Managing high-risk multiple myeloma

This study reviewed evidence on the management of high-risk multiple myeloma. 

Multiple myeloma is a diverse disease. Using predictors of treatment success is important to help select treatment approaches for patients. Higher risk patients may benefit from more aggressive treatment.

There are multiple methods for determinine patient risk. The International Staging System (ISS) is a method of separating patients by risk. The ISS takes 2 factors into account. They are beta2-microglobulin levels (indicators of tumor size and kidney function) and albumin levels (measure of disease activity). 

Certain chromosomal abnormalities (changes in the genetics of a cell) in multiple myeloma can make it more difficult to treat. These include deletion (13q), translocation (4;14), translocation (14;16), deletion (17p), and 1q abnormalities.

Lactate dehydrogenase is a marker of cell and tissue damage. High levels can be predictive of poor treatment outcomes. Plasma cell leukemia (PCL) is an aggressive form of multiple myeloma. It is characterized by high levels of abnormal plasma cells circulating in the blood.

The aim of this study was to review evidence on the management of high-risk multiple myeloma.

In a study of 100 newly diagnosed multiple myeloma patients, the average time until disease progression for patients with the deletion (13q) was 18.5 months. This was significantly shorter compared to patients who did not have this abnormality (36.5 months). However, overall survival (time from treatment until death from any cause) was similar in the two groups. The presence of deletion (13q) on its own may not be a predictor of survival.

Bortezomib (Velcade) was more effective than vincristine (Cytocristin) when added to doxorubicin (Adriamycin) and dexamethasone (Dexasone) for patients with translocation (4;14). However, overall survival remained lower (52%) compared to patients without the abnormality (75%). Some patients with translocation (4;14) may benefit from a tandem stem cell transplant. This is when two autologous (stem cells harvested from the patient) transplants are performed within a given period.

Of all the chromosomal abnormalities, deletion (17p) is the most consistent predictor of survival. Studies have shown that a third agent is important in addition to the standard lenalidomide (Revlimid) and dexamethasone combination. 5-year overall survival was 65% for patients with deletion (17p) when bortezomib was added to treatment. This was significantly greater compared to those not treated with bortezomib (18%). Bortezomib, lenalidomide, and dexamethasone may also be an effective maintenance therapy (with the aim to maintain remission). One study reported a 3-year overall survival of 93%.

One study randomized 722 patients to receive either ixazomib (Ninlaro), lenalidomide, and dexamethasone or lenalidomide and dexamethasone. Average time to disease progression was significantly improved with the addition of ixazomib from 14.7 to 20.6 months. For patients with deletion (17p) it was improved from 9.7 to 21.4 months. For patients with translocation (4;14) it was improved from 12 to 18.5 months.

Other treatments being investigated for patients with chromosomal abnormalities include monoclonal antibodies, such as elotuzumab (Empliciti) and daratumumab (Darzalex). Adding elotuzumab to lenalidomide and dexamethasone significantly improved time to disease progression. It was improved from 14.9 to 21.9 months for patients with deletion (17p). It was improved from 5.55 to 15.84 months for patients with translocation (4;14).

PCL is a rare and aggressive form of multiple myeloma. Currently there are no standard therapeutic approaches. One study reported similar outcomes after autologous stem cell transplants between multiple myeloma patients with PCL and those without. Overall survival at 3 years was 64%. PCL patients may benefit from a tandem stem cell transplant. Early results also show promising results in 3-drug treatment combinations involving bortezomib for PCL patients. 

This review concluded that a combination of immunotherapy agents (such as lenalidomide and pomalidomide) with proteasome inhibitors (such as bortezomib and ixazomib) has improved response rates and survival in patients with high-risk multiple myeloma. Investigations involving new agents, such as monoclonal antibodies, are ongoing.