Disease Milestones through Bibliometric Analysis of the Top 100 Cited Articles in Multiple Myeloma

Multiple myeloma (MM) accounts for 1.6% of all cancers and 5%-10% of all hematologic malignancies in the United States (US). Despite marked progress in disease management, it remains incurable with high rates of relapse. We conducted a bibliographic analysis on the Web of Science (WOS) from July 25, 2017 and July 29, 2017. Among the top 100 most-cited articles (1901-2012), the most cited article received 2404 citations and least cited article received 336 citations. Forty-four of 100 articles were published in journals with impact factors greater than 20. We observed that over the years, the focus of research has shifted from diagnosis, staging, and pathogenesis to better treatment outcomes. A subgroup analysis of the top 100 cited articles published in the last five years (2012-2017) demonstrated that several landmark studies, which will likely change the landscape of treating multiple myeloma, were not included in the top 100 list. Interestingly, most of these articles were focused on novel therapeutic agents. This bibliographic analysis provides a list of the 100 top-cited articles in multiple myeloma along with the captivating comprehension of the history and development in various aspects of disease processes. The landscape of this disease is rapidly evolving, and bibliometric studies such as the one presented provide a valuable tool that can highlight the important transitions in the field.


Introduction And Background
Multiple myeloma (MM) accounts for 1.6% of all cancers and 5% to 10% of all hematologic malignancies in the United States (US) [1]. Worldwide, approximately 154,000 cases are diagnosed, and 101,000 deaths are attributed to MM every year [2]. Due to the advent of novel therapeutic agents, median overall survival has increased from one to two years to seven to eight years with a meaningful improvement in the quality of life [1]. Although there has been marked progress in disease management, MM remains incurable with high rates of relapse. Ongoing clinical trials have significantly contributed to favourable disease outcomes; however, many of these interventions remain unknown to clinicians. This highlights the need for citation analysis to reflect these advances and substantial progress in this field.
Citation analysis is a type of bibliometric analysis in which evaluation and ranking of an article or journal is done on the basis citation count [3]. It identifies the milestones completed in understanding core aspects of a disease and emphasizes on major developments made in the subject matter [4][5]. Clinicians often modify their disease management based on research published in high impact journals [6] thus if most important articles can be highlighted via citation analysis it will help clinicians in making better choices for their patients. So far, no such study has been performed to conclude the most influential articles in the field of MM. The aim of the current study is to identify the 100 top-cited publications in MM and highlight the most significant advances made in the field over the preceding several decades.

Materials and methods
We conducted a bibliographic analysis on the Web of Science (WOS). The time covered in WOS is between 1900 and 2017. We included journals listed in the Science Citation Index Expanded, without specific restrictions on the journals. We retrieved articles for analysis by typing "Multiple Myeloma" into the WOS search box and conducted data search with the application of English language filter on July 25, 2017. We identified 27,718 articles that were published between 1901 and 2017, ranked the articles based on citation frequency from highest to lowest, and thereafter, shortlisted the top 100 cited articles. Statistical analysis of studies was not performed, and data were reported in the form of tables. To capture the most important and latest research, we conducted a second search on July 29, 2017 to limit articles to those published during the last five years.

Results
Among the top 100 included articles, the most cited article received 2404 citations while the least cited article received 336 citations. All articles were arranged according to citation frequency ( Table 1). The top 100 cited articles were published between 1990 and 2007. In our analysis, we found that the highest number of articles were published in the year 2007 ( Table 2). Forty-eight of the 100 articles were published in journals with impact factors (IF) greater than 20 ( Table 3). The journal with the highest number of publications was Blood with 33% of the publications (IF 13.16) followed by New England Journal of Medicine (NEJM) with 20% of the publications (IF 72.406). The country of origin with the highest number of publications on the topic of MM was the US (n=73) followed by France (n=10), Italy, and Germany ( Table 4). These 100 articles sourced from 50 major institutions, with top three most significant contributors being Dana Farber Cancer Institute, Mayo Clinic, and the University of Arkansas Medical Sciences ( Table 5). Most articles focused on disease management followed by pathogenesis and disease staging respectively ( Table 6).

