; thus, the MM treatment paradigm is differentiated by transplant eligibility. A summary of the current treatment paradigm is shown in Figure 4.

*Adapted from Rajkumar S.⁶

The recommendations for therapies in newly diagnosed MM, differentiated by transplant eligibility and risk status, are outlined in Figure 5.

ASCT, autologous stem cell transplant; DRd, daratumumab lenalidomide dexamethasone; VRd, bortezomib lenalidomide dexamethasone.
*Adapted from Rajkumar S.⁶

The treatment of relapsed/refractory MM consists of a range of agents, indicated by number of prior lines of therapy and refractory status, including:

• Proteosome inhibitors
• Immunomodulatory agents
• BCMA targeted antibodies
• Anti-CD38 targeted antibodies
• Chimeric antigen receptor T-cell (CAR-T) therapy.

Each has a different mechanism of action, described in Figure 6.

BCMA, B-cell maturation antigen; IL6, interleukin-6; MIP1α, macrophage inflammatory proteins; RANKL, receptor activator of nuclear factor-κB ligand; TNFα; tumor necrosis factor alpha; XPO1, exportin-1.
*Data from Tanenbaum, et al.⁹

Region-specific guidelines

• National Institute for Health and Care Excellence (UK)
• Portuguese Group of Multiple Myeloma
• International Myeloma Working Group
• Myeloma Australia
• Indian Council of Medical Research
• EHA ESMO Clinical Practice Guidelines