Transforming Expectations and Outcomes With Targeted Therapies

Kenneth C. Anderson, MD

With the arrival and incorporation into clinical practice of immunomodulatory drugs and proteasome inhibitor therapy, patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. In a recent review,¹co-authors 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.

Targeted Oncology: 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

Dr. Anderson:Since the advent of the immunomodulatory drugs 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 are achieve a higher extent of molecular complete response—or the absence of minimal residual disease, as measured 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 have 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 immunomodulatory drugs 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 proteasome inhibitors carfilzomib and ixazomib (MLN9708), you and your co-author 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 immunomodulatory drugs 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?

The analogy I like to make is that myeloma today is where chronic myelogenous leukemia was when Gleevec first came out. When Gleevec came out, it was the first time patients with CML could get a molecular complete response. Over the years, the clinical significance of that complete response was determined, and it is an amazing success story.

In myeloma, we don’t have one Gleevec, but we do have combinations of agents that for the first time can achieve molecular complete responses in the autologous setting. So now the challenge for us, as in CML, is to determine the clinical relevance: in other words, to determine the outcome of patients who achieve molecular response. Can we inform the use of maintenance of patients based on the presence or absence of minimal residual disease? A number of questions can now be asked because we are achieving this extent of response.

In theLeukemiaarticle, you and your coauthor discuss the issue of striving to achieve the maximum response from patients, in particular in the frontline setting without compromising tolerability to a great degree. Could you elaborate?

In the past, there has been discussion about whether intensive and maximal response was the goal versus using just enough therapy maintain disease control That dichotomy is from the days when we really didn’t have the ability to achieve such significant molecular complete responses as we do today.

References

Nowadays, we have agents that we can combine plus new classes of drugs coming that allow us to achieve a major response in the majority of patients. This is the impetus to utilize novel agents to obtain a more significant response, and then together with our patients, define its clinical significance.

1. Lonial S, Anderson KC. Association of response endpoints with survival outcomes in multiple myeloma.Leukemia. 2013 Jul 19, doi: 10.1038/leu.2013.220.