No. Author
Title Journal

Discussion
Bibliometric analysis has been used in the past to identify frontiers in specific fields and to evaluate the contribution of authors, institutions, and nations. The total number of citations received by an article represents its overall contribution to the clinical world.
Our study demonstrates that over the years, the focus of research has shifted from diagnosis, staging, and pathogenesis to better treatment outcomes in patients with MM (51 publications).
The timeline for the evolution of MM therapy has progressed starting with melphalanprednisone in 1960's which was the standard of care for about 30 years. During the next 30 years, therapy further evolved when drugs such as vincristine, doxorubicin, and dexamethasone (VAD), alkylating agents such as Carmustine (VBAD), cyclophosphamide and melphalan (VCMP) were introduced. However, these therapeutic agents did not significantly improve the outcomes. High-dose melphalan followed by autologous stem cell transplant (ASCT) was a step towards favorable clinical outcomes. The armamentarium against MM was revolutionized by the development of ground-breaking agents such as immunomodulators (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib).
After better treatment outcomes, the most frequently encompassed category was disease pathogenesis (29 publications). Over the years, a thorough understanding of aetiological factors and relation of genetic aberrations to pathogenesis has laid the foundation for significant improvement in disease management and prognostication. Two of the top ten most cited articles were aimed at the staging of disease. The first being the Clinical Staging System proposed by Durie BGM et al., although the most cited article in our list is no longer the primary staging system. Modern-day physicians rely on the International Staging System (eighth most cited article) and cytogenetics to classify MM.
The findings of this analysis demonstrated that 32 of 100 articles were published in general medical journals, for which there may be several reasons. Firstly, general medicine journals capture a wide range of population compared to speciality journals. Secondly, patients with MM are usually co-managed by internists and oncologists which would make the general medicine audience more interested in advancements in MM. Lastly, the novel therapeutic options have different mechanisms of actions and extensive side effect profiles. It is very important for the general internist to be aware of these side effects to effectively manage these patients in both inpatient and outpatient settings.
The authors of these studies targeted high impact factor journals which is evidenced by the fact that most of the articles were published in journals with impact factors greater than 20. This suggests that MM researchers tend to publish in prestigious and well-respected journals that capture a wide range of the population. We noted diversity amongst the authors, as only a total of 12 articles were contributed by the top two publishers as first authors. These findings suggest a diverse group of researchers involved in the MM field.
Among the top 100 cited articles, only seven studies were focused on bortezomib-containing regimens, whereas none of them included carfilzomib or ixazomib based novel therapeutic regimens. This shows that articles with a high frequency of citations consisted mostly of earlypublished articles. Therefore, one limitation of such articles is that they favour older studies. Among the top 100 list, only two articles from 2012 were included and the articles published after 2012 did not have enough citations to be included in top 100 list. Therefore, we conducted a subgroup analysis of top 100 articles published after 2011. A bibliographic analysis of top cited articles published in the last five years (2012-2017) showed different results from our original search. Only two studies from the sub group analysis were included in the primary analysis due to a lower number of total citations received. Studies 2012, and onwards were focused on latest developments in the field of MM including therapeutic agents such as novel proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies (daratumumab, elotuzumab), and chimeric antigen receptor T cell therapy [7][8][9][10][11].
Our primary limitation was conducting the search in the "title mode". Therefore, articles that did not contain MM in the title were not retrieved or included in our study. Secondly, our search was limited to the WOS database which excludes citations of textbooks and other databases which are weaker at tracking older publications. Finally, articles published in languages other than English were excluded.

Conclusions
This bibliographic analysis provides a list of the 100 top-cited articles in MM along with the captivating comprehension of the history and development in various aspects of disease processes. The landscape of MM is rapidly evolving, and bibliometric studies such as the one we present provides a valuable tool that can highlight important transitions in the field. As new evidence continues to emerge, these types of analyses can provide a quantitative instrument to guide the researchers and funding agencies to assess the overall direction of the field with limited health care resources.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.