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All response-evaluable patients were included in the efficacy analyses. Safety analyses included all response-evaluable patients who received at least 1 dose of study drug. The medians for time-to-event endpoints are based on Kaplan—Meier estimates, and the unstratified log-rank test was used for comparisons of these endpoints. Patients were grouped according to best response by investigator assessment using a data cutoff of 3 March , with a median follow-up of Of the patients in the intent-to-treat population, There were patients An additional 99 patients 6.

As indicated in the study flow diagram, 91 patients were still receiving treatment in the Rd continuous arm see Supplementary Figure 1 , available on the Leukemia website and of these patients, 49 were in CR There were no notable differences in baseline characteristics across response subgroups or treatment arms Table 1. The overall response rate in the Rd continuous arm was Of patients who achieved CR, median time to first CR was Median time to first VGPR was 5.

In contrast, 2.

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Cumulative response by treatment month for patients who achieved VGPR or better as best response. Percentage shown is for patients achieving VGPR or better in the current month. In particular, in patients achieving CR, responses were sustained by an additional 19 months or more in patients receiving Rd continuous vs MPT or Rd18 median duration of response, Kaplan—Meier estimates of duration of response.

This benefit was even more pronounced in patients with higher quality responses. A PFS benefit was observed with higher quality responses within all treatment arms Supplementary Figure 3. Kaplan—Meier estimates of PFS. NE indicates not estimable. After a median follow-up of Rates of 4-year survival of In the Rd18 arm, 4-year survival rates were Kaplan—Meier estimates of OS.

Among the patients who achieved CR and were evaluable at this time point, median OS was In line with results showing prolonged PFS, time to second-line antimyeloma treatment was considerably prolonged in patients treated with Rd continuous vs MPT or Rd18 across all subgroups of responding patients Table 2. Median time to second-line antimyeloma treatment was extended by Similarly, Rd continuous prolonged time to second-line antimyeloma therapy by 8.

The safety profile of each treatment was generally consistent across response subgroups. Rates of lenalidomide discontinuation with Rd continuous were generally comparable with rates of thalidomide discontinuation with fixed duration MPT across all response subgroups. In these patients, the median durations of lenalidomide and dexamethasone treatments were In addition, This retrospective post hoc analysis of the FIRST trial, the largest prospective phase 3 study of transplant-ineligible patients with NDMM to date, clearly demonstrates the benefits attained by continuing treatment with Rd until disease progression in all responding patients, irrespective of the quality of response.

An improvement in OS was also seen with Rd continuous for all groups of responders, with an increase observed in 4-year survival compared with MPT. Although the study was not powered for the comparison of Rd continuous vs Rd18, rates of 4-year survival were similar with Rd continuous vs Rd18 for all groups of responders. Although it is known that greater depth of response is associated with improved outcomes in patients with multiple myeloma, it remains to be determined whether continuing therapy once complete or high-quality responses are achieved improves patient outcomes.

This subanalysis of the FIRST trial is in agreement with the previous findings in favor of depth of response as a surrogate marker for survival, and also shows an added benefit of treatment duration.

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This subanalysis demonstrates that continuous treatment significantly benefits all patients, regardless of best response. This highlights the importance of factors beyond quality of response for determining outcomes, such as maintaining a response with continuous treatment. With appropriate dose modifications, continuous treatment with Rd until disease progression was feasible, resulted in rapid and sustained disease control, and improved long-term survival outcomes vs treatment with MPT.

These data support the use of Rd continuous therapy beyond achievement of best response until disease progression as a standard treatment regimen for transplant-ineligible patients with NDMM, especially patients who achieve high-quality responses. San Miguel J, Mateos M. Advances in treatment for newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplantation. Leukemia Supp ; 2 : S21—S Palumbo A, Mina R. Part II: role of maintenance therapy in transplant-ineligible patients. J Natl Compr Canc Netw ; 11 : 43— Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in total therapy protocols.

Blood ; : — Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer ; : — In April 70 AD, a few legions sent by Vespasianus and commanded by Quintus Petillius Cerialis eventually defeated the Batavians and negotiated surrender with Gaius Julius Civilis somewhere between the Waal and the Maas near Noviomagus Nijmegen , which was probably called "Batavodurum" by the Batavians. Dutch writers in the 17th and 18th centuries saw the rebellion of the independent and freedom-loving Batavians as mirroring the Dutch revolt against Spain and other forms of tyranny.

According to this nationalist view, the Batavians were the "true" forefathers of the Dutch, which explains the recurring use of the name over the centuries. Jakarta was named "Batavia" by the Dutch in The Dutch republic created in on the basis of French revolutionary principles was called the Batavian Republic. Even today Batavian is a term sometimes used to describe the Dutch people; this is similar to use of Gallic to describe the French and Teutonic to describe the Germans.

