During the course of their disease, multiple myeloma patients some­times develop what physicians call either "extram­edullary disease," "extra­medullary plasmacytomas," or "extra­medullary myeloma."

In medicine, when something is described as "extramedullary," it means it is located outside of the bone marrow.

So "extramedullary" myeloma is myeloma that is outside of the bone marrow.

It occurs when malignant plasma cells collect together and form tumors in parts of the body other than a patient's bones.

This can occur in any myeloma patient, but it appears to be more common in patients with relapsed or refractory multiple myeloma.

The following article provides a detailed introduction to extramedullary myeloma, including what it is, how it is diagnosed, and how it is treated.

What Is Extramedullary Myeloma?

Multiple myeloma is a cancer in which malignant plasma cells build up and form tumors ("plasmacytomas") inside the bone marrow.

Extramedullary myeloma is also a cancer involving malignant plasma cells forming tumors.  However, extramedullary tumors occur outside the bone marrow, in the soft tissue and organs of the body.  These tumors can occur in patients with - or without - myeloma tumors in their bones.

“Extramedullary disease can occur on its own, as a solitary extramedullary [tumor], in a patient who does not have myeloma,” explained Dr. S. Vincent Rajkumar, a myeloma specialist at the Mayo Clinic in Rochester, Minnesota.

It is not clear why extramedullary disease occurs in some myeloma patients and not in others.  However, “Extramedullary disease occurring in a patient with myeloma is generally considered a more aggressive disease,” according to Dr. Rajkumar.

This may be because, in patients with aggressive myeloma, the malignant plasma cells are better able to survive, spread outside the bone marrow, and accumulate in other parts of the body.

The focus in the rest of this article is on extramedullary disease in multiple myeloma patients.

Diagnosis

According to Dr. Mario Curti, a hematologist at Los Alamitos Medical Center in Los Alamitos, California, extramedullary myeloma is diagnosed when a biopsy reveals the presence of malignant plasma cells outside the bone marrow.

"Usually, [extramedullary disease] is found by accident on scans such as a chest X-ray or a CT scan, or if a patient has some complaint to cause a scan to be ordered,” said Dr. Curti.

“When a lesion is found, [it is likely to] grow quickly. I would not sit on it, and therefore would always order a biopsy, which should show sheets of [malignant] plasma cells [if the patient has extramedullary disease],” he explained.

Symptoms

Symptoms of extramedullary myeloma vary depending on the location and size of the tumor.

A large study published in the Annals of Oncology in 2009 showed that 85 percent of multiple myeloma patients with extramedullary disease had a tumor in the muscles, tendons, fat, and other soft tissue surrounding the axial skeleton, which includes the skull, rib cage, and vertebral column.

The remaining 15 percent of extramedullary disease cases affected the lymph nodes, liver, kidney, airways, skin, and breast.

“Often, [symptoms of extramedullary disease] are remarkably asymptomatic. Sometimes [patients] present with pain. Occasionally they will have fevers, night sweats, or weight loss,” said Dr. Martha Lacy of the Mayo Clinic in Rochester, Minnesota.

Prevalence

The Annals of Oncology study mentioned earlier found that approximately 13 percent of myeloma patients develop extramedullary disease. Specifically, 7 percent of myeloma patients have extramedullary disease at diagnosis, and 6 percent of patients develop the disease during the course of their myeloma.

Earlier, in 2003, another large study published in the Mayo Clinic Proceedings (abstract) suggested that extramedullary disease is present in less than 1 percent of myeloma patients at diagnosis.

“These differences are due to different populations and diagnostic methods,” explained Dr. Carlos Fernández de Larrea Rodríguez of the Hospital Clínic de Barcelona in Spain.

According to a new study conducted by Dr. Rodríguez and published last month in the Journal of Clinical Oncology (abstract), extramedullary disease occurs in 7 percent to 18 percent of multiple myeloma patients at diagnosis and in up to 20 percent at relapse.

“One explanation for the discrepancies [of extramedullary disease rates across studies] may be due to the differences in the time frames. [Before the year 2000], sophisticated imaging such as MRI and PET/CT scans was either unavailable or only ordered based on patient symptoms. In the era since 2000, these imaging studies are increasingly being ordered as part of the baseline work-up,” said Dr. Lacy.

“I think we won’t know the true rate [of extramedullary disease] at diagnosis until we have a large series that includes sophisticated imaging for all patients at baseline, a study that may not be feasible in the current economic times,” she added.

Treatment For Myeloma Patients With Extramedullary Disease

Multiple myeloma patients who develop extramedullary tumors are usually treated with the same therapies used to treat myeloma found only in the bone marrow -- treatments such as chemotherapy, high-dose chemotherapy followed by autologous stem cell transplantation, or novel agents.

