This year’s American Society of Clinical Oncology (ASCO) annual meeting began the morning of last Friday, and the meeting will run through Tues­day.

Multiple myeloma-related pre­sen­ta­tions are taking place every day of the meeting. Friday, how­ever, was the busiest day at the meeting in terms of oral pre­sen­ta­tions with new myeloma-related re­search. There were nine such pre­sen­ta­tions during a single afternoon session focused on multiple myeloma.

In addi­tion, there were myeloma-related education session pre­sen­ta­tions on Saturday, yesterday, and today. There also was a late-breaking ab­stract session yesterday (Sunday) with one pre­sen­ta­tion that sum­ma­rized im­por­tant new myeloma-related re­search.

There are more myeloma-related education session pre­sen­ta­tions on the agenda for today, plus a poster session this morning and several addi­tional oral pre­sen­ta­tions tomorrow (Tuesday) morning.

This ASCO multiple myeloma update will focus on the late-breaking abstract that was pre­sented yesterday as well as the oral pre­sen­ta­tions on Friday. Some of these pre­sen­ta­tions also will be covered in more detail – and with addi­tional back­ground in­­for­ma­tion – in standalone articles here at The Beacon.

Many of the myeloma re­searchers who gave pre­sen­ta­tions the last few days at ASCO have agreed to make their slides avail­able to the Beacon's readers. When that is the case, a link to the PDF file with the slides is in­cluded in the discussion of the pre­sen­ta­tion.

Readers who are un­familiar with the dif­fer­en­t types of pre­sen­ta­tions at medical meetings such as ASCO may wish to consult the “Organization of the ASCO Meeting” section at the end of this article.

The Beacon has compiled lists of all ASCO 2016 multiple myeloma-related oral pre­sen­ta­tions, poster pre­sentations, education session pre­sen­ta­tions, and e-abstracts. The lists in­clude pre­sen­ta­tion titles, authors, and links to each pre­sen­ta­tion's abstract and the related slides or poster (when avail­able). Links to the pages with these lists cur­rently can be found near the top of the Beacon's sidebar, on the right side of every Beacon page.

Initial Results Of the CASTOR Darzalex, Velcade, and Dexa­meth­a­sone Phase 3 Trial

Sunday's late-breaking abstract session at ASCO featured a pre­sen­ta­tion by Dr. Antonio Palumbo of the University of Turin in Italy. He reported initial results of the Phase 3 “CASTOR” (MMY3004) trial com­par­ing Darzalex (dara­tu­mu­mab), Velcade (bor­tez­o­mib), and dexa­metha­sone to Velcade and dexa­metha­sone alone in re­lapsed or re­frac­tory multiple myeloma patients (abstract).

Some of the results Dr. Palumbo pre­sented have been known since initial in­­for­ma­tion about the trial results was released in April. At the time, The Beacon reported on the results as part of its reg­u­lar “Myeloma Morn­ing” series of myeloma re­search and news updates. The Beacon's report in­cluded feedback from Beacon Medical Advisor Dr. Prashant Kapoor, a myeloma specialist at the Mayo Clinic. Dr. Kapoor described the CASTOR results as “unprecedented.”

The addi­tional in­­for­ma­tion that Dr. Palumbo pre­sented today is likely to con­tinue impressing myeloma specialists.

The CASTOR trial in­volve­s almost 500 multiple myeloma patients who had a median of two prior lines of ther­apy. Half the trial par­tic­i­pants were ran­domly selected to be treated with Darzalex, Velcade, and dexa­metha­sone (“DVd”). The other half were treated with Velcade and dexa­metha­sone alone (“Vd”).

The results in­di­cate that adding Darzalex to Velcade and dexa­metha­sone sig­nif­i­cantly in­creases the share of patients who respond to treat­ment and the time until dis­ease relapse.

The over­all re­sponse­ rate was 83 per­cent in the patients treated with Darzalex, Velcade, and dexa­metha­sone, versus 63 per­cent in the patients treated with Velcade and dexa­metha­sone alone.

Median pro­gres­sion-free sur­vival has not yet been reached – but should be at least 15 months – in the patients treated with Darzalex, Velcade, and dexa­metha­sone, versus 7.2 months in the patients treated with Velcade and dexa­metha­sone alone.

