Multiple Myeloma: Approaching Treatment at First Relapse

A. Keith Stewart, MB, ChB: Unfortunately, for many patients with myeloma, relapse is part of this disease. We do believe we could potentially be curing a fraction of patients, maybe as high as 25% or 30%. But probably only in those patients with low-risk disease, which fortunately makes up 65% to 70% of all myeloma patients. Nevertheless, for the vast majority, we do expect relapse to occur over time. This is driven in large part by the genetic makeup of the tumor, with some particular chromosome translocations and loss of chromosome 17 being the dominant markers that predict for prognosis. Those patients tend to respond quickly to therapy but also relapse quickly.

We’ve learned by studying the genomics of myeloma that this is not a static disease. First of all, we understand it’s not a single disease either. There are 8 different genetic flavors of the disease at diagnosis. Within a single patient, that tumor clone will evolve genomically over time. It will develop drug-resistance markers. It will develop deletion of chromosome 17 in many patients. It will evolve like a branching tree into many different flavors of myeloma and different clones of disease.

We have described it as an entity we call clonal ties, in which some of the myeloma clones will be responsive to chemotherapy and then will start to regrow when those drugs are stopped. There are some of the other clones will be eradicated by specific treatments, and some will be totally resistant. So, it’s a very complicated network of genetic aberrations that change over time. It also means that some therapies that worked many years ago, in which the patient failed, they may become responsive to again as different clones come and go over time.

Because of the genomic evolution of myeloma—for example, the emergence of drug resistance—at time of relapse, it is my most common practice to try to switch the types of drugs we’re using to different mechanisms of action and a different class of drugs. For example, in a patient who is taking an immune modulator drug and is beginning to progress on that drug, it is my own personal bias to switch to a different class, such as use of a proteasome inhibitor or perhaps a monoclonal antibody.

There is another solution. The most common maintenance drug is lenalidomide. We can switch that to a stronger, more potent version of the immune modulator, such as pomalidomide, at first relapse. What we see then is a starting position in which the drugs bortezomib and lenalidomide are being employed and the patient relapses are escalated to the second generation of those agents, such as carfilzomib and pomalidomide, or pomalidomide in combination with daratumumab, which is a different class of drug, a monoclonal antibody. It is my own preference to continue to use triplet therapy at relapse since the results tend to favor 3 drugs over 2 in numerous studies.