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25 things to eat before you die – the ultimate foodie bucket list
The World's 50 Best Restaurants have been announced, highlighting the best fine dining establishments on the planet. But for those on a budget, this list is pretty had to beat...
1. Fresh coconuts, St Lucia
Coconuts' nutrient-rich water is best slurped straight from the fruit itself. On a St Lucia beach (any will do), a few coins will buy you a green-golden orb, freshly cut from a leggy palm. With its top bit hacked off, you can pop in a plastic straw and guzzle up the refreshing elixir. Next, use your fingers to scoop out the sweet, gelatinous flesh: a messy yet very satisfying task.
2. Bagels, New York City
There is no bagel like a New York bagel. Though hotly disputed, our NYC expert reckons H&H and Zabars both have good options – best served with vegetable cream cheese.
3. Al Khalas dates, Oman
Dates aren't just a snack in the Middle East: they're fuel. The sweet, juicy dried fruits have sustained local people for centuries, in a land where only the hardiest plants thrive. They're no longer essential for survival today, but they're still one of the cornerstones of Omani culture.
In most homes and hotels you'll be welcomed with tiny cups of bitter coffee and a platter of plump dates – the traditional Omani greeting.
4. Pastel de natas, Portugal
Nowhere does custard tarts (or pastel de natas, as they're called here) quite like Portugal. And perhaps nowhere in Portugal does them as well as Pasteis de Belém in Lisbon, which is why queues for the sweet, rich and perfectly crisp tarts often stretch along the pavement.
5. Aperitivo in Milan, Italy
The Italian city is perhaps the best place to experience aperitivo - the ritual of early evening cocktails furnished with seemingly endless plates of "free" food. The Bulgari hotel's offering is among the finest. Nuts and olives are the least of it. Go for creamy risottos, mouthwatering burrata and succulent strips of salami washed down with a gin cocktail served in a glass the size of your head.
6. Clam cakes, US
You haven't lived until you've tried clam cakes (that's chopped clams in a cornmeal-based dough, deep-fried til golden) in Rhode Island – often served with clam chowder on the side. Confusingly, the best version of the latter is the New England style one (with a milky broth), not the Rhode Island style (which has clear broth).
7. Lingonberry juice, Sweden
When you sleep on ice in the Icehotel you're awoken in the morning by a person in a Ghostbusters-style uniform who dispenses a cup of sweet, steaming lingonberry juice from a vat carried on their back. The only way to wake up in the Arctic Circle.
8. Beijing dumplings, China
Dumplings in Beijing come in a vast array of flavours – lamb with carrot, pork and cabbage, or pork with garlic shoots.
On every table you'll find a range of condiments to eat them with – vinegar, soy sauce, chilli oil, and raw garlic cloves. These you nibble on while you're waiting, presumably to ensure good health, but effectively to ward off any possible romantic gestures for weeks afterwards.
9. Viennese Sachertorte, Austria
For pudding, you must have a Sachertorte. Freshly made in Vienna, they're wonderfully dense and rich.
10. Sushi and sashimi, Japan
You could nip into one of the many affordable sushi restaurants that envelop Tokyo's Tsukiji fish market, or for a fine-dining take on the experience Sushi Sora in the Mandarin Oriental Tokyo is incredible. The staff here speak English – not something you can take for granted in Tokyo – and are able to provide unusually informative details on the cuts, chefs' techniques, etiquette, and so on.
11. Grasshoppers, Mexico
You'll find chapulines – grasshoppers – of all shapes and sizes piled up in the markets of Oaxaca in southern Mexico. They have a satisfying crunch, and are often flavoured with salt, lime or chili – to boost their rather disappointing lack of flavour.
As the benefits of eating insects is being explored by nutritionists and economists alike, the people of Mexico have been ahead of the curve for centuries. Some say that grasshoppers are the cleanest insects, because they never touch the ground – only grasses. Snack on them like crisps in downtown Oaxaca, or wrap 'em up in a taco with cheese, ham and salsa.
12. Ripe figs, Spain
Sweet, sensuous figs are best enjoyed when freshly plucked from the tree, still warm from the afternoon sun. You'll find the finest in southern Spain, or the fig groves of Greece.
13. Full Scottish breakfast, Scotland
In addition to all the belt-busting trappings of a traditional British fry-up, the Scots like to start the day with tatties (potato scones) and a slice of black pudding too. On a particularly dreich morning in the Highlands, a Scottish breakfast is just the trick.
14. Gaufres, France
If you're ever wandering the cobbled streets of Lille's old town, make a beeline for Meert – the oldest patisserie in France, dating back to 1761. Whether you're queuing at the counter or sitting down in its decadent salon, be sure to try the signature gaufres. These 'waffles' bear a resemblance to the Dutch stroopwafels, but filled with creamy Madagascan vanilla. Charles de Gaulle was a fan, so you'll be in good company.
15. Laal mass, India
Laal maas, a fiery Rajasthani goat curry, calls for 45 chillies to a kilo of goat – with a few cloves of garlic, onion and yogurt. The curry is extremely hot but you don't eat it on its own; it's eaten with plain rice or flatbreads, yoghurt-like raita, chutney and poppadoms.
16. Ceviche, Peru
This medley of raw fish, chili, raw onion and coriander is tossed with a lime juice spritz. Try it in the street food stalls of surf-lashed Lima, where chefs make delicious work of the South Pacific's seafood bounty.
17. Sichuan hot pot, China
Chengdu is the heart of Sichuan's fiery cuisine, with dishes swimming in Sichuan peppercorns, the tongue-tingling and fragrant spice that numbs the mouth to set the stage for the region's plentiful chilli peppers. The bubbling hot pot is unmissable – paper-thin slices of lamb or beef and myriad vegetables are thrown into a cauldron of broth simmering in the middle of your table. Recover from the spices in a local teahouse.
18. Tom yum soup, Thailand
Some of Thailand's spiciest, tangiest tom yum soups can be eaten from roadside stalls. The hot and sour dish can be whipped up in a second by street vendors using fresh lemongrass, kaffir lime leaves and galangal. Other street food treats to try include rice with spicy stir-fried crabmeat and fresh yellow chillies.
19. Alba white truffles, Italy
The best way to sample the world's finest truffles? Freshly grated onto a plate of scrambled eggs, apparently – the perfect foil for the nutty, earthy flavours that truffles are prized for. The rare white Alba truffle is snuffled out by dogs (no pigs here), in the oak and beech forests of the Arno valley. They sell, for roughly £5 per gram, in Alba's Saturday and Sunday markets throughout October and on the first weekend of November.
20. Pizza in Napoli, Italy
In this city of superlative grub, L'Antica Pizzeria – which serves only tomato sauce or tomato sauce with mozzarella is the best. It puts all imitators to shame.
21. Thuringian sausages, Germany
The sausages of Weimar are no ordinary bangers. Their closely-guarded recipe is hundreds of years old, featuring finely minced meat (pork, beef or veal) with marjoram and garlic. These Thuringian sausages are charred on a bacon-rubbed grill, then stuffed into rolls, doused with mustard, and sold on the streets of Weimar.
22. Empanadas, Argentina
Humble empanadas are a street food favourite throughout South America – a throwback to the 16th-century Spanish conquistadors. These dinky pasties are stuffed with meat, vegetables and cheese, and baked or fried until crispy and golden.
After the lacklustre affairs you'll find across the Andes, Argentina's empanadas are light and tasty – and their fillings are more adventurous. Sweet dessert versions and spicy 'Arabian' styles are particularly tasty – and during Lent, fish versions are popular too.
23. Bunny chow, South Africa
When Indian immigrants arrived in South Africa in the 1800s, they bought their culinary heritage with them too – which lives on in some of the country's spiciest dishes. No visit to Durban is complete without devouring 'bunny chow' – a simple meat or vegetable curry served up in a hollowed-out loaf of bread. Eaten as street food rather than restaurant fare, it's cheap, simple, and just as messy as you'd imagine.
24. Cawl, Wales
With a recipe that's remained unchanged for centuries, cawl – a brothy stew – is just the kind of restorative fare you need after a day in the Brecons. Lamb (Welsh, of course), potatoes, onions and carrots form the hearty base of this dish – with the sweetness of swede, and an earthy kick from rosemary and thyme.
