Kenneth C. Anderson, MD
Jerome Lipper Multiple Myeloma Center
LeBow Institute for Myeloma Therapeutics
Dana-Farber Cancer Institute
With the arrival and incorporation into clinical practice of immunomodulatory drugs (IMiDs) and proteasome inhibitor therapy, patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. In a recent review,1
coauthors Sagar Lonial, MD, and Kenneth C. Anderson, MD, wrote that these responses call for a rigorous analysis of the relationship between patient response and survival, and perhaps a revision in treatment strategies that will enable a leap forward in the management of this challenging disease.
In this interview, Anderson, from Dana-Farber Cancer Institute and Harvard Medical School, discusses the improving prospects for outcomes using new targeted agents, and advances in assessment tools that enable refinements in response criteria.Could you speak about the general concepts you and your co-author raise in the recent Leukemia review paper, “Association of response endpoints with survival outcomes in multiple myeloma”1?Anderson: Since the advent of the IMiDs and proteasome inhibitors as novel agents, the paradigm for myeloma treatment has been completely transformed. This review points out that it is now possible to achieve a frequency and extent of response that simply wasn’t possible before these agents were available. As a consequence, patient outcomes have been markedly improved.
Nowadays, with the incorporation [into clinical practice] of these two classes of novel agents, often before high-dose therapy and transplant, and as consolidation and maintenance after transplant, we achieve a higher extent of molecular complete response—or the absence of minimal residual disease, as mea - sured by PCR or by multicolor immunofluorescence. Either one of these can detect perhaps even one myeloma cell in as many as 100,000 normal cells. This is an extent of response we have not been able to achieve before except with allogeneic transplantation.
Have improvements in measurements of response aided in this achievement?
Yes, the ability to achieve this extent of response has made possible a further refinement of our response criteria. So for example, complete response in the past has been defined as the absence of monoclonal plasma cells and the absence of a monoclonal protein in the blood or urine, with plasma immunofixation testing. That was modified a few years ago when the kappa/lambda free light chain test came along, and a stringent complete response now includes not only a normal bone marrow and absence of monoclonal protein, but also a normal kappa/lambda free light chain ratio.
Where in the adoption curve are these concepts, a revision of treatment goals, and use of novel agents?
The first-generation IMiDs and proteasome inhibitor, namely lenalidomide and bortezomib, respectively, have been broadly incorporated into the treatment paradigm and guidelines. That is a broadly accepted paradigm, and the guidelines in the United States and Europe reflect these changes.
Often nowadays, in a transplant candidate, the drugs are combined (lenalidomide, bortezomib, dexamethasone) as initial treatment. Transplantation is performed. Often, there is a consolidation with the same agents, and then lenalidomide maintenance. In the elderly nontransplant populations, we use the same regimens with reduced intensity in the United States, whereas in Europe these agents are combined with melphalan and prednisone in nontransplant patients.
The introduction of newer targeted therapies such as the IMiD pomalidomide, and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), you and your coauthor state, will provide even more options and promise in individualizing therapy and helping patients achieve meaningful responses. How have these newer agents advanced these goals?
These novel therapies are not only more potent and active than prior treatment, but in many cases are better tolerated. For example, carfilzomib or pomalidomide are more potent than bortezomib and lenalidomide, respectively, and have favorable side-effect profiles.
Are you saying that proteasome inhibitors and IMiDs promise to significantly change the paradigm of this disease?
With these two classes of agents, the excitement for the future is combining them with additional classes of novel agents such as monoclonal antibodies. We can expect that the overall response rate will [increase in] the majority of patients, but also that the number of people who achieve a molecular [complete] response will increase as well.
How far off do you think a real leap in the prospects of myeloma patients might be?