Myeloma specialists are likely to be particularly impressed with the pro­gres­sion-free sur­vival curves from the trial, which show an in­creas­ing gap be­tween the curves for the two treat­ment regi­mens (see Figure 1 below).

Figure 1 - Progression-Free Survival - CASTOR (MMY3004) Phase 3 Trial
(click on image to view a larger version of it)

There were no safety-related surprises during the trial, with the side effects of the DVd regi­men being in line with what one would ex­pec­t based on ex­peri­ence with Darzalex as a single agent and Velcade and dexa­metha­sone used as a two-drug com­bi­na­tion.

The three side effects that most noticeably were higher in patients treated with Darzalex, Velcade, and dexa­metha­sone com­pared to Velcade and dexa­metha­sone alone were low platelet levels (59 per­cent versus 44 per­cent), periph­eral neu­rop­athy (47 per­cent versus 38 per­cent), and diarrhea (32 per­cent versus 22 per­cent)

Initial Results of the EMN02/HO95 Phase 3 Stem Cell Transplantation Trial

The first pre­sen­ta­tion during Friday's multiple myeloma session at ASCO was given by Dr. Michele Cavo of Bologna University in Italy. He reported initial results of an im­por­tant European trial involving newly diag­nosed multiple myeloma patients. The trial, known as the EMN02/HO95 MM (“EMN02”) study, compares two dif­fer­en­t ap­proaches to treating newly diag­nosed patients. One ap­proach in­cludes au­tol­o­gous stem cell trans­planta­tion, while the other does not (abstract).

The Beacon previously reported on the design and results of this large, 1,500-patient study when the abstract for the pre­sen­ta­tion was made public in mid May. Briefly, all patients in the study re­ceived the same initial ther­apy – four cycles of Velcade, cyclo­phos­pha­mide, and dexa­metha­sone. Then, 60 per­cent of the patients were ran­domly selected to re­ceive either one or two au­tol­o­gous stem cell trans­plants, while 40 per­cent of the patients re­ceived four cycles of Velcade, mel­phalan, and pred­ni­sone (VMP).

After the trans­plants or treat­ment with VMP, some patients re­ceived con­sol­i­da­tion ther­apy, and all patients re­ceived Revlimid (lena­lido­mide) main­te­nance ther­apy.

Patients who re­ceived one or two trans­plants had longer pro­gres­sion-free sur­vival than the patients who re­ceived VMP rather than an up­front trans­plant. Three-year pro­gres­sion free sur­vival was 73 per­cent, 63 per­cent, and 58 per­cent in the two trans­plant, one trans­plant, and no trans­plant (VMP) groups of patients.

Median pro­gres­sion-free sur­vival has not been reached in the trans­plant patients, but is 44 months in the no trans­plant (VMP) patients. It appears from the graph of the pro­gres­sion-free sur­vival curves that patients who had a single trans­plant will have median pro­gres­sion-free sur­vival of 50 to 52 months (or 6 to 8 months longer than the no-transplant (VMP) patients.

There apparently is no dif­fer­ence in over­all sur­vival at this time be­tween the dif­fer­en­t groups of patients.

Dr. Cavo concluded his pre­sen­ta­tion by stating that, based on the results of the EMN02 study thus far, high-dose mel­phalan followed by an au­tol­o­gous trans­plant “continues to be the reference treat­ment of choice for fit patients with newly diag­nosed multiple myeloma.”

Although Dr. Cavo's conclusion has been reflected in the headlines of many news stories summarizing the results of the EMN02 study, it is unclear whether the study results will actually change any minds re­gard­ing the role of trans­plan­ta­tion in up­front ther­apy for multiple myeloma.

Myeloma specialists who in the past have questioned the need for up­front trans­plan­ta­tion already are noting that there is no over­all sur­vival ad­van­tage in the study, the size of the pro­gres­sion-free sur­vival ad­van­tage is not particularly large, and the treat­ment regi­men used in the no-transplant arm (VMP) is generally viewed as dated.

Revlimid Maintenance Therapy Following Stem Cell Transplantation

The second oral pre­sen­ta­tion on Friday was by Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York. Dr. McCarthy reported on results of a com­bined (meta) analysis of results from three clin­i­cal trials that have in­ves­ti­gated the impact of Revlimid main­te­nance ther­apy on sur­vival out­comes (abstract, presentation slides [PDF] courtesy of Dr. McCarthy).