25. Gelato, Italy
Top-notch ice cream is one of our favourite things about Italy, but where to venture for the best? Our Italy expert recommends Gelato Fantasia in Rome: "There are eight different chocolate flavours alone, plus savoury forays like gorgonzola. But for me nothing beats the salted peanut flavour." But really, you'll be hard-pressed to find bad gelato anywhere in the country – so go forth and find your own superlative scoops.
Have a dish you'd like to add to our bucket list? Tell us in the comments below...


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Kids are back in school, autumn has arrived and soon the leaves will begin to change. That means it is finally apple season. The best way to celebrate the season? Apple picking with your family, of course! You can enjoy the weather before it gets too cold, learn a few fun apple facts, and then get your kids into the kitchen to make some delicious apple recipes.
Before You Go…
Here are some fun apple facts:
- There are about 2,500 varieties of apples grown in the United States
- Apples are grown in all 50 states
- It takes 2 pounds of apples to make one 9-inch pie
- It takes about 36 apples to create one gallon of apple cider
- Apples are fat-free, contain no sodium and provide about 5 grams of fiber each
- Apple trees take 4 to 5 years to produce their first fruit
- As soon as you pick an apple it stops ripening
- Here's why apple slices turn brown and how to prevent it
- There's a really cool new apple that doesn't turn brown called the Arctic® Apple
At the Orchard…
You'll enjoy seeing different apple varieties and experiencing what makes each one special: flavor, crispness, sweetness. Some apples are better for baking, some are better for juicing and some are better just sliced up and eaten fresh. And everyone has their favorite – mine is Pink Lady, my husband prefers Honeycrisp and my kids both love Granny Smith.
Back at Home…
Now that you have more apples than you know what to do with, here are some ideas:
- Did you know that some apples should be refrigerated for best quality? Gala and Golden Delicious are two common varieties that should definitely be stored in the refrigerator, but all apples can be stored there to prolong freshness.
- It's easy to freeze apples for later use in pies and cooked desserts. Simply peel, cut and core the apples, then soak in ascorbic acid and place on a cookie sheet. Freeze until solid, then place in plastic bags or containers and return to the freezer.
- You can also dry apples at home with a dehydrator.
The next thing to do is get your kids into the kitchen to make your own homemade applesauce. This recipe is simple, delicious and certainly a celebration of the season!
So seize the day and take your family apple picking – make some memories and make some delicious apple recipes too.
Melissa Joy Dobbins, MS, RDN, CDE is a nationally recognized registered dietitian nutritionist with more than 20 years' experience helping people enjoy their food with health in mind. Melissa is a certified diabetes educator, a former supermarket dietitian, and also a former national media spokesperson for the Academy of Nutrition and Dietetics (AND). She was named Outstanding Dietitian of the Year in Illinois by AND and Outstanding Diabetes Educator of the Year in Chicago by the American Association of Diabetes Educators. Melissa is a paid contributor to Sucralose.org. Melissa is the CEO of Sound Bites, Inc. based in Chicago, Illinois, and you can connect with her on Twitter (@MelissaJoyRD), Pinterest,Facebook, and check out her blog at SoundBitesRD.com.


text:
the interviews
beefheart then, now and in-between
from TROUSER PRESS
#36 010279 usa
by cole springer
is 27.11.78 interview
i was listening to the radio. i thought: 'i can hear a place in there that í could be'. i had always thought that music was too formal, and i thought: 'well, i'll get into this and fix it'. silly sculptor, going into music. what i am is not a musician but a sculptor, which is why my music sounds different. i put it together a different way. - don van vliet in oui magazine, july 1973
beefheart was a major influence on devo as far as direction goes. 'trout mask replica' - there are so many people that were affected by that album that he probably doesn't even know about, a silent movement of people. - devo in 'search & destroy' #3, 1977
i have been a staunch admirer of captain beefheart since 1970. the singular nature of his music, and the joy, excitement and mystery that are an inextricable part of it, are so extraordinary and exhilirating that i find myself compelled to celebrate the man whenever i have the chance.
my first opportunity came late in 1970, while i was attending college. faced with the task of giving an oral report on a poet for a course entitled 'modern poetry', i decided to buck the system and chose don van vliet, unbeknownst to my teacher. after all, the 'accepted' modern poets we had been studying struck me as uninteresting and irrelevant, for the most part: i'd give them a réal modern, even if it meant flunking.
so, on the big day, i sat down in front of the class, gave a brief bio of the captain, read a few of his poems, and then played them three tracks from 'trout mask replica'. as the music played, the class seemed unsure how to react, although a couple of girls in the front row actually appeared to be fríghtened. the teacher's face had registered different shades of confusion and skepticism all through the presentation, yet i received an 'a' in the course.
slightly less than a year later, i found myself at another college sitting down to write my debut music column for the student paper. i wanted to make an impression straight off, so i did an essay on beefheart, the thrust of which was: if you haven't heard this guy yet, you just háven't líved. upon its publication, i began checking his bin in the campus record store to see if the pen was really mightier than the sword. after a few days and no sales, i gave up.
okay, so beefheart has always been one of your proverbial 'cult' artists. that's fine with me, i just happen to find it unfortunate that so many people listen to so much shit. i think he has accepted his 'cult' status, too. he tried to go commercial in 1974 and it just didn't work out; now he has a new band and he's playing what he wants to again. his new elpee, 'bat chain puller', is as great as anything he has ever done, and live at the 'bottom line' [new york, on 251178 - t.t.] he was nothing short of superb.
his spectacular four-octave voice lovingly shaped every note and then sent it booming throughout the room, while the new magic band was so ridiculously good i don't even want to talk about it. i mean. it's one thing for van vliet to compose that amazing music which defies all known logic, but on top of that he keeps finding people brilliant enough to play it.
two days after the bottom line shows i went to the new york offices of warner brothers records where i was scheduled to interview don van vliet. upon arrival, i was ushered into the large but empty conference room. since i was early and don was a little late, i had time to review his history one more time.
the most important thing to realize about van vliet is that his music is unique not because he tríes to make it so; rather, it is a natural, unforced expression of his remarkable personality. the man is a true genius, a total artist and visionary.
[note by teejo: then follows an overlook of the albums and lives of captain beefheart till then, which was the release of 'shiny beast (bat chain puller)' - although the interviewer hasn't noticed the change of the title of the record... however, the well-known story contains óne 'fact' never mentioned anywhere else (the fourth sentence):
from five to thirteen, he studied with a master sculptor from portugal, agostinho rodriques. when he was eleven, don had his own teevee show, originating from the griffith park zoo in los angeles. he would sculpt animals while rodriques looked on and commented. at thirteen, don lectured on sculpture and animals at the barnsdall art institute at ucla (university of california, los angeles - t.t.). this led to his winning a scholarship to study art in europe, effective at age sixteen.]
all of which leads back to your correspondent waiting in the warners conference room for the imminent arrival of don van vliet. the prospect of actually meeting the man is a pretty damned exciting one, to say the least. it's funny, but i almost met him once before, back in january of 1971. it was at a magic band concert at the rochester institute of technology. after the show, i was amazed to see that beefheart didn't leave the stage, but rather was hanging out back by the drums. i was one of a handful of people who jumped up on stage and went over to talk with him. as i got there, one kid was asking him about his harmonicas. i stood there for a minute or two and thought: 'this guy is such a genius... what the hell can i say to him beyond: 'i really like your music'?' i decided that i was satisfied just to have stood next to him, and split without saying a word...
finally, my warners contact came into the room with a pretty lady who was introduced as jan van vliet, the captain's wife. moments later, beefheart comes through the door, his hand outstretched, and wearing a surprised smile like he knows me and didn't expect to see me here. as we're shaking hands, he's booming out:
man. i haven't seen you in years! how have you been? great to see you again!
talk about instant disorientation! here's captain beefheart treating me like a long lost friend, and all i can think is that i've never met him before in my life. i start to tell him so when i suddenly flash on the r.i.t. incident. i know he is reported to have an extraordinary memory, as well as powers of esp {extra sensorial perception - t.t.], but surely he doesn't remember me from two minutes in 1971, when i didn't even tálk to him?! but as if it's the most normal thing in the world - after i stutter a few semi-coherent syllabes about the rochester thing. - he says:
sure i remember you. i said hello to you then, don't you remember?
