A team of Israeli researchers has expressed concern that surgical scars may be a particularly favorable environment for the development of difficult-to-treat extra­med­ul­lary disease in multiple myeloma patients.

Extramedullary disease occurs when myeloma cells form tumors outside of a patient’s bones.

The Israeli researchers also suggest that novel anti-myeloma therapies –such as thalidomide ^[1] (Thalomid), Revlimid ^[2] (lenalidomide), or Velcade ^[3] (bortezomib) – and perhaps stem cell transplantation may foster the de­vel­op­ment of extra­med­ul­lary disease in scar tissue.

The researchers describe their concerns in a recent journal article.  In it, they present case reports for three myeloma patients diagnosed between 2008 and 2012 at their cancer center. The patients developed extra­med­ul­lary disease in scars from previous surgical procedures.

In all three cases, the extra­med­ul­lary disease failed to respond to treatment, and the patients died shortly afterward.

In addition, the researchers explore in their article reasons why scar tissue may be a favorable location for extra­med­ul­lary disease to develop, and why certain novel anti-myeloma therapies may foster the de­vel­op­ment of extra­med­ul­lary disease.

The article by the Israeli team is accompanied by an editorial written by three Spanish myeloma specialists, including Dr. Joan Bladé, one of Spain’s leading myeloma researchers.

The Spanish authors provide additional perspective on the Israeli findings regarding extra­med­ul­lary disease and scar tissue, saying “Clinicians should be aware of the possibility of this type of relapse in order to plan the best treatment …”

Limited – And Potentially Conflicting – Evidence

Given how difficult it can be to treat extra­med­ul­lary disease, the concerns raised by the Israeli researchers are likely to draw the attention of other investigators.

The significance of extra­med­ul­lary disease, and the possibility that steps could be taken to avoid it in certain situations, are also key reasons The Beacon has chosen to publish this review of the Israeli researchers’ work. In addition, the authors provide a plausible explanation why scar tissue could be a favorable location for extra­med­ul­lary disease to develop.

It bears emphasizing, however, that the evidence supporting the researchers’ claims is limited.  The Israeli findings are case reports.  They are not results from a comprehensive retrospective study using specific criteria for the inclusion or exclusion of certain patients.  Such a study would provide results providing better perspective on the researchers’ claims, such as the percentage of patients who have experienced the type of extra­med­ul­lary disease the Israeli authors have highlighted.

Furthermore, there is evidence contradicting some of the points the authors make.

The Spanish researchers note in their editorial, for example, that a recent study found no link between treatment with the novel agents thalidomide or Velcade and the development of extra­med­ul­lary disease.

Dr. Shaji Kumar from the Mayo Clinic, who was not involved in the study, likewise told The Beacon, “There is no evidence to link extra­med­ul­lary disease with novel agents, except that these drugs may be allowing patients to live longer, and hence we are seeing a phase in its natural evolution, which we could not see before.”

“I agree that extra­med­ul­lary disease is an emerging problem and needs specific studies to address how to deal with it,” adds Dr. Kumar. “I am not certain that scar tissue-associated extra­med­ul­lary disease is a significant problem.”

“We are certainly seeing an increasing number of patients with extra­med­ul­lary disease in our practices,” Dr. Kumar added. “What is not clear is whether this represents a higher proportion, or just an increase in absolute numbers as more patients are living longer with relapsed disease."

Dr. Kumar and the Israeli and Spanish authors all agree, however, that there is a need for further research concerning extra­med­ul­lary disease.

“There is no doubt that advances in research will result in a better understanding of extra­med­ul­lary myeloma dissemination and, importantly, in a more effective therapy,” the Spanish researchers write in their editorial.

Background

Extramedullary disease ^[4] occurs when myeloma cells form tumors outside of the bone marrow, in the soft tissues or organs of the body (see related Beacon ^[5] news).