Researchers from the Mayo Clinic have pre­vi­ously pre­sented a meta analysis of Revlimid main­te­nance ther­apy trial results at a meeting of the American Society of Hematology (abstract, presentation slides [PDF]). The Mayo Clinic analysis found that Revlimid main­te­nance con­sis­tently im­proved pro­gres­sion-free sur­vival across the four trials in­cluded in the study. However, the impact on over­all sur­vival was less clear, but perhaps slightly pos­i­tive.

A broader meta analysis of main­te­nance ther­apy studies involving Revlimid and thalidomide, which is in the same class of drugs as Revlimid, also found that main­te­nance ther­apy with the drugs im­proves pro­gres­sion-free sur­vival, but does not im­prove over­all sur­vival (abstract).

Studies that in­ves­ti­gated main­te­nance ther­apy prior to the use of thalido­mide and Revlimid to treat multiple myeloma found that main­te­nance with chemo­ther­apy drugs, interferon, or steroids con­sis­tently im­proved pro­gres­sion-free sur­vival, but had an inconsistent effect on over­all sur­vival (see, for example, the first part of the “Results and Discussion” section of this International Myeloma Work­ing Group state­ment on main­te­nance ther­apy).

The study that Dr. McCarthy discussed during Friday's session takes a focused ap­proach to investigating the impact of Revlimid main­te­nance ther­apy on sur­vival. The study in­cludes only trials that in­ves­ti­gated Revlimid main­te­nance when it is admin­istered fol­low­ing an up­front stem cell trans­plant. Thus, the study in­cludes data from just three Revlimid main­te­nance ther­apy trials: the U.S. CALGB trial (460 patients), the French IFM 2005-02 trial (614 patients), and the Italian GIMEMA-RVMM-PI-209 trial (135 patients in the trans­plant arms of the trial).

The new meta analysis also focuses solely on the impact of Revlimid main­te­nance on over­all sur­vival.

Of the three trials in­cluded in the McCarthy analysis, only one – the CALGB trial – has results showing that Revlimid main­te­nance ther­apy has a statistically sig­nif­i­cant pos­i­tive impact on over­all sur­vival.

However, when data from the three trials are com­bined, the over­all dataset in­di­cates that Revlimid main­te­nance has a statistically sig­nif­i­cant pos­i­tive impact on over­all sur­vival (see the over­all sur­vival curves in Figure 2 below).

With a median follow up of 80 months, the median over­all sur­vival is 86 months for patients in the three studies who did not have Revlimid main­te­nance after their initial trans­plant.

Median sur­vival has not yet been reached for the patients who did have Revlimid main­te­nance after their initial trans­plant. However, Dr. McCarthy and his co-authors esti­mate the median could be as much as 2.5 years more than the 86 months observed for the non-maintenance patients.

Figure 2 - Overall Survival - Meta-Analysis Of Three Revlimid Maintenance Clinical Trials
(click on image to view a larger version of it)

Ninlaro-Based Treatment Regimens

There were two pre­sen­ta­tions related to Ninlaro (ixazomib) during Friday's oral session.

Ninlaro, Cyclophosphamide, and Dexa­meth­a­sone for Newly Diagnosed Patients

The first Ninlaro-related pre­sen­ta­tion was by Dr. Martha Lacy of the Mayo Clinic. She reported results from the Phase 2 portion of a clin­i­cal trial investigating the use of Ninlaro in com­bi­na­tion with cyclo­phos­pha­mide and dexa­metha­sone in newly diag­nosed multiple myeloma patients (abstract, presentation slides [PDF] courtesy of Dr. Lacy).

Like Velcade and Kyprolis (car­filz­o­mib), Ninlaro belongs to the pro­te­a­some in­hib­i­tor class of drugs. Unlike Velcade and Kyprolis, Ninlaro is admin­istered as a capsule rather than by in­jec­tion or in­fusion.

Ninlaro was approved by the U.S. Food and Drug Admin­istra­tion last No­vem­ber as a new treat­ment for multiple myeloma. Its ap­­prov­al is for use in com­bi­na­tion with Revlimid and dexa­metha­sone in myeloma patients who have had at least one prior ther­apy.