now that i think of it, i guess he did.
you don't really believe i remember you, do you?, he asks a few minutes later.
well, you're the only person in the world that i would believe cóuld remember someone like that!
we walk over to the table, sit down, and i set up my tape recorder. before i can even turn it on, don is talking slowly and evenly, but virtually non-stop, about new york, its inhabitants, and about the art exhibition he has just seen. within minutes i was cómpletely relaxed, a feeling i've never had in any other interview situation. we talked for well over an hour and the time just floated by. don's conversation twists and turns, and at times goes off on fantastic tangents, not unlike some of his music. the best i can hope to do here is to try and capture - through the use of lengthy, unedited quotes - some of the essence of this incredible man.
after raving about the paintings of franz kline, which he has just seen - the best, i think, other than van gogh - don pulls out his sketchbook and shows me some of his recent drawings, which are even more intricate and bizarre than those on his albums. i mention this to him and he says: i know. i wonder what that is? i venture that it is due to new york's influence, and he agrees, saying that they were done in new york.
additional picture
from 1977 or
'78 concert
from new york rocker #33 011180 usa
he mentions that he showed some of these drawings to his last bottom line audience, and adds that he likes to play here. even though you had some trouble with the monitors?at the time he seemed pretty exasperated with the technical staff, stopping the show at one point until they fixed the faulty monitors.
i just want to give everything i can, because i really appreciate people that care ánything about somebody that does art. i want to present a clear picture.
on to the subject of stage lighting:
lights are so demanding. when i go on the stage, i could be up there for a year if it wasn't for the lights. i like to look at the audience. i like to look at their expressions and gauge if i'm connecting, if they understand what i'm talking about or what's happening. and sometimes those lights - right when i'm looking - a light will blare up and all of a sudden the person's gone, i lose contact.
talking about the concerts gets don onto his latest lp, bat chain puller.
i'm more proud of that album than any album i've ever done. really, i think the sound is so great. glen kolotkin, who engineered it, is so good. so advanced. i mean, he did stravinsky's last album. he told me: 'i did electric ladyland' [jimi hendrix - t.t.], and i said; 'yeah', and he says: 'oh yes, you might be interested in this: i did stravinsky's last album'. right then i said: ' oh my god, are you kidding?' and then i just went right after him. i love stravinsky. i hate to hear anybody use anything that he has done. immediately i can spot it. i would never do that to him, or any other artist.
i ask him about reports that 'bat chain puller' had been in the can for over a year. don laughs:
they love to say things are in the can. i laid down a few things just to see if they would hold up as it went along till i signed to put the album out.
i love this group. they're nice. when they play, they smile and everything, they don't put on any silly airs - you know what i mean? i can't stand that. i think the only thing that holds up is somebody who is honestly playing and caring about what they're doing. then it's timeless - like van gogh. have you seen any of his things? he's brilliant! where is he hére? i would like to go to a museum and see some of his work. his paintings look like they were 'just done', and he is out somewhere going to the bathroom. i can't believe it, after a hundred years? how brilliant.
i begin to ask don about some of his influences, but as soon as i utter the words, he says very matter-of-factly:
i don't háve any. i don't. i would never put any influences into myself because it would distort what i do. and i'm a real funny person: if i were to take in influences...- oh, i make exceptions: animals, noises. i will take those influences in. but human influences, to me, i can áppreciate something somebody does, totally, because i don't get influences by it. i don't have that much ego, you know why? because i just don't want to páy for it. you know what ego does to you? i mean, it just puts you right out of the - i've hád ego before, a lot of it, but i stayed up for a year-and-a-half. did you ever read that? oh yeah, from the time i was 25 till i was 26½.
no sleep at all for a year-and-a-half?
no, not at all, and i've been thinking about it recently: i might stay up again. it's good, it's a mental fast - i mean, you get all of the things that have gone in, out. there you're ready right then to - if i take a paint brush, there's nothing between me and the brush hitting the canvas, very little, other than gravity. i mean, gravity is the master, period. of your feet get tired, it's because of gravity. other than that i don't think you'd even get tired.
what did you do during that year-and-a-half?
oh, i wrote about my entire life, as much as i could get down. i used to write 180 pages a day, just moving - like if a child is out playing and the mother calls the child: 'hey, come in here', the child doesn't even pay attention. and then they just go to sleep, after they just get bored with themselves. it is ímpossible to get bored. that's an égo thing. although: what is ego? that's something man invented...
during the beginning of our conversation, the captain had attempted to shut the windows behind us to keep out the noise of new york, since he has very sensitive hearing. now he jumps out of his chair and grabs the life-size cardboard cut-out of shaun cassidy that has been standing behind him.
i just can't take this anymore! i keep seeing it out of the corner of my eye. (he turns it around so that shaun is now facing the wall.) that's better... it looks more interesting now, more artistic.
as don sits down again, i ask if he can describe the methods he uses to compose his music.
i get a flash. i know exactly what i want - like a painting - and then play it on a piano, play it on a pencil, i mean the percussion, on a table, you know, anything. and then have it on tape. tape is really important. it's as important as ink is with paper because - you see - i have so many things in my head - god, i mean: not ín my head, they just cóme into my head. i don't keep thoughts, but they come in whenever i need them. i've never had it fail me yet.
then i would take the tape of what i had done, say the piano, then as i would play the tape and the musician would hear it, i would say: 'well, this is how i want that shaped: (he begins drawing)'. say i wanted that shape, i could draw it and still have it on the tape where they could hear it. then visually ánd hearing it they can see what i'm talking about, the shapes, movements. it really works, i get very close to éxactly what i want. that's very important to me, to have it be éxactly what i wanted.
it must have been hard for all of the musicians you've worked with to master the complex structures of your music.
it is hard, it really is. it's very difficult - and for not too much money either, because - uh - the thing that's really bad about creating with a lot of people like that is the gúilt of the fact that they don't make the móney that they shóuld for playing it. because not that many people like it.
still i'm sure your musicians would rather play with you than play crap just to make money.
well, i hope so. and then the words are informative. i mean, it might make people think about the way it is, and maybe try to change it. like [cites 'space ape couple' off 'lick my decals off, baby':] 'space age couple / why don't you flex your magic muscle? / why don't you cultivate the grounds / they're the only ones around'. that's ít. 'hold a drinking glass up to your eye / after you've scooped up a little of the sky / and it ain't blue no more / what's on the leaves / ain't dew no more'.
people have gotta wake up. they could dó something about it. it's awfully bad right now, but they could do something about it if they used their technology to do something about cleansing this place. it would take a long time for it to go back the way it really was, but it would start.
on the back of the new album is a legend which reads: 'dedicated to all conservation and wildlife preservation organizations everywhere'...
i hope that it does some good. if nothing else, if nobody likes it or anything, the thing is that maybe somebody will see that and think about it. that's very important to me. animals are wonderful, so wonderful.
all the new magic band members share these concerns, don tells me, as he begins to talk about the considerable talents of each musician. when he was speaking about guitarist richard redus, his rap took an astonishing hairpin curve which happened so fast that i didn't discover it until i was transcribing my tape...
richard, he's brilliant. he's a brilliant man. he wears no shoes, even in the winter. never. never wears shoes. isn't that something? think about that, think about walking down fifth avenue without shoes - in the winter!
and you know what else he does? have you ever heard of adrian desmond, he wrote 'the hot-blooded dinosaurs'? you gotta read that one - i mean: you don't gótta do anything, i'm not saying you gotta, you know, i mean (goes into old-timer's voice:) 'hey, you gotta read that!'. (normal voice:) an american saying - you know what i mean? i'm definitely an american, but i love it with america's - uh, you know, i ám an american. i mean, i'm from america and i enjoyed the constitution. i mean, all of those hip people like benjamin franklin.
do you know how smárt he was? wow! when i go to philadelphia i stay very near his grave. there's a holiday inn there - eeeyuhh, heh, heh - but there ís, and it's right there, and his grave, where he's buried is right just... i usually stay in the same window, and i swear that the energy, i mean, my háir curls - and i have straight hair! and not out of fear, certainly. maybe admiration. but then again i wonder, do you know what i mean? the idea that he had been there... (chuckles.) and not only that brilliant, but lóoked that good. i mean, don't you love the way he looked? like a dolphin. there's been some smart people, all of those smart people, together at that one time, with those great thoughts. i wish that people had gone along with them.