The true prevalence of extra­med­ul­lary disease in multiple myeloma patients has yet to be determined.  Prior studies have reported rates ranging from 7 percent to 20 percent in newly diagnosed myeloma patients, and from 6 percent to 20 percent in relapsed patients.

Previous research also has shown that myeloma patients with extra­med­ul­lary disease, either at diagnosis or relapse, have a poorer prognosis than those without. However, the mechanisms underlying extra­med­ul­lary disease are still not well understood.

According to the Israeli researchers, extra­med­ul­lary disease in scar tissue is uncommon in cancer patients and has been rarely reported in multiple myeloma patients.

Study Design and Results

Investigators at the Rabin Medical Center in Petah-Tikva, Israel, identified three myeloma patients who had developed extra­med­ul­lary disease in scars from recent invasive surgical procedures.

The patients were treated at their institution between 2008 and 2012.

All three patients had stage III multiple myeloma at diagnosis.

All three patients received induction therapy that included novel agents. One patient received mel­phalan ^[6] (Alkeran) plus predni­sone ^[7] and Revlimid followed by continuous melphalan and prednisone (MPR-MP).

The other two patients received treatment with a drug combination called VDT-PACE: Velcade, dexa­metha­sone ^[8] (Decadron), and thalidomide followed by cisplatin (DCEP), doxo­rubi­cin ^[9] (Adria­mycin), cyclo­phos­pha­mide ^[10] (Cytoxan), and etoposide (VP-16). VDT-PACE was followed by autologous stem cell transplantation in both patients.

All three patients responded well to the initial treatment, with stringent complete responses in the two who underwent stem cell transplants. The patient who received MPR-MP achieved a very good partial response.

The invasive surgical procedures that caused the development of scars differed among the patients. One patient fractured a bone in his shoulder that required surgery, one patient underwent surgery to remove part of a relapsed myeloma tumor, and one patient had a tooth surgically removed. In the first two patients, the surgeries were directly related to effects of their myeloma.

Extramedullary disease was confirmed with biopsies in all three patients.

In the first two patients, extra­med­ul­lary disease occurred as the only indicator of relapse before overall myeloma relapse. In contrast, in the third patient, extra­med­ul­lary disease occurred at the same time as overall myeloma relapse.

All three patients were initially treated with targeted radiotherapy for their extra­med­ul­lary disease. However, in all three, the disease progressed rapidly and caused death within several months.

Implications Of The Patient Cases

According to investigators, finding so many patients at one hospital in such a short period of time “might indicate an emerging and difficult-to-treat resistant disease in the era of targeted therapies in multiple myeloma.”

“Alternatively,” they write, “it may be an underreported phenomenon and, therefore, awareness by treating physicians should be heightened in the face of the dismal prognosis associated with these cases.”

The investigators explain that they do not yet understand the exact mechanism of this development. They speculate, however, that the extra­med­ul­lary disease may develop either due to accidental transfer of myeloma cells into the scar tissue during surgery, or due to the spread of myeloma cells through blood or lymph into the scar tissue after surgery.

In addition, the authors note that scar tissue “is rich in inflammatory mediators aimed to facilitate wound healing.”  Unfortunately, they add, “These mediators also support tumor growth and survival.”

Based on their findings and the potential reasons why scar tissue could promote extra­med­ul­lary disease, the Israeli researchers conclude that “Physicians treating multiple myeloma patients should be aware of this phenomenon and should consequently be careful when they select invasive procedures for these patients.”

For more information, please see study by Muchtar E. et al., "Myeloma in scar tissue - an underreported phenomenon or an emerging entity in the novel agents' era? A single center series,"  Acta Haematologica, January 10, 2014 (online) (doi: 10.1159/000354830) (abstract ^[11]) and the accompanying editorial by Rosiñol L et al., "Extramedullary myeloma spread triggered by surgical procedures: an emerging entity," Acta Haematologica, January 10, 2014 (online) (doi: 10.1159/000354833)  (preview ^[12]).