Ninlaro also has been under review for poten­tial ap­­prov­al in Europe. In a de­ci­sion that surprised and disappointed many myeloma specialists, a key European advisory com­mit­tee last week announced that it was rec­om­mending against the drug's ap­­prov­al (see related Beacon news article).

The three-drug com­bi­na­tion tested in the trial discussed by Dr. Lacy at ASCO on Friday would be the Ninlaro equivalent of the Velcade, cyclo­phos­pha­mide, and dexa­metha­sone regi­men (VCD / CyBorD) that has seen fre­quent use in the United States and many other countries. It also would be an all-oral regi­men, in contrast to the VCD / CyBorD regi­men, which requires in­jec­tions or in­fusions of Velcade.

The 45 patients who took part in the Phase 2 portion of the trial re­ceived Ninlaro 4 mg once a week for three weeks out of each four-week cycle. In addi­tion, the patients re­ceived 400 mg/m2 of cyclo­phos­pha­mide and 40 mg of dexa­metha­sone once per week during every week of the cycle.

Seventy eight per­cent of the Phase 2 trial par­tic­i­pants had at least a partial re­sponse­ to the three-drug regi­men, and one-year over­all sur­vival and pro­gres­sion-free sur­vival were 100 per­cent and 91 per­cent, re­spec­tive­ly.

These results are in line with results from a European trial that also tested a similar treat­ment regi­men in newly diag­nosed patients (abstract). The over­all re­sponse­ rate and depth of re­sponse­ seen with the Ninlaro-based regi­men, how­ever, appear to be slightly lower than what has been observed with VCD / CyBorD. For example, in recently pub­lished results of a French trial where one group of newly diag­nosed patients was treated with VCD, 84 per­cent of the patients had at least a partial re­sponse­ to the VCD regi­men (abstract, related conference abstract).

The most common side effects among the patients treated with the Ninlaro-based regi­men in the study discussed by Dr. Lacy were low blood counts, fatigue, gastro­in­tes­ti­nal issues, and periph­eral neu­rop­athy. Forty four per­cent of the patients ex­peri­enced some degree of periph­eral neu­rop­athy during the trial, but all cases were mild to mod­er­ate.

Only one patient had to have their Ninlaro dose reduced during the trial due to side effects.

Ninlaro, Pomalyst, and Dexa­meth­a­sone for Re­lapsed Patients

Later in the Friday oral session, Dr. Amrita Krishnan of the City of Hope Cancer Center in Duarte, California, pre­sented initial results from a Phase 1/2 study of Ninlaro, Pomalyst (poma­lido­mide, Imnovid), and dexa­metha­sone in re­lapsed multiple myeloma (abstract, presentation slides [PDF] courtesy of Dr. Krishnan).

The 25 patients who re­ceived the in­tended Phase 2 dose of the three-drug com­bi­na­tion had a median of two prior ther­a­pies. All patients had been pre­vi­ously treated with both Velcade and Revlimid, and all patients were resistant (refractory) to treat­ment with Revlimid; 60 per­cent were Velcade-refractory.

Treatment was carried out in four-week cycles with Ninlaro admin­istered at 4 mg per week for three of the four weeks, Pomalyst at 4 mg per day for 21 days on with 7 days off, and dexa­metha­sone at 40 mg once per week for every week of the cycle.

Thus far, 44 per­cent of the patients have responded to the treat­ment regi­men, with 16 per­cent achieving a very good partial re­sponse­ and 28 per­cent achieving a partial re­sponse­. No sur­vival data are avail­able at this time, and patients have re­ceived a median of two treat­ment cycles thus far.

The 44 per­cent re­sponse­ rate seen in the study is lower than – but still com­parable to – the over­all re­sponse­ rate seen in another trial exploring the same three-drug regi­men in a similar patient pop­u­la­tion. The other trial reported an over­all re­sponse­ rate of 55 per­cent in 20 patients who re­ceived four dif­fer­en­t dosing regi­mens of the Ninlaro, Pomalyst, and dexa­metha­sone regi­men (abstract, presentation slides [PDF]).