when we get back to the music, i remark that one of the reasons i love it so much is that it's not all laid out for the listener, that it forces the listener into doing some of the work.
that's the way it shóuld be, because if somebody just sits and fixates, it's no good. like this disco stuff, that beat: (strikes his chest) boom, boom, boom, boom. that's too bad. i mean, i've tried to change that for 13 years...
i remind him that he has influenced a lot of the new rock people and mention three who have said so in print: devo, pere ubu and johnny rotten (sex pistols - t.t.):
johnny? i saw him at every concert i did in england. i remember seeing him. i had never met him but he called me in england and he seems to be quite an intelligent person. i enjoyed talking with him.
much more was said in the course of our conversation, but not all of it seemed relevant to the printed page. this has been an attempt at an impressionistic verbal portrait of captain beefheart, a man who - by his very nature - resists definition and categorization. if you wish to know more, you'll just have to listen to his music and flex your magic muscle.
click clack back to the history or return to the power station
captain beefheart electricity
as felt by teejo


text:
The earliest known attempt to invent a sewing machine was made in London in 1790 by Thomas Saint who designed a machine for sewing leather.
In 1818 an American churchman, John Adams, and his partner John Knowles, produces a crude sewing device.
The needle with a hook point, first introduced by Thimonnier, a Frenchmen in 1830, for the purpose of forming the chain-stich, has given rise to the most varied construction of tambour-stitch machine.
It had similarities to a modern machine, with an overhanging arm to carry the straight vertical needle, and a simple form of presser foot held the horizontally supported fabric in position, ready for stitching.
In 1842 the first American patent was issued, to John Greenough, for an invention actually called a 'sewing machine'.
In 1873 Isaac M. Singer established his sewing machine factory on Newark bay. The factory was built on a 32 acre plot and once had a workforce of six thousand.
The I.M. Singer & Co. was the first American multinational company.
The invention of sewing machine


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After the dark and magical Harry Potter, Daniel Radcliffe's next role is set to be completely different.
As the actor prepares for his debut musical theatre role on Broadway, the 21-year-old has given a sneak peek of his dancing skills in a new photoshoot for U.S. Vogue.
The English star shares the stage with three scantily-clad showgirls in a stunning shoot by acclaimed photographer Leibovitz at the Theatre Royal Drury Lane.
Ready to move: Daniel Radcliffe dances on stage at the Theatre Royal Drury Lane in a Annie Leibovitz shoot for Vogue magazine to promote his upcoming role in the Broadway production of How To Succeed In Business Without Really Trying
In a departure from his role as the bespectacled wizard, Radcliffe will play the lead role of J Pierrepont Finch, a bow-tie wearing window cleaner who works his way up the corporate ladder thanks to a self-help book.
It will also be his first appearance on the Broadway stage since he starred in the 2008 production of Equus.
Moving on: Radcliffe has finished filming the Harry Potter films with Rupert Grint and Emma Watson
He said: 'I think I would be concerned by now had I not done Equus and My Boy Jack.'
Despite his international fame, it was somewhat out of his comfort zone to be posing for fashion bible Vogue.
He admitted: 'I'm always very surprised when I find myself at a photoshoot for Vogue. I'm out here with three indescribably beautiful supermodels and I'm just going, "(I'm) 5ft 5... pale... how on Earth did I get here.'
Giving audiences a hint of what to expect when the show opens, he said: 'The singing's alright and I've been having lessons for about three years now.
'Dancing is a different thing, my dancing pedigree is very good because my parents were very good dancers. My dad had one of the Northern Ireland ballroom dancing championships when he was about 15 or 16 and my mum won the all England for ballet when she was about 12, and so you would think it would be there in the genes... but it never showed up.'
How To Succeed In Business Without Really Trying, written by composer Frank Loesser, originally opened on Broadway in October 1961.
The musical follows the fortunes of window cleaner Finch as he attempts to work his way to the top of the World Wide Wicket company.
But matters are complicated by rivalry from the president of the company's nephew, as well as his budding romance with secretary Rosemary.
The show was a huge hit at the time, running for nearly four years and winning seven prestigious Tony theatre awards.
The show has since been revived a number of times, most recently in 2005 with Matthew Broderick and Will And Grace star Megan Mulally in the lead roles.
• Previews of How To Success In Business Without Really Trying are scheduled to begin at the Al Hirschfield Theatre on February 26.


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By no means a bad power metal album, but just not the masterpiece some claim it to be.
One of the more exciting new bands on the power metal circuit (at least in the beginning), Australian metallers Black Majesty impressed me a lot with their 'Sands of Time' debut a number of years ago. Something about their more guitar-based approach, somewhat progressive, with a cool Jag Panzer meets HammerFall vibe was what seemed to set them apart from their fellow countrymen, bands such as Dungeon and Pegazus who had more in common with the traditional schools, rather than with what was going on in Europe at the time. Over the years, Black Majesty have shed a lot of their progressive leanings for a more melodic, straight-forward sound, something that seems to have stuck, as it's all that permeates the band's fourth album, the much lauded 'In Your Honour', though unlike their previous works, I just can't get too excited about it.
The problem with these guys lies somewhere in their production. Their albums always have a warm, almost analogue sound, something that doesn't benefit the stylish flavour of their material. Musically, the band continues to proliferate their Iron Maiden leads and Helloween-esque melodies, but there is nothing new here from the band, nothing that grabs and excites. True, punchy opener 'Far Beyond' and the catchy 'Witching Hour' are essential additions to the band's discography, but nothing found within the ridges surpasses the grace found on either 'Sands Of Time' or their blistering sophomore effort 'Silent Company'. Truth is, the band haven't budged an inch since their second record, and it looks like innovation is not part of their future plans. 'In Your Honour' is by no means a bad power metal album; it's just not the masterpiece some claim it to be. Puts one in mind of the latest Excalion, when you think about it.
Bruce Turnbull


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The mission of the Greater Altoona Career and Technology Continuing Education Office is to provide occupational specific education to adults in collaboration with business, labor, and community in preparation for the demands of the 21st Century.The Continuing Education Office further believes that vocational technical education should be an integral part of lifelong education with a dual purpose: (a) to provide individuals with the skills and knowledge needed to enter employment or to pursue further education; and (b) to assist in the economic development of the area by providing business and industry with productive, adaptable, and competent workers.
The Continuing Education Office subscribes to the philosophy that it can enrich an ever-expanding community by providing educational programs to help each individual student grow as a person, as a worker, and as a citizen. By accepting all persons, each at their respective level of development, the GACTC asserts that it believes in the best possible education for all Americans, regardless of race, creed, national origin, and past development.This institution recognizes that an ever growing number of persons are in need of experiences that will allow them to compete in and contribute to the rapidly changing technological society. To this end, the Continuing Education Office believes that it must provide an occupation oriented education for the training and retraining of both young and mature adults in order to meet its responsibility to local, state, and national needs for skilled workers who are sufficiently flexible to respond to changing demands and sufficiently creative to find new means of meeting these demands.The Continuing Education Office believes that education is a continuing need for every citizen. It stands ready to provide training and enrichment for all members of the community, both through formal instruction in all areas of adult needs and interests, and through informal means by its involvement in community affairs. The area school firmly maintains the position, both through its philosophy and its action, that education should be the leaven in the loaf of community life.
In sum, the Continuing Education Office believes it is uniquely fitted through its diversified, yet united programs to contribute to the development of the individuals within the geographic area it serves and thus, the development of the area itself. It believes that, to function in a society marked by rapid technological advance and vast diversification and specialization, the individual needs to acquire an understanding both broad and deep of the great inherited body of knowledge and the democratic tradition. It believes that it has a responsibility to help all people toward the fulfillment of their desire to be "more intensely human, more greatly good.


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Natasha lying on her side, knees bent, she spread her buttocks hand, watching him.
Alex began applying cream to her. Nat moaned with pleasure.
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- Generally not sure, I know well that will hurt – doubting said Natasha, and there is already added resolutely. – But, I now this probably want!
- What do you want? Yahoo hot girls sex video chat.


