A probable case of multiple myeloma from Bronze Age China.

OBJECTIVE: Paleopathological evidence of cancer from past populations is rare, especially outside of Europe and North Africa. This study expands upon the current temporal and spatial distribution of cancer by presenting a probable case of multiple myeloma from Bronze Age China. MATERIAL: The human skeletal remains of an adult male from the Qijia culture horizon (1750-1400 BCE) of the Bronze Age cemetery of Mogou (), located in Gansu Province, Northwest China. METHODS: The human skeletal remains were assessed macroscopically and radiographically using plain x-rays. RESULTS: Multiple ovoid-shaped osteolytic lesions with sharply demarcated margins were observed. The axial skeletal had the greatest involvement, specifically the vertebrae, ribs, and sternum. Radiographic imaging revealed more extensive destruction of cancellous than cortical bone, indicating that the marrow was the focal point of the disease. CONCLUSION: Based on the nature, distribution, and radiographic appearance of the lesions, the most likely diagnosis is multiple myeloma. SIGNIFICANCE: This is one of the only cases of cancer identified in archaeological human skeletal remains from East Asia and is the first published case of a hematopoietic malignancy from mainland China. The analysis and publication of examples of neoplasia from areas that expand upon the current known temporal and spatial distribution is necessary in order to better reconstruct the history and evolution of cancer. LIMITATIONS: Poor skeletal preservation prevented the full extent of osteolytic lesions to be observed. SUGGESTIONS FOR FUTURE RESEARCH: By placing case studies such as this into a temporal and spatial framework, it is possible for future research to begin to interrogate possible underlying causes of cancer in ancient populations within the context of changing environmental conditions and subsistence strategies.

Incidence and survival of multiple myeloma: a population-based study of 10 524 patients diagnosed 1982-2017.

Population-based studies from high-quality nationwide cancer registries provide an important alternative to clinical trials in the assessment of the impact of modern myeloma treatment. Based on data from the Cancer Registry of Norway, we investigated trends in incidence and relative survival (RS) for 10 524 patients in three age groups diagnosed between 1982 and 2017. Nationwide myeloma drug consumption statistics were obtained from the Norwegian Institute of Public Health. Patients aged <65 years had a steady increase in both 5- and 10-year RS across all calendar periods from 1982. For patients aged 65-79 years, RS was stable until the calendar period 1998-2002, followed by an improvement in both 5- and 10-year RS. The 5-year RS for patients aged ≥80 years also increased significantly between the first and the last calendar period. In conclusion, we demonstrate a significant improvement in 5-year RS in all age groups. Improved RS in patients aged ≥80 years at the time of diagnosis is only rarely described in other population-based studies. For patients aged ≥65 years, the improvement in RS coincides with the introduction of modern drugs, whereas patients aged <65 years had an ongoing improvement before the introduction of autologous stem-cell transplant.

Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWP.

OBJECTIVES: The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. METHODS: A retrospective analysis of the EBMT database (1991-2012) was performed. RESULTS: A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P < .001) but not after 2002 (HR = 1.2, P = .276). CONCLUSION: From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

Real-world epidemiology, treatment patterns and survival of multiple myeloma patients in a large nationwide health plan.

BACKGROUND: Survival of patients with multiple myeloma (MM) has improved significantly with access to autologous stem cell transplant (SCT) and new treatments. This study aims to describe epidemiology, treatment patterns, and outcomes of MM in Israel. METHODS: A retrospective observational study was conducted in Maccabi Healthcare Services, a 2-million-member nationwide health plan in Israel. MM was defined by cross-linking data on MM diagnoses, dispensed treatments, and serum free light-chain assays. Point prevalence (31/12/2016) and incidence (2012-2016) rates were age-standardized. Newly diagnosed and treated patients (2009-2015) were followed through 31/12/2016 for progression to second-line (L2), with death as a competing risk. RESULTS: MM prevalence and incidence rates were 26.2 and 4.6 per 100,000 population, respectively. In the treatment cohort (N = 552), mean ±â€¯SD) age was 65.6 ±â€¯11.3) years (60.1% male) and median (95% CI) OS in years was 5.2 (4.3-6.1) overall and 6.5 (4.9-8.1) for first-line (L1) bortezomib (N = 421). In a multivariable analysis, OS was significantly higher among patients starting L1 in 2012-2015 vs. 2009-2011. Within a year, 38.4% underwent SCT. Cumulative incidence of L2 was 38.2% and 51.4% within 1 and 2 years, respectively, and was associated with older age (≥65y; P < 0.001). CONCLUSION: These results from a large heterogeneous population demonstrate MM incidence and survival rates that are in line with the literature, together with a significant improvement in overall survival over time. Approximately half of newly treated patients progressed to L2 within two years. These results will serve as a baseline for further research to evaluate the clinical impact of new interventions.

