Multiple myeloma (MM) is an incurable, malignant B cell disorder characterized by frequent relapses and a poor prognosis. Thus, new therapeutic approaches are warranted. The phosphatidylinositol-3-kinase (PI3K) pathway plays a key role in many critical cellular processes, including cell proliferation and survival. Activated PI3K/AKT (protein kinases B)/mTOR (mammalian target of rapamycin) signaling has been identified in MM primary patient samples and cell lines. In this study, the efficacy of PI3K and mTOR inhibitors in various MM cell lines representing three different prognostic subtypes was tested. Whereas MM cell lines were rather resistant to PI3K inhibition, treatment with the mTOR inhibitor temsirolimus decreases the phosphorylation of key molecules in the PI3K pathway in MM cell lines, leading to G0/G1 cell cycle arrest and thus reduced proliferation. Strikingly, the efficacy of temsirolimus was amplified by combining the treatment with the Mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Our findings provide a scientific rationale for the simultaneous inhibition of mTOR and MEK as a novel strategy for the treatment of MM.

• Keywords
• MEK, mTOR, multiple myeloma, targeted therapy, temsirolimus, trametinib,
• Publication type
• Journal Article MeSH

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.

• Keywords
• clinical presentation, plasma cell disease, risks factors, survival, treatment,
• MeSH
• Cyclin D1 genetics   MeSH
• Exosome Multienzyme Ribonuclease Complex genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Histone Demethylases genetics   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma diagnosis   epidemiology   genetics   therapy   MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   MeSH
• Plasma Cells immunology   pathology   MeSH
• Repressor Proteins genetics   MeSH
• Risk Factors MeSH
• Transcriptional Elongation Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• CCND1 protein, human MeSH Browser
• CDCA7L protein, human MeSH Browser
• Cyclin D1 MeSH
• DIS3 protein, human MeSH Browser
• ELL2 protein, human MeSH Browser
• Exosome Multienzyme Ribonuclease Complex MeSH
• Histone Demethylases MeSH
• KDM1A protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Repressor Proteins MeSH
• Transcriptional Elongation Factors MeSH

Survival in multiple myeloma (MM) has developed favorably over the past decades for reasons that have been ascribed to new medications and treatment. However, development of survival over a long period and comparison to other hematopoietic neoplasms (HN) is less well known. Here we used Swedish cancer data from the Nordcan database, spanning a 50-year period from 1967 to 2016, and analyzed 1- and 5-year survival data. As a novel type of analysis we calculate the difference in survival between year 1 and 5 which indicates how well survival was maintained in the 4-year period following year 1 after diagnosis. The relative 1- and 5- year survival increased constantly; the 5-year survival graph for women was almost linear. The difference between 1- and 5-year survival revealed that the 5-year survival gain was entirely due to the improvement in 1-year survival, except for the last period. Survival improvement in all HNs exceeded that in MM. The linear 5-year survival increase for female MM patients suggests a contribution by many small improvements in the first year care rather than single major events. The future challenges are to push the gains past year 1 and to extend them to old patients.

• MeSH
• Databases, Factual statistics & numerical data   MeSH
• Hematologic Neoplasms diagnosis   mortality   therapy   MeSH
• Incidence MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma diagnosis   mortality   therapy   MeSH
• Mortality trends   MeSH
• Registries statistics & numerical data   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Geographicals
• Sweden epidemiology   MeSH

PURPOSE: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. PATIENTS & METHODS: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan-Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. RESULTS: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. CONCLUSIONS: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.

• MeSH
• Biomarkers MeSH
• Kaplan-Meier Estimate MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Multiple Myeloma diagnosis   epidemiology   mortality   therapy   MeSH
• Odds Ratio MeSH
• Cancer Survivors * statistics & numerical data   MeSH
• Prognosis MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Population Surveillance MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH

Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and -naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Dexamethasone administration & dosage   MeSH
• Glycine administration & dosage   analogs & derivatives   MeSH
• Kaplan-Meier Estimate MeSH
• Lenalidomide MeSH
• Humans MeSH
• Multiple Myeloma drug therapy   mortality   pathology   MeSH
• Follow-Up Studies MeSH
• Retreatment MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Recurrence MeSH
• Boron Compounds administration & dosage   MeSH
• Thalidomide administration & dosage   analogs & derivatives   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Dexamethasone MeSH
• Glycine MeSH
• ixazomib MeSH Browser
• Lenalidomide MeSH
• Boron Compounds MeSH
• Thalidomide MeSH