Commentary Archive

Attacking Multiple Pathways

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Kenneth C. Anderson, MD
Kraft Family Professor of Medicine
Harvard Medical School
Chief, Division of Hematologic Neoplasia
Director, Jerome Lipper Multiple Myeloma Center
Director, LeBow Institute for Myeloma Therapeutics  
Dana-Farber Cancer Institute
Boston, Massachusetts

The opinions contained within this commentary are solely those of Kenneth C. Anderson, MD and are not supported or endorsed by MediCom Worldwide, Inc. or Millennium Pharmaceuticals, Inc. and its affiliates or Cephalon Oncology.

Welcome to Managing Myeloma. I am Ken Anderson from the Dana-Farber Cancer Institute to report on the progress at the American Society of Clinical Oncology meeting in 2010 in Chicago.

I particularly want to focus on the use of science which allows us to understand in a biologic sense those pathways that are important for growth survival, drug resistance, and migration of myeloma cells. And having defined their importance to attack single pathways, but more importantly to inform the design of clinical trials of combinations of targeted agents which are designed to inhibit more than one pathway at the same time to avoid the development of drug resistance, and if we utilize more than one drug predicated upon science, we can often use lower doses which will have a more favorable side effect profile. So examples of using drugs to target more than one mechanism in newly diagnosed patients, including the elderly, for example, melphalan, prednisone, and bortezomib. Melphalan is an alkylating agent doing DNA damage and bortezomib, the proteasome inhibitor, is known to inhibit the damage repair that is triggered or induced by melphalan. So the combination of melphalan, prednisone and bortezomib has been shown to be superior to melphalan and prednisone predicated upon that scientific observation, and has achieved extent and frequency of response, event-free and overall survival prolongation in elderly patients.

Similarly, in the newly diagnosed patients who are transplant candidates, there have been similar studies. Perhaps the most exciting illustration of this concept is the combination of the novel immunomodulatory drug lenalidomide with the novel proteasome inhibitor bortezomib. They are being combined not just because they are novel agents but because lenalidomide in particular triggers caspase-8-mediated apoptosis of myeloma cells whereas bortezomib triggers caspase-9-mediated apoptosis. Preclinical studies in our laboratory and animal models of human myeloma in the bone marrow microenvironment have shown that, in fact, inhibiting both of these pathways, caspase 8 by utilizing lenalidomide and caspase 9 by utilizing bortezomib, can in fact induce or trigger synergistic myeloma cell death. So this rapidly translated from the bench to the bedside in clinical trials of lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma. And remarkably, 58% of patients whose myeloma was resistant to either bortezomib or lenalidomide responded to the combination.

Even more excitingly, predicated again upon this triggering of dual apoptotic signaling, the use of bortezomib, lenalidomide, and dexamethasone in newly diagnosed myeloma is reported here at ASCO this year to achieve 100% responses in newly diagnosed patients with myeloma, 72% of patients having a very good partial response or better, and 52% of patients achieving a complete or a near-complete response. These are simply put, unprecedented results in multiple myeloma and do reflect the rapid translation of signaling or pathway-based science from the bench to the bedside to benefit patients. We, even now, having reports this year at ASCO of the use of this regimen, bortezomib, lenalidomide and dexamethasone, in a large number of patients, 1,000 patients with newly diagnosed myeloma, and half of those patients will then be randomized to receive a high-dose therapy and transplant and the other half will not undergo early transplantation. This exciting possibility is true today, that is we can ask the relative merit of asking or adding high-dose melphalan to lenalidomide, bortezomib, and dexamethasone for the first time because we can achieve such high extent and frequency of response. So we will ask whether transplant has added value. In those patients who are randomized to receive bortezomib, lenalidomide, and dexamethasone but not transplantation, we will learn what the durability is of this very high extent and frequency of response; but this is perhaps the best example of science informing the design of clinical trials and achieving unprecedented results.

In the relapsed/refractory patients we also have many examples today of adding drugs together predicated upon science to trigger multiple signaling pathways. So with lenalidomide, for example, there is the combination of lenalidomide and the monoclonal antibody elotuzumab based upon the preclinical science that lenalidomide as an immunomodulatory drug can augment antibody-dependent cellular cytotoxicity of multiple myeloma cells that is related to the monoclonal antibody elotuzumab. In the case of bortezomib, we have combinations of bortezomib with the Akt inhibitor called perifosine. This combination was based upon preclinical data showing that bortezomib can induce Akt and if one blocks that induction of Akt in preclinical models, there is synergistic killing of myeloma cells. That combination, bortezomib with the addition of perifosine to block in patients the activation of Akt, has resulted in phase I/II trials showing sensitization and the ability to overcome resistance to bortezomib, and now we have an ongoing phase III trial of bortezomib versus bortezomib and the Akt inhibitor perifosine for FDA approval.

Perhaps the most exciting combination of all is the combination of bortezomib, the proteasome inhibitor which scientifically blocks the breakdown of ubiquitinated protein in the proteasome, with histone deacetylase inhibitors; there are two of them, either panobinostat or vorinostat, and these histone deacetylase inhibitors block the other pathway called the aggresomal degradation of ubiquitinated protein. So our preclinical studies have shown that the addition of bortezomib to block the proteasomal degradation with histone deacetylase inhibitor panobinostat or vorinostat to block aggresomal degradation of ubiquitinated protein achieves synergistic cell death, and at ASCO this year remarkable response rates are being reported. For example, panobinostat to block the aggresome with bortezomib to block the proteasome in clinical trials can achieve 60% responses in bortezomib-refractory myeloma. So this combination is among the most synergistic and promising that we have ever seen.

In summary, in the past, clinical trials often were predicated upon empiricism, drugs that were active or combined but simply because they were the available drugs at the time. In those days, the success rate, even at the level of phase III clinical trials, was very, very low and only 1 in 20 drugs actually made it from the bench to the bedside to FDA approval. What is so important today is we now have science. We have the ability to understand mechanisms of killing of myeloma cells, mechanisms of drug resistance that allow us to have the scientific basis in our models to inform the design of clinical trials and what this years’ ASCO attest is that when you use preclinical models and science to inform the design of clinical trials, the success rate is very high indeed, and we have several phase III combination clinical trials that are ongoing internationally, very likely to lead to FDA and EMEA approval of new treatment options for our patients with myeloma.

 

References

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