Multiple myeloma in paleopathology: A critical review.

This paper provides a critical literature review concerning paleopathological evidence of multiple myeloma discovered both in the Old and in the New World. A critical assessment of the bioarchaeological and paleopathological documentary sources permitted to identify a total of 25 ascertained cases of multiple myeloma from different geographical areas in the world ranging from Prehistoric times up to the Contemporary age. The distribution of multiple myeloma findings in past times shows that the majority of cases have been discovered in the Old World (n = 18) and extend back to the Middle Ages, while the evidences in the New World (n = 7) seems to date back to the pre-Columbian era. The demographic profile suggests a sex ratio of 1.3:1, while 91.7% of affected individuals (n = 24) are adults. This critical review also discusses the diagnostic criteria and methodological issues commonly attempted in paleo-oncological research, with particular regard to the differential diagnosis of multiple myeloma. As such, the main focus of this work is to present a comprehensive and exhaustive scrutiny of the skeletal manifestations identified as multiple myeloma in order to improve the accuracy of diagnoses within the field of paleopathology.

Heterogeneity of Second-Line Treatment for Patients With Multiple Myeloma in the Connect MM Registry (2010-2016).

BACKGROUND: The treatment landscape for multiple myeloma (MM) has undergone recent changes with the regulatory approval of several new therapies indicated for second- and later-line disease. Using data from Connect MM, the largest multisite, primarily community-based, prospective, observational registry of MM patients in the United States, selection of second-line treatments was evaluated during a 5-year period from 2010 to 2016. PATIENTS AND METHODS: Eligible patients were aged ≥ 18 years, had newly diagnosed MM ≤ 2 months before study entry, and were followed for up to 8 years. Patients who received ≥ 2 lines of therapy were analyzed. "Tepee" plots of stacked area graphs differentiated treatments by color to allow visualization of second-line treatment trends in MM patients. RESULTS: As of February 2017, 855 of 2897 treated patients had progressed to second-line treatment. Treatment selection was heterogeneous; shifting patterns of treatment choices coincided with the approval status of newer agents. The most common treatment regimens in the early part of the decade were lenalidomide and/or bortezomib, with or without dexamethasone, with increasing use of newer agents (carfilzomib, pomalidomide, daratumumab, and elotuzumab) and triplet combinations over time. The influence of the baseline patient characteristics of age, history of diabetes, peripheral neuropathy, and renal function on treatment choice was also examined. CONCLUSION: These findings indicate that community physicians are current in their MM management practices, with uptake of new drugs and acquaintance with results of randomized clinical trials using combinations almost concurrent with their regulatory approval and publication.

A probable case of multiple myeloma in a female individual from the Simon Identified Skeletal Collection (late 19th-early 20th century, Vaud, Switzerland).

We present the case of an individual from the Simon Identified Skeletal Collection (Vaud, Switzerland) who appears to have been affected by a form of neoplastic disease. A detailed description and differential diagnosis of the lesions was conducted and is presented here. Considering the biological profile of the individual, the distribution of the lesions, and their appearance, a case is made for multiple myeloma as the most likely diagnosis. This case study demonstrates the importance of adopting a detailed approach for recording the metric and non-metric traits of lesions, using multiple methods of analysis, and providing graphic and photographic documentation in order to provide valuable comparison material through publication. The good preservation of the remains and the background information available for the individual also make this case ideal for inclusion in future comparative studies.

A historical perspective on milestones in multiple myeloma research.

The first well-documented case of multiple myeloma was reported in 1844 by Samuel Solly. In this article, the author presents a historical review of the disease. In particular, the review is focused on the main steps, including the definition of Bence Jones proteinuria, the characterization of tumoral plasma cells and serum globulins, and the fundamental contribution of Jan Waldenstrom. Finally, treatment of multiple myeloma, as well as the development of new agents, is discussed.

Improved survival in multiple myeloma, with a diminishing racial gap and a widening socioeconomic status gap over three decades.

