Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma.

Pomalidomide is a distinct oral IMiD(®) immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30.

Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

Preventing and treating chronic disorders using the modified vaccination technique.

It is anticipated that the ultimate solution for the prevention and termination of autoimmune disorders will be based on somehow manipulating the cells of the immune system to attain antigen (ag) specific downregulation and termination. In the last few years we have developed a new vaccination technique that we call "modified vaccination technique" (MVT). It has with equal effectiveness both prevented and terminated autoimmune disease causing events in an experimental autoimmune kidney disease model. We expect that our technique will be similarly applicable to the specific treatment and cure of numerous other chronic disorders presently treated only by drugs. The vaccine is composed of two components, an ag and a specific antibody against it. When these are combined at slight ag excess they constitute a vaccine which is capable of treating chronic ailments by redirecting immune response outcomes in the vaccinated host. Both components, like drugs, will have to be produced ex vivo in order to maintain uniformity, safety, efficacy, and specificity.

New vaccination technology for endogenous antigen-derived ailments.

Neither autoimmune disorders nor cancer can be prevented with treatment modalities that are currently available. These diseases are generally treated with immunosuppressive agents and cytotoxic drugs, both of which can cause numerous side effects. However, scientific evidence now exists to suggest that such endogenous antigen-derived ailments can be controlled and even terminated by immunological approaches. Both autoimmune disorders and cancer can progress into chronic, irreversible conditions because of the abnormal presentation of endogenous antigens to the cells of the immune system. By appropriate regulation of the autoimmune system, both types of ailments could be curable. This feature review describes various autoimmune events that may occur both to the benefit and the detriment of the host, and highlights a new vaccination technique against slowly progressive Heymann nephritis. This modified vaccination technique holds promise in the prevention and cure of autoimmune system-related disorders. The vaccination has been employed both against endogenous antigen-induced diseases (autoimmune disorders and cancer) and against exogenous antigens. In each study performed to date, the technique has been demonstrated to induce specific, predetermined immune response outcomes.