Bone Marrow Macrophages Could Predict Resistance to Velcade, Study Suggests

The multiple myeloma therapy Velcade (bortezomib) can induce the formation of pro-inflammatory macrophages — a kind of white blood cell — that promote the growth of myeloma tumors, Israeli researchers found.

The presence of such cells in the bone marrow could help explain why some myelomas turn resistant to Velcade. Measuring these cells on marrow biopsies could be used to spot patients who are more likely to become resistant.

The study with the findings, “Pro-inflammatory macrophages promote multiple myeloma resistance to bortezomib therapy,” was published in the journal Molecular Cancer Research.

Multiple myeloma is a cancer that forms on a type of white blood cells called plasma cells. In people with myeloma, malignant plasma cells accumulate in the bone marrow, crowding out healthy plasma cells that produce antibodies to help fight infections.

Proteasome inhibitors that control and destroy multiple myeloma cells — like Takeda‘s Velcade and Amgen‘s Kyprolis (carfilzomib) — are a standard treatment for the disease, used throughout all of its stages.

Velcade is “among the most widely used and effective agents for the treatment of MM [multiple myeloma],” the researchers said. It can be given as a first-line treatment, as well as to people whose disease comes back (relapses) after prior therapy. It is often given in combination with other medications, and can be given to patients who have received it already.

Despite its demonstrated benefit in prolonging patients’ survival, some individuals relapse and subsequently develop resistance to Velcade. When this happens, the prognosis is very poor.

Prompted by these observations, researchers at Israel Institute of Technology and Rambam Health Care Campus, in Israel, wanted to investigate what mechanisms underpin relapse and resistance following Velcade treatment.

Using a combination of human cell lines and animal models, the researchers found that Velcade treatment promotes the enrichment of tumor-initiating cells (TICs), also known as cancer stem cells.

These cells represent a small proportion of cancer cells, but have the ability to self-renew, serving as a storage of cells for tumor initiation and growth.

Specifically, Velcade induced the formation of a type of white blood cells, called macrophages, involved in inflammation. Velcade-treated mice had nearly a 40% increase in the percentage of pro-inflammatory macrophages when compared with mice treated with a placebo.

Such macrophages released factors that promoted the growth of human TICs growing in petri dishes. Consistent with this finding, mice implanted with human myeloma had more TICs in their bone marrow, and lived for a shorter time, after treatment with Velcade.

Further experiments suggested that Velcade drives the expansion of TICs in part due to the release, by macrophages, of interleukin-1-beta (IL-1β) — an inflammatory protein.

These findings are in line with ongoing clinical trials assessing IL-1β blockades as a treatment strategy for multiple myeloma. One ongoing Phase 1/2 trial (NCT02492750) is evaluating Kineret (anakinra), combined with Revlimid (lenalidomide) and dexamethasone, a corticosteroid,  for treating early myeloma.

Finally, to support the clinical relevance of their findings, the researchers compared cells in bone marrow biopsies of 34 multiple myeloma patients at the time of diagnosis and several months following Velcade treatment.

Confirming their first results, the investigators found more pro-inflammatory macrophages and TICs in the patients’ marrow after treatment with Velcade. An increased percentage of pro-inflammatory macrophages in these patients also was associated with a shorter survival.

“Overall, our results uncover a pro-tumorigenic cross-talk involving pro-inflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population,” the researchers said.

“Based on our findings, we propose that macrophage state and TIC levels in the BM [bone marrow] compartment of newly diagnosed MM patients can be used as a predictive tool for relapse,” they emphasize.

“At present, with the wide repertoire of treatment options for MM patients, it is imperative to incorporate biomarkers that would preclude one treatment modality over the other in clinical decision making,” they added.