The re­sponse­ rate in both trials is lower than has been seen with Velcade, Pomalyst, and dexa­metha­sone in re­lapsed myeloma patients. A joint Mayo Clinic, Dana-Farber, and University of Chicago study of the Velcade-based regi­men found that it had an over­all re­sponse­ rate of 85 per­cent in 47 patients who had a median of two prior treat­ment regi­mens (related abstract with early results of study). The patients in this study, how­ever, were not as exposed and resistant to treat­ment with pro­te­a­some in­hib­i­tors as the patients in the study discussed on Friday by Dr. Krishnan.

Isatuximab and Aplidin

Results of re­search related to two poten­tial new myeloma ther­a­pies also were pre­sented during Friday's oral session at ASCO.

Single-Agent Isatuximab in Heavily Pretreated Multiple Myeloma

First, Dr. Joshua Richter of the John Theurer Cancer Center in Hackensack, New Jersey, pre­sented updated results of the TED10893 Phase 2 study of single-agent isatuximab (SAR650984) in heavily pre­treated myeloma patients (abstract, presentation slides [PDF] courtesy of Dr. Richter).

Isatuximab is a mono­clonal anti­body that targets the CD38 protein found on most multiple myeloma cells. CD38 also is the protein targeted by Darzalex. Isatuximab is being devel­oped by the French pharma­ceu­tical com­pany Sanofi.

The TED10893 study is designed to de­ter­mine the optimal dose of isatuximab while also providing insight into the drug's efficacy and safety. Thus far, 74 patients have been treated at the three higher doses tested during the study. These patients have had a median of five prior lines of ther­apy. About 90 per­cent are resistant to both Revlimid and Velcade, and 40 per­cent are resistant to Revlimid, Velcade, Pomalyst, and Kyprolis.

The over­all re­sponse­ rate among the 74 patients was 24 per­cent, the median pro­gres­sion-free sur­vival was 3.6 months, and the median over­all sur­vival was 18.6 months.

In the SIRIUS clin­i­cal trial, single-agent Darzalex was tested in a similar patient pop­u­la­tion (heavily pre­treated myeloma patients with a median of 5 prior lines of ther­a­pies). The over­all re­sponse­ rate to single-agent Darzalex was 29 per­cent, and median pro­gres­sion-free sur­vival was 3.7 months (related presentation slides).

Based on these results and the updated results for isatuximab pre­sented by Dr. Richter, it appears that isatuximab has anti-myeloma activity com­parable to that of Darzalex.

Aplidin in Com­bi­na­tion with Velcade and Dexa­meth­a­sone in Re­lapsed Multiple Myeloma

Immediately after the pre­sen­ta­tion by Dr. Richter, Dr. María-Victoria Mateos of the University Hospital of Salamanca in Spain pre­sented results of a Phase 1 trial investigating the com­bi­na­tion of Aplidin (plitidepsin), Velcade, and dexa­metha­sone (abstract, presentation slides [PDF] courtesy of Dr. Mateos).

Aplidin is an in­fused drug being devel­oped as a poten­tial new treat­ment for multiple myeloma by the Spanish pharma­ceu­tical com­pany PharmaMar. The active ingredient in Aplidin, plitidepsin, was originally found in a species of marine animals known as ascidians, or “sea squirts.”

The Phase 1 trial discussed by Dr. Mateos on Friday is designed to estab­lish­ the best dosing regi­men for the com­bi­na­tion of Aplidin, Velcade, and dexa­metha­sone. Three dosing regi­mens were tested, all of which in­volve­d a 28-day cycle with Aplidin admin­istered once every two weeks, Velcade twice a week for the first two weeks of the cycle, and dexa­metha­sone at 40 mg per week for every week of the cycle.

Twenty two patients have been enrolled in the trial. They have a median of three prior lines of ther­apy, and almost all the patients (about 90 per­cent) have pre­vi­ously been treated with both Revlimid and Velcade.

The three-drug com­bi­na­tion of Aplidin, Velcade, and dexa­metha­sone achieved an over­all re­sponse­ rate of 55 per­cent, and a median pro­gres­sion free sur­vival of 8.3 months.

Smoldering Multiple Myeloma

There also were two pre­sen­ta­tions related to smol­der­ing multiple myeloma during Friday's ASCO session.

Improving the Identification of High-Risk Smoldering Myeloma

Dr. Praful Ravi of the Mayo Clinic pre­sented one of the two smol­der­ing myeloma pre­sen­ta­tions. He sum­ma­rized work he and his colleagues have done to de­ter­mine how changes in the M-spike and hemoglobin level of smol­der­ing myeloma patients affect the likelihood of their progressing to symp­tomatic multiple myeloma.

