Q: What are the challenges and key considerations in your approach to salvage therapy for multiple myeloma?

I describe salvage therapy as treatment for patients who have failed frontline treatment. It is very much an art, and it is very complicated. There are multiple patient-level considerations, such as the response to prior therapy and the ability of the individual to tolerate additional treatments. There are challenges related to limited data from clinical trials, and cost-effectiveness of the salvage regimen is also a consideration. The assessment of progression in multiple myeloma relies heavily on the accurate measurement of the monoclonal protein or immunoglobulin marker, which is an imperfect tool. Improvements in progression-free survival (PFS) are not always mirrored by improvements in overall survival (OS), which, to me, suggests that progression may occur, but it may escape detection in some patients with our current methods. I would caution against taking the leap of faith that a PFS advantage automatically translates to an OS advantage. It often does not, and treatment based on PFS data can result in the use of additional therapies when they may not have been necessary. Unnecessary treatment places a burden on the health care system with unnecessary costs, and it can also impact the patient with unnecessary treatment side effects. We must be careful when interpreting end points that are not very well demarcated. If we had the ability to measure the actual disease burden in all patients except those who have truly no minimal residual disease, we would be better able to accurately assess the clinical significance of published survival data. It is also important to be careful when interpreting trials performed in other parts of the world where treatment options are limited. For instance, I find it difficult to interpret a lot of the data from trials conducted in Europe because I do not think that the practices there are relevant to what happens at my clinic on a daily basis. In the United States, patients are fortunate to have access to additional treatment options that are not available in Europe. Thus, there are several factors to consider when determining one’s approach to salvage therapy in an individual patient, including patient-related factors, cost-related factors, and factors related to the patient’s previous response to treatment.

While it is true that PFS does not necessarily equate to OS, if we wait for the studies to show differences in OS, we run the risk of not having the data necessary to help us make these treatment decisions. It is desirable to see OS benefits, but our patients often switch from one treatment regimen to another, making it difficult, ultimately, to determine which treatments are having the most impact. We all are trying to make the best decisions we can, based on the data and patient preferences. Many of our patients receive their therapy from a local oncologist, and we serve as the “quarterbacks,” if you will. It is a wonderful collaboration that allows patients to be treated closer to their homes while also taking advantage of expert care in a disease that becomes even more complicated as, thankfully, additional lines of therapy become available. I know that my community physicians rely on this collaboration extensively and are pleased to have it. Salvage therapy is simply another line of therapy, and it is a term that can be used interchangeably with later lines of treatment for relapsed disease.

The critical message here is that multiple myeloma treatment is not a zero-sum game; it is not a matter of using one treatment vs another treatment. We need all of the tools in the toolbox, and the challenge lies in determining how to best use these tools. At the end of the day, although I have wonderful long-term survivorship, I would never use the word cure. With respect to functional control for long periods of time and good quality of life, there is great news for patients. But, especially with the excitement surrounding chimeric antigen receptor T-cell therapy and other therapies, many are saying that a cure is right around the corner. This is not the case, in my opinion. It is true that PFS benefit does not necessarily translate to OS benefit in every setting, but, in the majority of highly successful therapeutics, PFS does translate to OS. In the relapsed/refractory space, response to previous therapy is certainly relevant in determining salvage treatment, and we have had some progress in that area in recent years. The OPTIMISMM trial, for example, compared bortezomib-dexamethasone as a continuous therapy (as an initial salvage strategy) to the triplet platform of pomalidomide-bortezomib-dexamethasone. We chose this triplet platform because it had been shown to be safe, well tolerated, and effective in phase 1 and 2 trials. Further, it would be a cost-effective platform with bortezomib now being generic, upon which we could build by adding an antibody or other agent. We exclusively targeted lenalidomide-exposed patients, and we wanted to determine the best treatment strategy once lenalidomide fails. All patients were lenalidomide exposed and 70% were lenalidomide refractory. The final outcomes favored the triplet regimen, and the strength of the signal at first relapse was a pleasant surprise. Pomalidomide-bortezomib-dexamethasone generated more than 20 months of PFS compared with the control group among lenalidomide-exposed, nonrefractory patients. In addition, salvage was successful to the extent that not only was the overall response rate for the group above 80%, but the median PFS in first relapse was also approaching 18 months in lenalidomide-refractory patients, with a hazard ratio of 0.55. Adverse events in the OPTIMISMM trial were generally consistent with the known adverse events of pomalidomide, bortezomib, and dexamethasone, and included neutropenia, thrombocytopenia, anemia, and infection. There is also a strong PFS-OS trend emerging with carfilzomib-based and elotuzumab-pomalidomide platforms, so there are multiple promising options for salvage therapy.