Modern scholars of the Migration Period are in agreement that the Frankish identity emerged at the first half of the 3rd century out of various earlier, smaller Germanic groups, including the Salii , Sicambri , Chamavi , Bructeri , Chatti , Chattuarii , Ampsivarii , Tencteri , Ubii , Batavi and the Tungri , who inhabited the lower and middle Rhine valley between the Zuyder Zee and the river Lahn and extended eastwards as far as the Weser , but were the most densely settled around the IJssel and between the Lippe and the Sieg.

The Frankish confederation probably began to coalesce in the s. The Franks eventually were divided into two groups: the Ripuarian Franks Latin: Ripuari , who were the Franks that lived along the middle-Rhine River during the Roman Era, and the Salian Franks , who were the Franks that originated in the area of the Netherlands. Franks appear in Roman texts as both allies and enemies laeti and dediticii. By about , the Franks had the region of the Scheldt river present day west Flanders and southwest Netherlands under control, and were raiding the Channel , disrupting transportation to Britain.

Roman forces pacified the region, but did not expel the Franks, who continued to be feared as pirates along the shores at least until the time of Julian the Apostate , when Salian Franks were allowed to settle as foederati in Toxandria , according to Ammianus Marcellinus. Three factors contributed to the probable disappearance of the Frisii from the northern Netherlands.

What happened to them, however, is suggested in the archaeological record.

History of the Netherlands

The discovery of a type of earthenware unique to 4th-century Frisia , called terp Tritzum , shows that an unknown number of them were resettled in Flanders and Kent , [36] likely as laeti under Roman coercion. Second, the environment in the low-lying coastal regions of northwestern Europe began to lower c.

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Tectonic subsidence , a rising water table and storm surges combined to flood some areas with marine transgressions. This was accelerated by a shift to a cooler, wetter climate in the region. Any Frisii left in the lower area's of Frisia, would have drowned. As a result of these three factors, it has been postulated that the Frisii and Frisiaevones disappeared from the area, leaving the coastal lands largely unpopulated for the next two centuries.

As climatic conditions improved, there was another mass migration of Germanic peoples into the area from the east. This is known as the " Migration Period " Volksverhuizingen. The northern Netherlands received an influx of new migrants and settlers, mostly Saxons , but also Angles and Jutes. Many of these migrants did not stay in the northern Netherlands but moved on to England and are known today as the Anglo-Saxons. The newcomers who stayed in the northern Netherlands would eventually be referred to as "Frisians", although they were not descended from the ancient Frisii.

These new Frisians settled in the northern Netherlands and would become the ancestors of the modern Frisians. Old Frisian is the most closely related language to Old English [45] and the modern Frisian dialects are in turn the closest related languages to contemporary English. By the end of the 6th century, the Frisian territory in the northern Netherlands had expanded west to the North Sea coast and, by the 7th century, south to Dorestad. During this period most of the northern Netherlands was known as Frisia. In the 7th and 8th centuries, the Frankish chronologies mention this area as the kingdom of the Frisians.

This kingdom comprised the coastal provinces of the Netherlands and the German North Sea coast. During this time, the Frisian language was spoken along the entire southern North Sea coast. Dorestad was the largest settlement emporia in northwestern Europe. It had grown around a former Roman fortress.

It was a large, flourishing trading place, three kilometers long and situated where the rivers Rhine and Lek diverge southeast of Utrecht near the modern town of Wijk bij Duurstede. Between and around Dorestad was often fought over between the Frisians and the Franks. After Roman government in the area collapsed, the Franks expanded their territories until there were numerous small Frankish kingdoms, especially at Cologne , Tournai , Le Mans and Cambrai.

By the s, Clovis I had conquered and united all the Frankish territories to the west of the Meuse , including those in the southern Netherlands. He continued his conquests into Gaul. After the death of Clovis I in , his four sons partitioned his kingdom amongst themselves, with Theuderic I receiving the lands that were to become Austrasia including the southern Netherlands.

A line of kings descended from Theuderic ruled Austrasia until , when it was united with the other Frankish kingdoms of Chlothar I , who inherited all the Frankish realms by He redivided the Frankish territory amongst his four sons, but the four kingdoms coalesced into three on the death of Charibert I in Austrasia including the southern Netherlands was given to Sigebert I. The southern Netherlands remained the northern part of Austrasia until the rise of the Carolingians.

Battle of Hondschoote

The Franks who expanded south into Gaul settled there and eventually adopted the Vulgar Latin of the local population. It completely disappeared as a spoken language from these regions during the 10th century. A widening cultural divide grew between the Franks remaining in the north and the rulers far to the south in what is now France. In the late 19th century, Dutch historians believed that the Franks, Frisians, and Saxons were the original ancestors of the Dutch people.

Some went further by ascribing certain attributes, values and strengths to these various groups and proposing that they reflected 19th-century nationalist and religious views. In particular, it was believed that this theory explained why Belgium and the southern Netherlands i. The success of this theory was partly due to anthropological theories based on a tribal paradigm. Being politically and geographically inclusive, and yet accounting for diversity, this theory was in accordance with the need for nation-building and integration during the — period.

The theory was taught in Dutch schools.