Multiple myeloma (MM) is estimated to have 30,280 new cases and be associated with 12,590 deaths in 2017. However, quantitative analysis for survival, based on a large population, is lacking. Data were extracted from a total of 33,170 cases from nine registry sites in the Surveillance, Epidemiology, and End Results database. The current study shows that the incidence for MM remained relatively stable between 1981 and 2010, with 4.6, 4.7, and 4.7 per 100,000 persons in each decade. In addition, survival for MM improved each decade with a larger increment in the last two decades, with a narrowing survival gap among races and a widening gap among socioeconomic status (SES) groups. The survival gap changes in races and SES groups may guide clinicians to design better treatment protocols and call for the pressing need for health-care policy to fill the gap among SES groups.

Variation in incidence and survival by ethnicity for patients with myeloma in England (2002-2008).

Incidence and relative survival of myeloma by ethnic group was estimated using data from cancer registries in England (2002-2008). Multiple imputation was used to address missing ethnicity data. In total 24 361 cases of myeloma were identified. Age-standardized incidence rate (ASIR) (per 100 000) was higher in the Black ethnic category at 15.00 (95% confidence interval [CI] 13.50-16.40), than amongst South Asians (ASIR = 5.45, 95% CI 4.76-6.14) or the White group (ASIR = 6.11, 95% CI 6.00-6.22). There was a lower risk of death in the Black group for both 1- and 3-year survival (hazard ratio [HR]1 year = 0.66, 95% CI 0.55-0.79; HR3 year = 0.69, 95% CI 0.58-0.83) and South Asians at 1, 3 and 5 years (HR1 year = 0.65, 95% CI 0.51-0.82; HR3 year = 0.72, 95% CI I 0.57-0.90; HR5 year = 0.68, 95% CI 0.50-0.92) when compared to the White population. Further study of differences in myeloma and precursor biology between population groups is important.

Where we were, where we are, where we are going: progress in multiple myeloma.

The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.

Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups.

This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60-69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.

Recent improvement in survival of patients with multiple myeloma: variation by ethnicity.

Abstract Survival for patients with multiple myeloma has increased during the first decade of the 21st century. However, it is unknown whether the improvements in survival have extended equally in all ethnic groups. Using data from the United States Surveillance, Epidemiology and End Results Program, we assessed trends in survival and disease-related mortality for patients with myeloma by ethnic group, including non-Hispanic whites (nHw), African-Americans (AA), Hispanics and people of Asian and Pacific Islander descent (API) from 1998-2001 to 2006-2009. Overall, age adjusted 5-year relative survival increased, from 35.6% in 1998-2001 to 44% in 2006-2009. The greatest improvements were observed for patients aged 15-49, for whom survival increased by + 16.8% units for nHw and + 14.4% units for AA, whereas improvement was less pronounced and not statistically significant in Hispanics and API. Excess mortality hazard ratios were 1.20 (95% confidence interval [CI]: 1.09-1.33) for AA and 1.25 (95% CI: 1.11-1.41) for Hispanics compared to nHw in 2006-2009. Although survival increased greatly for nHw with myeloma between 1998-2001 and 2006-2009, smaller increases were observed for people of other ethnic groups. Persistent excess mortality was seen for AA and Hispanic patients with myeloma. Ethnic inequalities persisted or even increased from earlier periods to 2006-2009. The results suggest that ethnic minorities may not have benefited from newer treatments to the same extent as nHw patients have.

Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis.

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population-based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988-96 (conventional therapy), 1997-05 (high dose melphalan and autologous transplant), and 2006-09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997-05 and 2006-09 compared with previous years and a trend to improvement was observed from 1997-05 to 2006-09. For patients aged 65-74 years, RS improved significantly in 2006-09 compared with 1988-96 and 1997-05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65-74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.

Human tumor stem cells, the petri dish and the patient. A tribute to Sydney E. Salmon.

During the last ten years, much work has been devoted to the concept of tumor stem cells, a concept first introduced by Virchow in 1855. Despite the importance and the quality of these works, they ignore the major step forward made by SE Salmon and his group from the University ofArizona atTucson, USA, during the seventies'. The purpose of this review is to (i) contribute to the original work of SE Salmon as a pioneer in the field of cancer stem cell research (ii) emphasize the importance of his contribution in this field of research and (iii) underline the other fields of his research, especially in the domain of mathematical oncology. Finally, we would like to show that SE Salmon made Multiple Myeloma a model in Oncology, many study groups being engaged into Myeloma research now in the world.