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Data Validate a Shorter, More Patient-Friendly Outcomes Assessment for Revision TKA
Researchers from Hospital for Special Surgery (HSS) have confirmed that a significantly shortened, 7-question patient survey on pain, function, and quality of life is a valid and efficient tool for assessing patient outcomes following revision total knee arthroplasty (TKA).
The findings were presented at the 2017 Annual Meeting of the American Academy of Orthopaedic Surgeons.
The previous commonly used knee replacement survey was 42 questions long, often leaving physicians with partial, unusable information. The shorter survey, known as KOOS JR. (Knee Injury and Osteoarthritis Outcome Score), and its hip replacement counterpart, HOOS JR., have already been adopted for Medicare's primary total joint replacement bundled payment program.
Research presented by HSS provides peer-reviewed data demonstrating that KOOS JR. is a valid outcomes measure for knee replacement surgery.
"At HSS, we are continually improving how we measure outcomes and KOOS JR. is a direct result of these efforts," said Alexander McLawhorn, MD, MBA, an orthopedic surgeon at HSS.
"We saw a need for a shorter, more patient-friendly survey in an area where outcomes data are essential to improving quality of care. In fact, knee replacement revisions, which are more complex than primary knee surgery, are under-studied in this regard."
Revision TKA procedures have doubled over the last 10 years, and are expected to grow 600% between 2005 and 2030. Approximately 700,000 primary knee replacements are done in the US, and approximately 10% may require a second operation within 15 to 20 years.
"With the influx of surgeries expected over the next 5 to 10 years, it is essential that we deepen our understanding of revision knee replacement outcomes," said Steven Haas, MD, chief of Knee Service at HSS.
"This shorter patient survey will help the orthopedic community obtain necessary measurement information while minimizing the burden on patients and data collection administrators."
For the study, HSS researchers looked at the results of 314 patients who underwent revision TKA between May 2007 and December 2011 and completed KOOS JR. patient–reported outcome measure surveys before surgery and 2 years later.
The KOOS JR. measures proved to be as valid, and have as much internal consistency, external validity, and other measures of reliability, in determining outcomes for these patients as they did in patients who had primary TKA.
"There are increasing incentives and requirements from the government and private insurers for providing patient-reported outcome measures," said Stephen Lyman, PhD, director of Healthcare Research Institute at HSS.
"This short form should reduce the burden and fatigue of patients in busy clinical settings when gathering this information. This study supports extending the use of KOOS JR. to patients having revision knee replacements."


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Mitchell, L (2017) 'Treasuring things of the least': Mary Hope Greg, John Ruskin & Westmill, Hertfordshire. Guild of St George Publications, York. ISBN 978-0-9955915-1-6Full text not available from this repository. (Request a copy)
Mary Hope Greg (1850-1949) was a
lifelong follower of John Ruskin, and
a Companion of Ruskin's Guild of St
She was a passionate supporter of museums
during the early 20th century, giving collections of
domestic crafts and children's toys to Manchester
City Art Galleries and London's Bethnal Green
She established her own museum in the
Hertfordshire village of Westmill as a memorial to
her late husband, fellow collector and local
landowner Thomas Tylston Greg. She later set up
the T&M Greg Trust to preserve land and property
in the village for future generations. She was also
a keen amateur naturalist and watercolour
painter, recording the changing seasons of the
Hertfordshire countryside in her nature diaries,
now in the collections of the Guild. She did most
of this between the ages of 70 and 99.
Until recently, however, little was really known
about her life. In this talk, Liz Mitchell shares the
latest findings of her PhD research. She provides
fascinating insights into the development of Mrs
Greg's dedication to Ruskin from her early life in
Liverpool as a member of a family of
wealthy philanthropists, through to the diverse
achievements of her old age.
|Item Type:
|Faculty / Department:
|Faculty of Arts & Humanities > Fine and Applied Art (up to 30th April 2018)
|Depositing User:
|Liz Mitchell
|Date Deposited:
|26 Feb 2018 15:53
|Last Modified:
|26 Feb 2018 15:53
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We recognise the importance of supporting young people who are considering a role in the arts as a profession. As a result we have a commitment to support up to four work placements per year. These can be located across our organisation in a wide range of departments.
Placements usually last 1 week and offer participants a chance to work with various departments, including Creative Learning, Box Office, Front of House, Development, Marketing and Production.
If you are interested in applying for a work experience opportunity at Macrobert Arts Centre please get in touch with our Creative Learning Team.


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Posts Tagged 'books'
So, I have an interest in blacksmiths. I will admit that Perrin Aybara is top of my list of fictional characters that I'm in love with. I'm sure 75% of it, is that blacksmiths are like the green beret of making things, and I enjoy watching a project come together. Probably the rest of it is the fact that they, by way of their profession, naturally seem to be in control of themselves and the world around them. I guess in an era of impulse control issues, someone who is the antithesis of that type of behavior is attractive to me.
So at the library today I didn't have anything specific I was looking for, so I wandered and did random searches on the computer. (Am I the only one who misses a proper card catalog, by the way? It seemed so much more straight forward than trying to find a computer and navigating the website, especially since my library is part of a network and any books you find may or may not be at that branch. Anyway.) One of the searches I did was for "blacksmith" under fiction.
Happily, one of the books on the first page was "Black Blade Blues" by J.A. Pitts. The description reads thusly:
"Sarah Beauhall is a young woman who has loved fire and the lure of the forge all her life. She is now living her dream as a blacksmith, by day creating works that are practical and fanciful, and working nights as a props manager for low-budget movies to pay the bills.
When Sarah's favorite sword is broken on the set of a new movie, it sends the director into fits, and Sarah agrees to repair the blade to avoid reshooting scenes. One of the extras – who claims to be an actual dwarf – shows up at her forge and offers to help Sarah with her destiny.
That's when things start to get weird. Could the sword really be magic, as he claims? Are dragons really living among us as shape-shifters, and are evil power brokers controlling our world? And why would he think that Sarah would be willing to kill a Portland investment banker just because he says that the guy is one of those supposed creatures?
She refused to believe…and then one of the dragons makes its move. Suddenly, what was unthinkable becomes all too real.
And Sarah will have to decide if she can reject what is safe and become the heroine that is needed to save her world."
The short blurb that was on the library's computer also mentioned that Sarah is a member of the Society for Creative Anachronism. I was intrigued.
As it was pouring out, I waited in the car and started the book before going in to my next errand. (Amusingly, I was waiting for it to stop raining so I could go buy a gallon of water. Lol) I'm now seven chapters in.
Not only has the SCA been mentioned a couple of times, but also Renn Faires, conventions, and the like. So we'll have to play the "Was this written by a SCAdian?" game while I read the book. Obviously this is an author who has heard of these things, and has a passing knowledge (enough so far to know that SCAdians don't use real swords, anyway), but we will have to see!
Aside from looking for the things that had initially captured my interest, I have to say that I can tell this is going to be a quick read. Not that it's short. Just shy of four hundred pages, it's a decently sized book, but the writing style is easy to follow, and so I'll probably fly through it. The characters so far have been introduced smoothly and reasonably, and I don't really have any questions about the plot. Except, perhaps, which group Black Briar is associated with, since Sarah seems to be involved in everything nerdy in order to sell her swords.
I'm loving that the main character is a female blacksmith. That just tickles me. Especially since it was written by a male author. I am kind of missing the apron in the cover art, but I guess I can forgive that. What's the leather collar for though? I'm pretty sure that won't protect her from anything a forge might throw at her.
Perhaps it will become apparent as I continue reading.
Want to read it? Click here to go through the author's page: http://www.japitts.net/buy-the-books/ I'm not sure if he gets some kind of kickback if you buy it through their website, but it couldn't hurt!
As a side note, I found this receipt in the book after I got it home. I'm always interested in what people use for bookmarks, and what those things might say about them. Looks like this person was travelling while reading, and bought a newspaper and a bottle of water at LAX back in July. Neat!
Strawberry Coffee Cake
Posted August 3, 2012on:
This coffee cake is not my recipe. In fact, it's the first coffee cake I've ever made. I got the recipe from a fabulous blog I love, called Diamonds For Dessert. Seriously, if you love to bake, you need to follow Susan. And I'm not just saying that because she also loves Ender's Game and Back to the Future.
It's just good stuff.
