Putting the E (evidence) in a new Era for myeloma

The evaluation of new treatments and their impact on the natural history of a given malignancy can be a challenging endeavor. Often, phase III clinical trial experiences do not adequately represent a ‘real world’ experience for the typical patient with cancer, yet they are required for the establishment of level 1 evidence and regulatory approval. True ‘natural history changing’ treatments in oncology include the use of imatinib or rituximab, which have significantly improved overall and progression-free survival for patients with chronic myeloid leukemia (CML) and lymphoma, respectively. However, the benefit of both rituximab and imatinib can be measured not only in clinical trials, but also in population-based assessments where their use has been shown to alter the natural history of these diseases. The use of new drugs in myeloma such as lenalidomide, bortezomib, and thalidomide has revolutionized the care of patients with myeloma. Each of these agents has had a major impact on the overall response rate, progression-free survival, and overall survival for patients in the induction, relapse, and refractory phases of disease as reported by multiple large clinical trials [1,2]. However, a major limitation of large clinical trials is that they represent a small subset of patients treated predominantly at tertiary medical centers, and true population-based assessments are few.

This brings us to the current article from Venner et al. [3] in the January issue of Leukemia and Lymphoma. These investigators are uniquely positioned, based on their healthcare system, to evaluate the effect of new drugs (by date of approval) on overall survival among a large population of similarly treated patients with equal access to new treatments. This same group has already performed a similar analysis demonstrating the impact of rituximab on patients with diffuse large B-cell lymphoma [4], and sought toperform a similar analysis among patients with myeloma. An advantage of this population- and time-based analysis is that it decreases the biases associated with a retrospective single-center analysis, and adds a significant level of clinical relevance, as these are patients often treated in community settings, not tertiary referral centers. In this article, Venner et al. pooled transplanted patients who subsequently relapsed all within a single province in Canada over two different treatment eras. The first era was before 2004 when access to lenalidomide and bortezomib was not a treatment option, and the second was after 2004 when lenalidomide and bortezomib were routinely available. These patients were evaluated at the time of relapse, and were assessed in terms of overall survival and post-relapse survival as determined by era of treatment and International Scoring System (ISS) stage. For patients with early relapse (within 12 months of their transplant), survival in the post-2004 era was three times higher than survival of the same type of patients prior to 2004. For patients with late relapse (remission longer than 12 months following transplant), the overall survival was double for the post-2004 era when compared with earlier cohorts. The early-relapsing patients are particularly intriguing, as they are a group of patients known tohave very poor overall survival as determined in other datasets [5], yet seemed to have a significant improvement in overall survival in the post-2004 era.

Additionally, it is worth noting that the observed improvement in survival from 15.1 months to 42.8 months (a net improvement of 27 months) is superior to what was reported in the randomized studies of lenalidomide (improvement in survival of 6.4 months) and bortezomib (improvement in survival of 6.1 months) in the relapsed setting [6,7]. This may be a result of evaluating only transplanted patients in the current study, but also suggests that perhaps the use of two novel agents enhances the efficacy of other treatments, or that their use earlier in the disease course is able to impart additional benefit not necessarily seen when patients are treated in refractory relapse, as is often the case inearly clinical trials with new agents. It is also important to understand that this analysis does not represent sequential cohorts treated at a single center, but rather demonstrates improvement in overall survival as measured in a province where care is relatively uniform based on access to treatment.

Changes in survival as measured by population metrics are of critical importance as we continue to develop new strategies and treatment approaches. As we are forced to become more cost-conscious in our care plans, demonstrating not only clinical benefit as measured by extent, frequency, and duration of response, but also population-based improvement in outcome is of critical importance. While such studies are not conducted with the standard rigor of large randomized phase III clinical trials, their demonstration of an impact on a population as a whole represents the real goal of evolving cancer therapy. In order to truly declare that we are in a new era of treatments for patients with myeloma, we must first demonstrate that our treatments are impacting the natural history of the disease with the goal of improving the quality of care for all patients afflicted with a given cancer, not just those who are fit, are able to travel, or live near a tertiary center. The article from Venner et al. finally provides tangible evidence that we are in a new era of patient care in myeloma.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.