Based on a review of the Mayo Clinic records for 190 smol­der­ing myeloma patients diag­nosed be­tween 1973 and 2014, the re­searchers found that rapid changes in a smol­der­ing patient's M-spike or hemoglobin level after diag­nosis signal a high likelihood of pro­gres­sion to symp­tomatic dis­ease.

A rapid change in M-spike was defined as either a 10 per­cent in­crease in M-spike within 6 months of diag­nosis in cases where the M-spike is 3 g/dL or greater at diag­nosis, or a 25 per­cent in­crease in M-spike within 1 year of diag­nosis (with at least an 0.5 g/dL absolute in­crease).

A rapid change in hemoglobin was defined as an 0.5 g/dL or greater drop in hemoglobin in the first year after diag­nosis.

Based on these definitions, the Mayo re­searchers defined three risk factors for rapid pro­gres­sion: a rapid change in M-spike; a rapid change in hemoglobin; and greater than 20 bone mar­row per­cent plasma cell per­cent­age at diag­nosis.

Patients with all three of these risk factors at diag­nosis had a median time to pro­gres­sion of just 1 year from the time of their diag­nosis.

On the other end of the spectrum, smol­der­ing patients who had none of these risk factors had a median time to pro­gres­sion of 12.3 years.

Genetic Mutations in Smoldering versus Symptomatic Multiple Myeloma

The second smol­der­ing myeloma pre­sen­ta­tion was by Dr. Sham Mailankody of Memorial Sloan-Kettering Cancer Center in New York City. He summarized results of study investigating genetic mutations in the plasma cells of two groups of multiple myeloma patients. One group in­cluded high-risk smol­der­ing myeloma patients. The other group was newly diag­nosed symp­tomatic multiple myeloma patients.

Dr. Mailankody and his colleagues found that the two groups of patients had com­parable numbers of genetic mutations in their plasma cells. However, mutations that are typically asso­ci­ated with multiple myeloma were found almost ex­clu­sively in the patients with symp­tomatic multiple myeloma. This finding, Dr. Mailankody and his colleagues say, could have implications for when cer­tain smol­der­ing myeloma patients should start active treat­ment of their dis­ease.

Presentation Discussions During Friday's Oral Session

There also were discussion / review pre­sen­ta­tions at Friday's multiple myeloma session and at the late breaking abstract session yesterday. During these pre­sen­ta­tions, invited speakers discuss pre­sen­ta­tions made earlier in the session, highlighting key findings and putting the results in perspective.

On Friday, Dr. William Bensinger of the Swedish Cancer Institute in Seattle discussed the pre­sen­ta­tions by Drs. Cavo, McCarthy, and Lacy (presentation slides [PDF], courtesy of Dr. Bensinger). Dr. Ajai Chari of the Mount Sinai hos­pi­tal in New York City discussed the pre­sen­ta­tions by Dr. Praful and Dr. Mailankody (pre­sentation slides [PDF], courtesy of Dr. Chari). And Dr. Suzanne Trudel of the Princess Margaret Cancer Center in Toronto discussed the remaining Friday pre­sen­ta­tions.

Yesterday, Dr. Paul Richardson of the Dana-Farber Cancer Institute discussed the Darzalex results pre­sented by Dr. Palumbo.

Organization of the ASCO Meeting

New re­search findings pre­sented at ASCO and other scientific meetings are generally communicated in either oral pre­sen­ta­tions or poster summaries.

Oral pre­sen­ta­tions usually report results of re­search that is con­sidered particularly im­por­tant, either because the subject itself is im­por­tant, or because the results are based on sub­stan­tial amounts of evi­dence (for example, a sizable clin­i­cal trial).

Poster re­search summaries are made avail­able during specific “poster sessions,” when re­searchers dis­play summaries of their studies on posters in a large exhibition hall.

Compared to the re­search summarized during oral pre­sen­ta­tions, the findings in poster summaries generally are in earlier stages of devel­op­ment and may in­volve­ only laboratory re­search or clin­i­cal trials with just a small number of patients.

The ASCO meeting also has what are known as education sessions. During these sessions, leading specialists give oral pre­sen­ta­tions summarizing the latest re­search related to specific topics.