I made a red velvet/cream cheese frosting cake for a friend's low-key wedding a few days before this. So I had a ton of strawberries and cream cheese left, because I can't seem to stop myself from buying everything on the shelves for whatever it is I need to bake. I guess I've not gotten enough a few too many times. Don't ask how many boxes of light brown sugar I have. I think it would give you diabetes just looking at it.
First, you mix up your crumb topping. I've done this before; I love crumb topping. It makes me happy just to see pictures of crumb topping!
Then you mix together all the rest of your ingredients in that way that you do when you're baking. (Wet together first, then add the dry to the wet.) I'm not going into too much detail, because it's not my recipe. Also, look at my lovely Sunbeam Mixmaster. That poor thing. I think if you look closely enough you can see the smoke coming out of the vent from the severe overuse I put it through. I've had it for about 10 years, but if mixers could talk, he'd say he felt 90, I'm sure. (Yes, he, for the same reason that ships are male. ) Allow me to quote obnoxiously for a moment:
"A ship is alive, and he is like a man, with a true man's heart. Treat him well and care for him properly, and he will fight for you against the worst sea. He will fight to keep you alive even after the sea has long since given him his deathstroke. Neglect him, though, ignore the small warnings he gives of danger, and he will drown you in a flat sea beneath a cloudless sky." Jorin din Jubai White Wing, pg 296, The Shadow Rising, Robert Jordan.
So once you have your batter mixed, put half of it in the bottom of your greased pan and slather it with jam. Not only is it tasty, but it's fun to say slather. Then line up your strawberries in a covering layer. Then put the rest of your batter on top of that and smoosh it around until it covers all the strawberries. The directions say you can use a spatula or your fingers, but trust me on this and just skip the spatula.
Yummy crumb topping is next! Bake it all up and you get a lovely, light and fluffy cake that is absolutely scrumptious. Since I had more leftover strawberries (seriously, guys and gals, I have a PROBLEM.), I put two little slices on each square. This thing held up surprisingly well to sitting out on my butcher block, traveling in the car in plastic baggies and being passed around to various people!
1. Coffee cake does not have coffee in it. I really thought that! It's the sole reason why I have never even looked at a coffee cake recipe until now!
2. I should possibly not type blog posts when I'm sleepy. I get a little silly.
3. The picture below is while making the red velvet cake. There is a very good reason why I only do my baking when my husband is not at home:
Tackling the Car
Posted July 25, 2012on:
I didn't mention it last week when I posted about fixing up my craft room, but I started following this blog on organizing your home. The site has a 52 week challenge, but you don't have to start it in January, you can jump in any time. Many thanks to Taylor at Home Storage Solutions 101 for hosting the challenge.
Well, it so happens that last week was organizing your crafting space, which I took as a sign that I should stick with this plan for a while and see where it takes me.
This week's challenge (they're posted on Mondays) is organizing the car. Admittedly, I don't have much in my car right now, since it's not running, but there was still some unnecessary clutter. By which, I of course mean books.
So, I followed the steps. Pull everything out, sort and decide what goes back, what gets thrown away, and what just needs to go elsewhere.
Now in my glove box, all I have are the car manual and other paperwork, and some napkins. I have a trash bag that's tucked into the storage pocket in the backseat, and some wet wipes up under the dash in a weird space that you can barely see. I'm not sure why they built it this way, to be honest.
Anyway. I had this jar lying around, and it fits perfectly in the cup holder, so I decided to put it there and use it for loose change. In my center console, I have all my chargers and other car cords.
Everything else is in a plastic tub in the trunk. It's not the most crafty way to store all my car supplies, extra hair and tooth brushes, puzzle book, CD player and sewing kit, but it does its job. Everything that's not the tote in the left hand corner is what's going into the house to be put away.
After a quick vacuum and wipe down, it looks so much nicer!
Things I learned:
1. I think I'm already finding that the steps to organizing anything are basically the same.
2. Some of these weekly challenges are going to be easier than others. My craft room took 7 days. This took me 20 minutes.
Next week, it looks like we're tackling pet supplies. I'm sure Teddy Bear will be thrilled.
~ Rosie
p. s. Since someone may ask, the origami peacock was made by a former coworker of mine who has since passed away. It moves around my car as the whim takes me.


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General Question
Why do they want to do surgery?
Asked by Mitsu_Neko (762) September 12th, 2008
I bent my thumb on my right hand backwards on 8/27 at work. The boss waited a week to fill out an accident report, so on 9/2 I saw a doctor who put it in a cast like thing and then on 9/8 they took it off and told me don'tstrain but my hand was better. I went to work the next day and my hand was aching and making me cry worse than when I first hurt it. The cold makes it hurt so bad that I want to scream.
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World Heritage Day: Five must-visit sites in India
On World Heritage Day, HT City lists five popular heritage sites in India.travel Updated: Apr 18, 2015 17:55 IST
From the magnificent Taj Mahal, architectural ruins of Hampi, captivating Badami cave temples in Karnataka to the historic Jallianwala Bagh in Amritsar -- India, as we know, is rich in culture, heritage and history. The glorious past of the country is truly reflected in the monuments and its architecture.The lure of these innumerable heritages sites is such that people from all across the globe travel to India to get a first-hand experience. "Over the last couple of years, there has been an increase in the number of foreign tourists arriving in the country. Heritage tourism India has registered an immense growth in the last few years, ever since additional initiatives were taken by the government of India to boost India's image as a destination for heritage tourism," says Ranjeet Oak, chief business officer-Holidays, MakeMyTrip, about heritage tourism in the country.
On World Heritage Day, HT City lists five popular heritage sites in India.
Taj Mahal
As most travellers say, it's a dream come true moment when you visit the Taj Mahal. It's best to take an authorised guide for the tour of the Taj. If you are lucky enough, you can also have the good fortune of seeing the Taj Mahal, one of the Seven Wonders of the World, on a moon-lit night. According to Wikipedia, this UNESCO World Heritage Site in 1983, attracts some three million people every year. Khajuraho Temples
Known for its bold and erotic sculptures, detailed architecture and artistic carvings, Khajuraho temples, Madhya Pradesh, built by the Chandela kings, continue to attract thousands of tourists every day. Make sure you don't miss the light and sound show at this UNESCO World Heritage Site. Ajanta and Ellora Caves
You need to see it to believe it. These rock-cut caves, situated in Aurangabad district of Maharashtra, will mesmerise you. While Ajanta has 29 Buddhist caves dating from the 2nd century BCE to about 480 or 650 CE, the Ellora Caves has 34 caves with Buddhist, Jain and Hindu rock-cut temples. The architectural brilliance, artistic sculpture and paintings on the caves will certainly hypnotise you. Red Fort
The majestic marble jharokha (canopy) at Diwan-i-Am (hall of pubic audience) at the Red Fort, Delhi, will transport you back to the Mughal era where emperor Shah Jahan and later his successors heard the grievances of the public. This UNESCO World Heritage Site is an experience in itself and will take at least two hours to see and understand the history of the place. The light and sound show at the Red Fort, constructed by Shah Jahan, is another must see event. Mahabodhi Temple
Buddha was enlightened here. People from all over the world come to Mahabodhi temple at Bodh Gaya to pray. The ambience is meditative and serene. It's believed that in 250 BCE, 200 years after Buddha attained enlightenment, Emperor Asoka came to Bodh Gaya and built the Buddhist temple. The holy Bodhi tree lies on the western side of the temple. This UNESCO World Heritage Site should also be on your must-visit list if you are a heritage lover.
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- Ian Lobas
The 5 Key Ingredients of Leading a Movement with Eiji Morishita- EP 54
Activism is on the rise, and you may be called to do your part and join—or perhaps lead—a movement that you are passionate about. But what, exactly, makes a movement successful? How do you gain the courage to follow the call? And how do you learn to speak with spiritual authority so that people will listen?
Eiji Morishita is the founder of Movement Makers, an organization that seeks to empower leaders in starting meaningful movements that impact millions of lives. He is passionate about igniting souls to 'step into their calling and share their wisdom without apology.' A catalyst for several movements himself, Eiji was an integral part of the spread of the Sushi Movement in North America and an effort to build schools in Guatemala. His genius lies in creating fun, easy and purposeful businesses.
