multiple myeloma

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Multiple Myeloma

Overview

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated B cells (plasma cells) that accumulate in the bone marrow, produce a monoclonal immunoglobulin (M protein), and cause systemic end-organ damage. It is one of the most common lymphoid malignancies, with approximately 30,000 new cases/year in the United States. The median age at diagnosis is 65-70 years; it is more common in males and, notably, occurs approximately twice as frequently in people of African descent compared to those of European descent.

Robbins & Kumar Basic Pathology, p. 422
Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 758

Pathogenesis

MM arises from a post-germinal center plasma cell. Several key molecular events drive its development:

Mechanism	Detail
IgH translocations	Chromosomal translocations fuse the IgH locus (chr 14) to oncogenes such as CCND1 (cyclin D1) and CCND3 (cyclin D3), dysregulating D cyclins and driving proliferation
IL-6 signaling	Interleukin-6 from bone marrow stromal fibroblasts and macrophages is the principal growth factor for myeloma cells
RANKL upregulation	Myeloma-derived factors upregulate RANKL on bone marrow stromal cells → osteoclast activation → bone resorption
Osteoblast suppression	Tumor-derived factors inhibit osteoblast function, creating the net lytic skeletal effect
MYC translocations	Appear late in disease, especially in aggressive/refractory cases

Cytogenetics divide myeloma into two broad groups with prognostic significance:

Hyperdiploid (trisomies of odd-numbered chromosomes): favorable prognosis
Hypodiploid/non-hyperdiploid: adverse prognosis

Adverse markers: del(17p13) [TP53], t(4;14), t(14;16), t(14;20), del(13q14) Favorable markers: t(11;14), t(6;14)

Robbins & Kumar Basic Pathology, p. 422
Henry's Clinical Diagnosis and Management, p. 758

M Protein Distribution

Isotype	Frequency
IgG	~60%
IgA	~20-25%
Light chain only (κ or λ)	~20%
IgD, IgE, IgM	Rare
Nonsecretory	~1%

Clinical Features - the "CRAB" Criteria

End-organ damage defines symptomatic myeloma requiring treatment:

C	Hypercalcemia	Bone resorption releases calcium → confusion, weakness, lethargy, polyuria, constipation
R	Renal insufficiency	Bence Jones (free light chain) cast nephropathy, AL amyloid deposition, hypercalcemia-related damage; renal failure in up to 50% of patients
A	Anemia	Normocytic normochromic anemia from marrow replacement; leukopenia and thrombocytopenia may also occur
B	Bone lesions	Lytic "punched-out" defects 1-4 cm, most commonly in vertebral column, ribs, skull, pelvis, femur, clavicle, scapula; pathologic fractures are common

Additional manifestations:

Recurrent bacterial infections: Myeloma cells suppress normal B-cell function, severely depressing functional antibody production despite elevated total IgG (mostly non-functional M protein)
Hyperviscosity syndrome: Particularly with IgA or IgM M proteins; causes visual changes, neurologic symptoms, bleeding
Peripheral neuropathy: Especially with AL amyloidosis
Rouleaux formation on blood smear with markedly elevated ESR

Bone Marrow Histology

The image below shows myeloma infiltrating the bone marrow - large, atypical plasma cells with prominent nucleoli, abnormal chromatin, and Russell bodies (cytoplasmic immunoglobulin inclusions):

Myeloma cells in bone marrow - large plasma cells with nucleoli (×1000)

Bone marrow aspirate showing large neoplastic plasma cells - Henry's Clinical Diagnosis, p. 758

Morphologic findings:

Plasma cells typically >30% of marrow cellularity in active disease
Cells may show large nucleoli, cytoplasmic inclusions (Russell bodies), and varying degrees of anaplasia
Immature (plasmablastic) variants carry worse prognosis
In advanced disease, visceral spread and plasma cell leukemia can occur

Immunophenotype: CD38(+), CD138(+), loss of CD19 (normally present on plasma cells), CD20(-); monotypic light chain restriction

Myeloma Kidney

Renal involvement occurs through several mechanisms:

Cast nephropathy (most important): Bence Jones proteins form obstructive casts in distal convoluted tubules and collecting ducts, surrounded by multinucleate giant cells; tubular epithelium adjacent to casts undergoes necrosis
AL amyloidosis: Light chains deposit as amyloid in glomeruli and vessel walls
Light chain deposition disease: Non-amyloid linear light chain deposits in glomeruli/interstitium
Metastatic calcification: From hypercalcemia
Bacterial pyelonephritis: From hypogammaglobulinemia

Renal failure is second only to infections as the leading cause of death in myeloma.

