Results from a small Australian study provide new evidence that the immune systems of myeloma patients may play an important role in why some patients survive much longer than others.

In particular, the Australian researchers found that myeloma patients who live for more than 10 years after diagnosis have more robust immune function as compared to other myeloma patients.

Certain killer immune cells were more common, and divided more read­i­ly, in long-term myeloma survivors than in patients with shorter sur­vival.

The investigators also found that long-term survivors had more helper cells (which promote immune responses) and fewer regulatory cells (which suppress immune responses) than other myeloma patients.

According to the researchers, understanding how the immune system behaves in long-term survivors may provide insights helpful for the development of immune-based myeloma therapies.

Dr. Leif Bergsagel from the Mayo Clinic, who was not involved with the study, agreed that the study results call for further research into therapies that affect a myeloma patient’s immune response.

He also said that the findings support the view that characteristics of a myeloma patient’s immune system play an important role in survival.

“As much as I believe that tumor genetics are of paramount importance, I also think the changes in the host immune system may contribute to progression from MGUS [a myeloma precursor disease] to multiple myeloma, and in long-term disease control,” said Dr. Bergsagel.

However, he also indicated that disease characteristics – such as lower tumor mass, responsiveness to therapy, chromosome abnormalities, and genetic mutations – that differ across patients may lead to different immune responses in patients who experience long-term survival.

Background

Previous evidence has shown that the immune system is impaired in patients with active multiple myeloma. Components of the immune system – including T cells, B cells, natural killer cells, and dendritic cells – are considerably altered.

Immunomodulatory drugs, such as thalidomide ^[5] (Thalomid), Revlimid ^[6] (lenalidomide), and Pomalyst ^[7] (poma­lido­mide, Imnovid), boost the patient’s immune system to better enable it to attack and destroy mye­lo­ma cells.

T cells are a particular type of white blood cells that help the body to identify and kill various types of microbes and cancers.

Two distinct types of T cells, called killer (or CD8) cells and helper (or CD4) cells, work together to mount immune responses. As their names suggest, killer cells can directly kill infected or cancerous cells, while helper cells secrete proteins that aid in the development of killer cells.

Helper cells are further divided into a number of subsets based on the type of proteins they secrete. In the current study, the Australian researchers focused on a particular subset of helper cells called T helper 17 (or TH17) cells that secrete interleukin-17.

Regulatory T cells, on the other hand, are helper cells that suppress immune responses. Previous studies have yielded mixed results regarding the frequency and role of regulatory cells in myeloma patients.

Other studies have examined the immune systems of myeloma patients who show long-term disease con­trol (see related Beacon news ^[8]). Results from these studies indicate that patients with long-term disease con­trol may have increased numbers of killer cells and fewer regulatory cells.

Long-term survival with multiple myeloma is oten defined as survival of 10 years or longer after diagnosis. Several factors such as younger age, lower tumor mass, and response to therapy have previously been associated with long-term survival.

The Australian researchers hypothesized that the immune function of multiple myeloma patients with long-term survival is different from that of patients with shorter survival.

In the current study, the Australian investigators sought to further characterize differences in immune function between long-term survivors and other myeloma patients.

Study Design

Twenty patients who were treated at the Royal Prince Alfred Hospital in Sydney, Australia, for more than 10 years after diagnosis were designated as long-term survivors and included in this study.

The median age of these patients at diagnosis was 58 years, with an age range of 32 years to 73 years.

All patients had received conventional chemotherapy, and 40 percent had been treated with novel agents, such as thalidomide, Revlimid, or Velcade ^[9] (bortezomib). Half of the patients had undergone autologous (own) stem cell transplantation, and 15 percent had undergone allogeneic (donor) stem cell transplantation.

The researchers compared various characteristics of the immune systems of these 20 long-term survivors with data for 264 "short-term follow-up" myeloma patients.   The latter group included 144 myeloma patients who had been visiting the clinic for shorter periods of time, as well as 120 patients who had participated in an Australian clinical trial that investigated the role of thalidomide maintenance therapy.

The 264 short-term follow-up patients, it should be noted, likely included some patients who will become long-term survivors, meaning that the comparisons in the study were not strictly between results for long-term myeloma and shorter-term myeloma survivors.

Also, the number of short-term follow-up patients included in the specific immune system comparisons carried out during the study varied due to data availability issues.

The researchers also compared the data from long-term myeloma survivors and short-term follow-up myeloma patients with data from a group of healthy individuals.

Study Results

The researchers first measured the frequency of various killer cell clones. A clone is a group of immune cells that are identical. Once an immune cell recognizes a specific target, such as a multiple mye­lo­ma cell, it multiplies rapidly to produce a large number of clonal cells. Such clonal expansion of killer cells is a sign of immune system activity against a target.

The researchers found killer cell clones in 100 percent of long-term survivors, but only in 54 percent of short-term follow-up patients who were treated at their institution and 48 percent of patients who participated in the clinical trial.

Based on these results, the researchers conclude that long-term survival may be linked to higher immune system activity against myeloma.

Next, the researchers examined the ability of clonal killer cells to multiply under laboratory conditions. They found that clonal killer cells from long-term survivors proliferated at a much higher rate than those of short-term follow-up patients. The median proliferation rate was about ten times higher for clonal cells from long-term survivors (62 percent versus 6 percent).

Since TH17 helper cells and regulatory cells oppose each other’s function, the researchers next sought to study the balance between these cell types in long-term survivors.

Comparing the frequencies of these two cell types, the researchers found that short-term follow-up patients had markedly fewer TH17 helper cells, but more regulatory cells, than long-term survivors or healthy in­di­viduals.

In fact, long-term survivors had a lower ratio of regulatory T cells to helper cells than healthy patients, sug­gest­ing that helper T cells are particularly important for long-term survival of myeloma patients.

Based on these results, the researchers conclude that the ratio of regulatory cells T cells to TH17 helper cells may be a key indicator for immune response in myeloma patients.

For further information, please see the study in Blood Cancer Journal ^[10].