Today, Eiji joins Emerald to explain why he is drawn to movement makers who focus on social impact. He shares the value in trusting the call, even if your vision is not perfect the first time out. Eiji also offers his take on the rise of activism as a societal trend, explaining why making the change is more important than getting credit for leading a particular movement. Listen in to understand the role of faith in creating a movement and learn the five key ingredients of becoming a movement maker!
What You Will Learn
Eiji's insight on the resistance you may feel toward your calling
Eiji's pull toward leaders who focus on social impact
How to follow the call despite having an imperfect vision
Eiji's role as a Generator who waits to respond, rides the wave
How to recognize and answer the call each time it comes up
Eiji's take on the rise of activism as the #1 societal trend
The importance of personal development in starting a movement
How to 'do your part' by tying in to a larger, global movement
Why making the change is more important than getting credit
Why freeing yourself up financially is Step One in leading a movement
The five key ingredients of a movement
Spiritual development
The three crucial components of demonstrating faith
Positive expectancy
Grateful in advance
Express joy in actions
Connect with Eiji Morishita
UN Sustainable Development Goals
Connect with Emerald GreenForest
Email email@example.com
This episode is sponsored by the Creative Age Consulting Group. Men - Is it time NOW for you to make your mark? Visit timetomakeyourmark.com to apply for an invitation-only consultation.
#EijiMorishita #MovementMakers #purposefulbusiness #Activism #socialimpact #personaldevelopment


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Author Affiliations
- Martin Kropff1⇓,
- Honorata Giongco Baylon2,
- Jens Hillengass3,
- Tadeusz Robak4,
- Roman Hajek5,
- Peter Liebisch6,
- Stefan Goranov7,
- Cyrille Hulin8,
- Joan Bladé9,
- Tommaso Caravita10,
- Herve Avet-Loiseau11,
- Thomas M. Moehler12,
- Claire Pattou13,
- Lela Lucy13,
- Elisabeth Kueenburg13,
- Axel Glasmacher13,
- Robert Zerbib13 and
- Thierry Facon14
- 1Hematology/Oncology, University of Muenster, Muenster, Germany
- 2Blood & Marrow Transplant Center, St. Luke's Medical Center, Quezon City, Metro Manila, Philippines
- 3Internal Medicine V - Haematology/Oncology, University of Heidelberg, Heidelberg, Germany
- 4Department of Hematology, Medical University of Lodz, Lodz, Poland
- 5Department of Internal Medicine and Hematooncology, Faculty Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic
- 6Klinik für Innere Medizin II, Johanniter-Krankenhaus Duisburg-Rheinhausen, Duisburg, Germany
- 7University Hospital for Active Treatment "St. George", Plovdiv, Bulgaria
- 8Centre Hospitalier Universitaire of Nancy-Brabois, France
- 9Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
- 10Department of Hematology, St Eugenio Hospital, Tor Vergata University, Rome, Italy
- 11Hematology Department, Hopital de Nantes, Nantes, France
- 12Hematology, Oncology, Rheumatology, University of Heidelberg, Heidelberg, Germany
- 13Celgene International Sàrl, Boudry, Switzerland
- 14Maladies du Sang, CHU, Lille, France
- Correspondence: Martin Kropff, MD, Department of Medicine, Hematology/Oncology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, Muenster D-48129, Germany. Phone: international +49.251.8347590., Fax: international +49.251.8346019. E-mail: martin.kropff{at}ukmuenster.de
Background Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.
Design and Methods We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.
Results In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.
Conclusions Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569)
Current treatments for multiple myeloma (MM) offer patients periods of remission in response to therapy, followed by relapse. Patients typically require multiple lines of therapy which are separated by progressively shorter periods of response.1,2 Nevertheless, survival rates in MM patients have improved in recent years, due in part to the introduction of novel therapies, such as thalidomide, lenalidomide, and bortezomib.3
To date, no randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed and/or refractory MM. However, two systematic literature reviews have summarized the findings from phase II studies evaluating thalidomide in this setting.4,5 Glasmacher et al. reviewed the results from 42 clinical trials involving a total of 1674 patients; the dose of thalidomide used in these studies varied from 50 to 800 mg/day.4 Overall, thalidomide monotherapy produced a response rate of 29.4%, including a modest complete response rate of 1.6%. Median survival was 14 months (range, 5–58 months) and 1-year survival was 60%. Similar results were reported by Prince et al., who assessed a more restricted subset of nine large published trials involving a total of 712 patients.5 They found a response rate of 29.8%, including a complete response rate of 1.6%. Reported 1-year overall survival rates ranged from 49% to 86%. These results are generally comparable to those achieved with dexamethasone monotherapy,6,7 which is considered a standard treatment option for patients with relapsed and/or refractory MM and has been used as a control arm in several recent randomized trials.8–10
The optimal dose of thalidomide when used as monotherapy in this setting is unknown. In the studies included in the analyses mentioned above, doses of thalidomide ranged from 50 mg/day to 800 mg/day. In 2005, based on a request from the European Union (EU) regulatory authorities, we initiated the first prospective, randomized controlled trial to compare the efficacy and safety of thalidomide, at three different doses, with dexamethasone in patients with relapsed and/or refractory MM who had received one to three prior therapies.
Design and Methods
In order to determine the optimal dose of thalidomide monotherapy in patients with relapsed and/or refractory MM, as requested by EU regulatory authorities, we conducted a randomized, open-label, parallel-group, active-controlled, four-arm, phase III trial. The primary objective was to compare the time to progression (TTP) in patients with relapsed and/or refractory MM treated with three different doses of thalidomide (100, 200, or 400 mg/day) with the TTP in patients treated with dexamethasone, and to select the optimum dose of thalidomide in terms of time to progression and toxicity. Secondary objectives were to compare each dose of thalidomide with dexamethasone in terms of the following outcomes: response rate, progression-free survival, and overall survival. The safety of thalidomide and dexamethasone were also assessed; particular attention was paid to the evaluation of neuropathy in patients treated with thalidomide. The final protocol was approved by independent ethics committees at each participating center, and the trial was designed and monitored in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient prior to entering the study.
Eligible patients were aged 18 years or more, had received one to three prior lines of therapy for MM, and required additional therapy due to disease progression. Patients with secretory MM and measurable monoclonal protein (M-protein) in serum (>10 g/L of immunoglobulin [Ig] G M-protein and >5 g/L IgA M-protein) or urine (≥200 mg/24 h) were eligible. Patients with the rare subclasses of IgD, IgE, or IgM were allowed to participate if the level of M-protein was >5 g/L in the serum or ≥200 mg/24 h in the urine; patients with Waldenström's macroglobulinemia were excluded. Other inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status scores of 0, 1, or 2; and life expectancy of more than 3 months. Patients had to be willing and able to adhere to the study visit schedule and other protocol requirements, and provide written informed consent. For 4 weeks before starting treatment, during treatment, and 4 weeks after the last dose, women of child-bearing potential had to agree to use two methods of contraception: one effective (i.e. hormone therapy, tubal ligation) and one barrier (i.e. latex condom, diaphragm). Men had to agree to use barrier contraception (latex condom) when engaging in sexual activity during treatment and for 4 weeks after the last dose.
Exclusion criteria included: serum creatinine levels of >3.0 mg/dL; severe cardiac dysfunction (New York Heart Association class III or IV); grade 2 or higher peripheral neuropathy; or prior treatment with thalidomide or lenalidomide.
Study design and treatment
Screening tests for eligibility were performed no more than 28 days before the first day of treatment for invasive tests (i.e. electrocardiogram, nerve conduction studies, skeletal survey, and bone marrow collection) or 14 days for laboratory evaluations. Patients were stratified according to the number of prior therapies received (1 versus 2–3), prior autologous stem-cell transplantation (yes versus no), and disease stage based on the International Staging System (ISS; stage I or II versus III). Patients were randomized in a 1:1:1:1 fashion to dexamethasone (DEX) or thalidomide given at a dose of 100 mg/day (THAL 100), 200 mg/day (THAL 200), or 400 mg/day (THAL 400) for twelve 28-day cycles. All study medication consisted of capsules or tablets to be taken orally by patients at home. Treatment was administered in an open-label fashion. Dexamethasone was given at a dose of 40 mg/day on days 1–4, 9–12, and 17–20 of each 28-day cycle for the first four cycles, and then on days 1–4 only for the subsequent eight cycles. Thalidomide was given daily at the appropriate dose for 12 cycles. Treatment beyond 12 cycles was left to the investigator's discretion.
