Leaving the Bone Marrow: Extramedullary Disease in Multiple Myeloma

Extramedullary disease (EMD) in multiple myeloma (MM) can be confusing for both oncology nurses and patients, especially because the medical literature uses inconsistent terminology. In simple terms, EMD refers to MM cells that form tumors outside the bone marrow. Understanding its complexities is essential for oncology nurses because EMD represents a biologically distinct and often aggressive form of MM that is frequently misunderstood by patients and caregivers.

Defining EMD Versus Paramedullary Disease

EMD can be confused with paramedullary disease (PMD). EMD occurs when MM cells leave the bone marrow to form independent tumors in soft tissues, organs, or the blood. In contrast, PMD occurs when MM extends directly from the bone marrow into the adjacent tissue space.

To avoid confusion, some researchers use the term bone-independent EMD (BI-EMD) for clarity when describing EMD. Kumar and colleagues use illustrations of PMD, organ-associated EMD, and soft-tissue EMD to help oncology nurses and patients understand the differences.

EMD Locations

EMD may present as:

A solid lesion: extramedullary plasmacytoma
Circulating plasma cells in the peripheral blood: plasma cell leukemia

EMD lymph node involvement is common, suggesting Hodgkin’s lymphoma or non-Hodgkin’s lymphoma  before MM is diagnosed. Other sites of EMD include skin and subcutaneous tissues, liver, spleen, and peritoneum (as intra-abdominal masses). Presentation varies, with patients potentially experiencing palpable masses (painful or nonpainful), hepatomegaly, or splenomegaly.

Although rare, central nervous system involvement (CNS-MM) can be extremely aggressive with meningeal infiltration or intraparenchymal plasmacytomas. If it involves the cerebrospinal fluid, treatment strategies may require agents that cross the blood-brain barrier.

Timing and Occurrence of EMD

EMD incidence varies throughout the disease trajectory, with it being rare in newly diagnosed patients (up to 5%), but more prevalent in those with relapsed or refractory (R/R) disease (up to 14%). Location also varies with the timing of occurrence. For example, head and neck involvement is more common at diagnosis, whereas liver infiltration and pleural involvement are more frequently seen in patients with R/R disease.

High-Risk Cytogenetics

Patients with EMD often have high-risk cytogenetic abnormalities, such as:

del(13q) and del(17p)
gain(1q21)
t(4;14), t(14;16), and t(14;20)

A small study (n=15) of whole-genome sequencing suggests a link between EMD and the mitogen-activated protein kinase (MAPK) pathway, particularly RAS–RAF mutations.

Real-World Data on EMD

In a single-center, retrospective, real-world analysis from London, investigators reported outcomes for adults with newly diagnosed MM, referring to EMD as BI-EMD. Among 906 patients, BI-EMD was observed in 33 (3.6%) at diagnosis and 22 (2.4%) at relapse. These findings differ from those of other studies, which often report higher incidence rates in R/R disease. The median follow-up was 45 months. Consistent with previous research, EMD is recognized as an entity distinct from MM requiring sensitive imaging and often more intensive management.

Oncology Nursing Implications

Oncology nurses must understand the role of CRAB (hyperCalcemia, Renal insufficiency, Anemia, lytic Bone lesions/osteopenia) and biomarkers (such as M-protein or free light chain) in EMD. CRAB and EMD can coexist in patients with MM (particularly in those with R/R or advanced disease), or EMD can be present without CRAB. Often, biomarkers do not correlate with the EMD burden.

Because early diagnosis is critical to optimizing outcomes, oncology nurses must remain vigilant in assessing patients and encouraging them to report any masses, enlarged lymph nodes, or new symptoms. In addition, oncology nurses can identify patients at high risk for EMD at the time of relapse or recurrence and anticipate use of aggressive therapies, such as chimeric antigen receptor (CAR) T cells or dual-target bispecific antibodies.

One patient education resource is this video titled, “What Is Extramedullary Disease in Myeloma.” By recognizing new assessment findings, understanding disease biology and high-risk characteristics, and educating patients, oncology nurses can improve the care of patients with EMD.