Robbins & Kumar Basic Pathology, p. 422

Diagnostic Criteria

MGUS vs. Smoldering vs. Active Myeloma

Feature	MGUS	Smoldering Myeloma	Active Myeloma
Serum M-protein	<30 g/L	≥30 g/L	Any level
Marrow plasma cells	<10%	≥10%	Clonal plasma cells present
CRAB features	None	None	Present
Treatment needed	No	Generally no	Yes

Progression risk of smoldering myeloma:

10% per year for first 5 years
3% per year for years 5-10
1% per year thereafter

Definitive diagnosis requires:

Bone marrow biopsy showing clonal plasma cells
Serum/urine protein electrophoresis (SPEP/UPEP) with immunofixation to identify and type the M protein
Serum free light chain assay
Imaging (skeletal survey, CT, PET-CT or whole-body MRI) for bone lesions

Henry's Clinical Diagnosis and Management, p. 758

Staging

Revised International Staging System (R-ISS):

Stage	Criteria	Median OS
I	β2-microglobulin <3.5 mg/L + albumin ≥3.5 g/dL + standard cytogenetics + normal LDH	~Not reached
II	Neither I nor III	~83 months
III	β2-microglobulin ≥5.5 mg/L + high-risk cytogenetics [t(4;14), t(14;16), del(17p)] or elevated LDH	~43 months

Treatment

Newly Diagnosed - Transplant Eligible

Current standard of care uses triplet or quadruplet induction followed by autologous stem cell transplantation (ASCT):

VRd: Bortezomib (proteasome inhibitor) + Lenalidomide (IMiD) + Dexamethasone
Dara-VRd: Daratumumab (anti-CD38 monoclonal antibody) + VRd - increasingly adopted as preferred quadruplet regimen
ASCT remains standard of care when feasible; early transplant vs. delayed transplant outcomes are comparable in overall survival but early transplant provides longer PFS
Tandem ASCT may benefit high-risk patients

Newly Diagnosed - Transplant Ineligible

VRd (reduced intensity) or DRd (Daratumumab + Lenalidomide + Dexamethasone)
Continuous therapy until progression

Maintenance Post-ASCT

Lenalidomide maintenance is standard; extends PFS and OS
High-risk cytogenetics: add bortezomib

Relapsed/Refractory Multiple Myeloma (RRMM)

Key drug classes available:

Proteasome inhibitors: Bortezomib, Carfilzomib, Ixazomib
Immunomodulatory drugs (IMiDs): Thalidomide, Lenalidomide, Pomalidomide
Anti-CD38 monoclonals: Daratumumab, Isatuximab
Anti-SLAMF7: Elotuzumab
Bcl-2 inhibitor: Venetoclax (t(11;14) myeloma)
BCMA-targeted therapies (newer agents):
- CAR-T cells: Idecabtagene vicleucel (ide-cel), Ciltacabtagene autoleucel (cilta-cel)
- Bispecific antibodies: Teclistamab, Elranatamab, Talquetamab

A 2024 meta-analysis in J Immunother Cancer comparing CAR-T vs. bispecific antibodies as third-line or later treatment found comparable efficacy, informing sequencing decisions in RRMM.

Role of Allogeneic Transplantation

Limited role due to high treatment-related toxicity
Reduced-intensity allogeneic transplant may be considered in selected patients who relapse after ASCT
Goldman-Cecil Medicine, International Edition

Prognosis

Without treatment, patients with multiple lytic lesions survive 6-12 months
With modern therapy, median survival has improved to approximately 5-7+ years in some series
Smoldering myeloma may require no treatment for many years
Renal failure and infections are the leading causes of death
High-risk cytogenetics [del(17p), t(4;14), t(14;16)] carry significantly worse prognosis

Clinical Variants

Variant	Key Features
Smoldering (asymptomatic) myeloma	High M protein or marrow plasma cells but no CRAB; watch-and-wait
Nonsecretory myeloma	~1% of cases; tumor cells do not produce/secrete Ig; diagnosis by marrow biopsy and FLC assay
Solitary plasmacytoma	Single bone or soft tissue lesion; treat with radiotherapy; monitor for progression to MM
Plasma cell leukemia	>20% circulating plasma cells; aggressive variant
POEMS syndrome	Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes

Summary

Multiple myeloma is a systemic plasma cell malignancy defined by the production of monoclonal immunoglobulin, bone marrow infiltration, and end-organ damage (CRAB). Treatment has been transformed by proteasome inhibitors, IMiDs, anti-CD38 antibodies, and most recently BCMA-directed CAR-T and bispecific antibody therapies. Recent PubMed evidence (2024-2026) focuses heavily on optimizing the role of CAR-T vs. bispecific antibodies in relapsed/refractory disease, with second primary malignancies after CAR-T and non-relapse mortality being important safety signals to monitor.

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