“When a myeloma patient develops extramedullary disease, it means that the myeloma is relapsing and is becoming more aggressive. The disease is still a systemic disease [a disease that affects multiple organs], and systemic diseases need systemic treatments,” said Dr. Rajkumar.

However, Dr. Curti pointed out that treatment for extramedullary disease may also depend on the location, symptoms, and the state of the patient’s myeloma. Therefore, in some instances, patients may be treated with more localized therapies, such as radiation or surgery.

“Although I tend to treat extramedullary disease with typical myeloma treatments, if the extramedullary disease is in a location causing problems, and understanding that extramedullary disease does not respond as well to the usual therapies we give to myeloma patients, I would not hesitate to try local treatment such as surgery or radiation, especially if the myeloma in general is under some control,” said Dr. Curti.

Chemotherapy/High-Dose Chemotherapy

Conventional chemotherapy or high-dose chemotherapy with melphalan (Alkeran) followed by a stem cell transplant are among the standard forms of treatment for myeloma patients who have extramedullary disease.

In a 2009 study published in Leukemia & Lymphoma (abstract), British researchers found that high-dose chemotherapy followed by a stem cell transplant significantly improved overall survival among myeloma patients who had extramedullary disease at the time of their multiple myeloma diagnosis.

The researchers therefore argued that stem cell transplants should be "an integral component of first-line treatment" for newly diagnosed myeloma patients with extramedullary disease.

Therapy With Novel Agents

Results of several clinical trials have shown that Velcade (bortezomib), Revlimid (lenalidomide), and pomalidomide may improve outcomes for myeloma patients with extramedullary disease. However, most of these studies are small, and the role of novel agents in treating extramedullary disease in myeloma patients is still unclear.

Results of a small study published in the European Journal of Haematology (abstract) showed that extramedullary disease disappeared in three out of four myeloma patients treated with Velcade.

Another small study that also was published in the European Journal of Haematology (abstract) found that 61 percent of myeloma patients with extramedullary disease responded to Revlimid, with 44 percent experiencing complete tumor disappearance.

In addition, a study published in the journal Leukemia (abstract) reported that 31 percent of myeloma patients with extramedullary disease responded to treatment with pomalidomide, with 15 percent of patients experiencing complete tumor disappearance (see related Beacon news).

On the other hand, the majority of studies investigating the role of thalidomide (Thalomid) in myeloma patients with extramedullary disease have suggested that it is ineffective in treating extramedullary disease. Two such studies, published 2001 in the British Journal of Haematology and 2004 in Haematologica (pdf), showed that while thalidomide may be effective in relapsed myeloma patients, no myeloma patients with extramedullary disease experienced a decrease in tumor size.

Potential Link Between Extramedullary Disease And Treatment With Novel Agents

In recent decades, there has been both an improvement in the quality of therapies for multiple myeloma and, at the same time, an increase in the rate of extramedullary disease among myeloma patients.

Between 1971 and 1993, when myeloma patients received mostly conventional chemotherapy, one in every 150 myeloma patients developed extramedullary disease per year.

Between 2000 and 2007, after novel agents became more common in the treatment of myeloma, this ratio increased to one in every 65 myeloma patients per year.

The parallel change in the rate of extramedullary disease and the use of novel therapies has raised concerns that novel therapies may be increasing the risk of extramedullary disease.

“A question left unanswered is, ‘Does treatment with novel agents select for [myeloma cells] that are capable of causing extramedullary disease, or does the development of extramedullary disease occur because patients are now living longer due to novel agents?’,” said Dr. Lacy.

In a study published in 2006 in the Annals of Oncology, researchers argued that novel agents could have either a detrimental or therapeutic effect with regard to extramedullary disease.

For instance, the researchers indicated that, because thalidomide is particularly active within the bone marrow, it may encourage the spread of myeloma cells outside the bone marrow.  Other drugs, such as Velcade, may have poor penetration into areas such as the central nervous system, allowing extramedullary disease to develop in those parts of the body.

However, researchers also have speculated that the rate of extramedullary disease among myeloma patients may be increasing simply because targeted therapies prolong life and therefore allow a greater time for extramedullary disease to develop.

Other researchers have suggested that more advanced imaging techniques have allowed detection of more cases of extramedullary disease than in the past.

Nevertheless, according to many myeloma experts, a more sophisticated understanding of how myeloma cells spread, as well as the biology of extramedullary tumors, is needed to develop better strategies for the treatment of extramedullary myeloma.