Autologous stem cell transplant as a platform for multiple myeloma treatment is the standard of care for patients who can safely withstand the procedure. Before novel agents were introduced, one-third to one-half of patients did not achieve partial response at transplant. Previous medical literature has showed that in this past era, absence of initial response to induction therapy had no impact on progression-free survival and overall survival after high-dose therapy. Lack of response to initial induction did not preclude a good response after stem cell transplant. With the introduction of novel agents-immunomodulatory drugs and proteasome inhibitors-response rates with initial therapy are now between 70% and 100%. This retrospective study analyzes progression-free survival and overall survival in patients who do not have a partial response (never responded or progressed during continuous therapy) after induction therapy with a regimen that contains thalidomide or lenalidomide. Unlike patients in reports published previously-before immunomodulatory drugs-patients who do not achieve partial remission have a significantly shorter overall survival from transplant (73.5 vs 30.4 months) and a shorter progression-free survival (22.1 vs 13.1 months; P<.001). Absence of a response to induction therapy with thalidomide or lenalidomide predicts a poorer outcome after high-dose therapy.

The objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, gender, transplantation status, and dexamethasone-dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (p<0.001); very good partial response rates were 34.2% and 12.0%, respectively,(p<0.001). Patients receiving len/dex had longer time-to-progression (median 27.4 vs 17.2 months; p=0.019), progression-free survival (median 26.7 vs 17.1 months; p=0.036) and overall survival (median not reached vs 57.2 months; p=0.018). A similar proportion of patients in the two groups experienced >/=1 grade 3-4 adverse event (57.5% vs 54.6%, p=0.568). Main grade 3-4 toxicities of len/dex were hematological, mainly neutropenia (14.6% vs 0.6%, p<0.001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p=0.058) and peripheral neuropathy (10.4% vs 0.9%, p<0.001). Len/dex appears well-tolerated and more effective than thal/dex as initial therapy for myeloma. Randomized trials are needed to confirm these results.

Background Tyrosine kinase inhibitors (TKI) such as imatinib are not considered curative for chronic myeloid leukemia (CML)- regardless of the significant reduction of disease burden during treatment - since they do not affect the leukemic stem cells (LSC). However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited DESIGN AND METHODS: We study the natural history of a large cohort of virtual patients with CML under TKI therapy using a computational model of hematopoiesis and CML that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. RESULTS: We find that in the overwhelming majority of patients the LSC population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to TKI attack, are the natural target for CML treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predict that early diagnosis together with administration of TKI opens the path to CML eradication, leading to the wash out of the aberrant progenitor cells, ameliorating the patient's condition while lowering the risk of blast transformation and drug resistance. Conclusion TKI therapy can cure CML, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the relevance of stochastic effects on the dynamics of acquired HSC disorders and have direct impact on other HSC derived diseases.

Dexamethasone (Dex), alone or in combination, is commonly used for treating multiple myeloma. Dex as single agent for initial therapy of myeloma results in overall response rates of 50-60%. It is unclear whether steroid responsiveness reflects any biological characteristic that impacts long-term outcome. We studied a cohort of 182 patients with newly diagnosed myeloma seen between March 1998 and June 2007, initially treated with single-agent Dex for at least 4 weeks. The median age at diagnosis was 63 years (range, 39-81) and the median estimated survival was 55 months. At a median duration of therapy of 15 weeks, 91 (50%) patients had a partial response or better, 80 (44%) had less than partial response and the remaining (6%) patients were not evaluable. The median overall survival from diagnosis for the responders was 75 months compared to 71 months for remaining patients, P = 0.6.There was no correlation between baseline disease characteristics and Dex responsiveness. While overall survival was longer for the 130 (70%) patients who proceeded to an autologous stem cell transplant, no correlation was found between survival and Dex responsiveness among either group. Among this cohort of patients with myeloma, failure to respond to single agent steroid did not have an adverse impact on eventual outcome.

Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy. It is part of a spectrum of monoclonal plasma cell disorders, many of which do not require active therapy. During the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life. Identification of well-defined and reproducible prognostic factors and introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease. Although these risk-adapted strategies have not been prospectively validated, enough evidence can be gathered from existing randomized trials, subgroup analyses, and retrospective studies to develop a working framework. This set of recommendations represents such an effort-the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence.

Vaccines are attractive as consolidation therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We report the results of a phase II trial of the immunotherapeutic, APC8020 (Mylovenge), given after ASCT for MM. We compared the results with that of other patients with MM who underwent ASCT at Mayo Clinic during the same time period. Twenty-seven patients were enrolled on the trial between July, 1998 and June, 2001, and the outcomes were compared to that of 124 consecutive patients transplanted during the same period, but not enrolled on the trial. The median (range) follow-up for patients still alive from the vaccine trial is 6.5 (2.9-8 years), and 7.1 (6-8 years) in the control group. The median age was 57.4 range (36.1-71.3) in the DB group and 56.4 (range, 30-69) in the trial group. Known prognostic factors including PCLI, B2M, and CRP were comparable between the groups. The median overall survival for the trial patients was 5.3 years (95% CI: 4.0 years-N/A) compared to 3.4 years (95% CI: 2.7-4.6 years) for the DB group (P = 0.02). The median time to progression and progression-free survival for the trial group was similar to the DB group. Although not a controlled trial, the vaccines given after ASCT appear to be associated with improved overall survival compared to historical controls. This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma. Am. J. Hematol. 2009.(c) 2009 Wiley-Liss, Inc.

Several viruses preferentially infect and replicate in cancer cells by usurping pathways that are defective in the tumor cell population. Such viruses have a potential as oncolytic agents. The aim of tumor virotherapy is that after injection of the replicating virus, it propagates in the tumor cell population with amplification. As a result, the oncolytic virus spreads to eradicate the tumor. The outcome of tumor virotherapy is determined by population dynamics and different from standard cancer therapy. Several models have been developed that provided considerable insights on the potential therapeutic scenarios. However, virotherapy is potentially risky since large amounts of a replicating virus are injected in the host with a risk of adverse effects. Therefore, the optimal dose, number of doses, and timing are expected to play an important role on the outcome both for the tumor and the host. In the current work, we combine a model of the dynamics of tumor virotherapy that was validated with experimental data with optimization theory to illustrate how we can improve the outcome of tumor therapy. In this first report, we demonstrate that (i) in most circumstances, anything more than two administrations of a vector is not helpful,(ii) correctly timed delivery of the virus provides superior results compared to regularly scheduled therapy or continuous infusion,(iii) a second dose of virus that is not properly timed leads to a worse outcome compared to a single dose of virus, and (iv) it is less costly to treat larger tumors.

Background:There is variability in the cancer phenotype across individuals: two patients with the same tumour may experience different disease life histories, resulting from genetic variation within the tumour and from the interaction between tumour and host. Until now, phenotypic variability has precluded a clear-cut identification of the fundamental characteristics of a given tumour type.Methods:Using multiple myeloma as an example, we apply the principles of evolutionary game theory to determine the fundamental characteristics that define the phenotypic variability of a tumour.Results:Tumour dynamics is determined by the frequency-dependent fitness of different cell populations, resulting from the benefits and costs accrued by each cell type in the presence of others. Our study shows how the phenotypic variability in multiple myeloma bone disease can be understood through the theoretical approach of a game that allows the identification of key genotypic features in a tumour and provides a natural explanation for phenotypic variability. This analysis also illustrates how complex biochemical signals can be translated into cell fitness that determines disease dynamics.Conclusion:The present paradigm is general and extends well beyond multiple myeloma, and even to non-neoplastic disorders. Furthermore, it provides a new perspective in dealing with cancer eradication. Instead of trying to kill all cancer cells, therapies should aim at reducing the fitness of malignant cells compared with normal cells, allowing natural selection to eradicate the tumour.British Journal of Cancer advance online publication, 1 September 2009; doi:10.1038/sj.bjc.6605288 www.bjcancer.com.

PURPOSE: Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. PATIENTS AND METHODS: Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. RESULTS: Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. CONCLUSION: The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.