Patients were assessed at baseline and every 4 weeks thereafter until week 48. A visit to confirm disease progression was conducted within 1–4 weeks after the first evidence of disease progression. A final visit was scheduled 30–33 days after the last dose had been administered, and the follow-up period began immediately after this visit. During follow-up, patients were assessed every 6 weeks until disease progression and every 12 weeks after disease progression was observed. All patients who discontinued treatment for any reason other than disease progression or death — including patients who completed the planned 12 cycles of therapy — were followed for disease progression and/or survival until study closure. To minimize bias in this open-label study, response and TTP were also assessed by an independent review committee that was blinded to the type of treatment each patient received. Study closure was triggered when progression had occurred in 160 patients in the DEX and THAL 400 groups, as documented by the independent review committee, and the last patient's end-of-treatment visit was completed.
Assessment and statistical analysis
The primary end-point was TTP, defined as the time from randomization to the date of first documentation of progressive disease, according to the European Group for Blood and Marrow Transplantation (EBMT) criteria,11 as determined by the independent review committee. Patients without documented progression during the treatment or follow-up periods were considered a censored observation and were censored at the date of their last documented progression-free disease assessment. Secondary endpoints included response rate (complete response plus partial response), progression-free survival, overall survival, and duration of response. Response was assessed using EBMT criteria at each cycle and confirmed at 8 weeks.11 Progression-free survival was defined as the time from randomization to the time of first documentation of disease progression or death, and overall survival was defined as the time from randomization to the time of death from any cause.
The average daily dose was calculated as the total dose received during the treatment period divided by the number of days that the patient was scheduled to receive a dose. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Neuropathy was assessed using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity questionnaire and nerve conduction studies.
Additional exploratory analyses were performed for TTP within the following subgroups: number of prior therapies (1 versus 2–3); prior autologous stem cell transplantation (yes versus no); ISS stage (I or II versus III); age (<65 versus ≥65 years); ECOG performance status (0 versus 1 versus 2); geographic region (EU versus non-EU); chromosome 13 deletion (yes versus no); gender (male versus female); baseline serum β2-microglobulin (≤3.5 versus >3.5 mg/L); and cytogenetic risk (standard versus high risk). High risk was defined by the presence of chromosome 17 deletion and/or translocation t(4;14). Cytogenetic profiles were determined in a central laboratory based on samples collected during screening.
The target accrual was 496 patients (124 in each treatment arm). The primary analysis consisted of three ordered comparisons of TTP with a stratified log-rank test, each conducted at a two-sided alpha level of 0.05. Stratification was based on the three factors used to stratify the randomization (number of prior therapies, prior autologous stem cell transplantation, and ISS stage). The first comparison was between the DEX and THAL 400 groups. If this comparison was not statistically significant, then the analysis was to be stopped and the conclusion would be that none of the three thalidomide doses provided superior TTP compared with dexamethasone at an alpha level of 0.05. If this first comparison was statistically significant, then the second comparison (DEX versus THAL 200) was to be conducted. If this comparison was not statistically significant then the analysis was to be stopped and the conclusion would be that TTP differed significantly at the overall 0.05 alpha level between DEX and THAL 400 only. If the second comparison was statistically significant, then the third comparison (DEX versus THAL 100) was to be conducted. If only one thalidomide group demonstrated significantly superior TTP compared with dexamethasone, it would be considered the optimum thalidomide dose. If two or more thalidomide doses provided superior TTP compared with dexamethasone and were considered equally efficacious (difference in median TTP <6 weeks), then the dose with the lowest toxicity proportion (defined by the proportion of patients with a dose reduction, interruption, or discontinuation) was to be selected as the optimum dose. If two or more thalidomide doses were considered equally toxic (toxicity proportion within 15% of the lowest toxicity proportion achieved), the lowest dose was to be selected as the optimum dose.
Patients' characteristics
Between March 2006 and January 2009, 499 patients were randomized (intent-to-treat population) from 67 sites in Europe, India, Philippines, and South Africa. A total of 497 patients received at least one dose of study medication (safety population), and 465 had no major deviations from protocol (per-protocol population). The most common deviation from protocol was lack of valid assessment by the independent review committee (n=20; THAL 100 n=3, THAL 200 n=5, THAL 400 n=5, and DEX n=7). Other deviations included administration of study treatment as first-line therapy (n=3; n=1 each in the THAL 100, THAL 400, and DEX groups) or to patients who had received ≥3 prior therapies (n=3; THAL 100 n=1 and THAL 200 n=2); no study treatment given (DEX n=2); administration of the incorrect dose of thalidomide (THAL 400 n=2); lack of serum M-protein assessment within 28 days prior to randomization (THAL 400 n=2 and DEX n=1); inclusion of patients refractory to dexamethasone (THAL 100 n=1); use of prohibited antimyeloma treatment during the study period (THAL 400 n=1); and the inclusion of patients who had received dexamethasone (THAL 400 n=1) or corticosteroids (DEX n=1) within 4 weeks prior to randomization.
Of the 499 randomized patients, 121 (24%) completed the planned 12 cycles of therapy; major reasons for discontinuation were disease progression (53%) and adverse events (10%). Other reasons included withdrawal of informed consent (8%), death (4%), or loss to follow-up (0.4%) (Figure 1).
The distribution of the patients' baseline characteristics was comparable among the four treatment groups (Table 1). Approximately 30% of patients were treated at centers outside of Europe. The median age was approximately 64 years, and most patients had ISS stage I or II disease. The median time since diagnosis was 2.5 years, and most patients had received one prior therapy for relapsed and/or refractory MM. The most common reason for change in last treatment was relapse or disease progression (72%) followed by resistance to current therapy (13%), which may explain the relatively short interval between diagnosis and randomization for some patients (Table 1). Approximately a third of patients had previously undergone autologous stem cell transplantation, and 15% had received prior treatment with bortezomib. Patients were distributed evenly across the 3.5 mg/L baseline β2-microglobulin cut-off in each treatment group. Approximately 50% of patients were assessed for cytogenetic risk, the majority of whom had standard-risk profiles. In each arm, 10–12% of the patients had high-risk cytogenetics (5% in the THAL 200 arm).
Time to progression
In the intent-to-treat population (N=499), the median TTP in the DEX, and THAL 100, 200 and 400 groups was 6.1, 7.0, 7.6, and 9.1 months, respectively (Figure 2A). The difference between the DEX and THAL 400 groups was not statistically significant [hazard ratio (HR), 0.73; 95% confidence interval (95% CI) 0.53–1.00; P=0.055). The estimated proportion of patients without disease progression at 1 year in the THAL 400 group was nearly double that in the DEX group (41% versus 23%). In the per-protocol population (n=465), the median TTP was 6.0, 7.0, 8.0, and 9.1 months, respectively. The difference between the DEX and THAL 400 groups was statistically significant (stratified log-rank P=0.049), in favor of THAL 400.
Exploratory analyses were performed to compare TTP between the THAL groups and DEX in various populations within the intent-to-treat population. Notably, thalidomide at all dose levels produced significantly longer TTP than dexamethasone in patients who had received two or three lines of therapy before entering the study (Table 2). An advantage for thalidomide was also seen in younger patients (aged <65 years) and those with ISS stage I or II disease, lower β2-microglobulin levels, and favorable cytogenetics (no chromosome 17 deletion and no translocation t(4;14) – patients with a t(4;14) translocation and a chromosome 17 deletion are typically considered refractory to thalidomide) (Table 2). In general, the benefit of thalidomide over dexamethasone was evident in patients with favorable prognostic factors, although benefit was also observed in patients who had received more than one prior therapy.
Response and survival
The overall response rate determined by the independent review committee in the DEX, THAL 100, THAL 200, and THAL 400 groups was 25%, 21%, 18%, and 21%, respectively (Table 3). Complete responses were observed in 2%, 3%, 2% and 2% of patients, respectively. There were no significant differences between the DEX and individual THAL groups in terms of response at weeks 24 and 48. There were higher response rates in the DEX group at the beginning of treatment because patients were given a high-dose DEX regimen for the first four cycles. Response rates changed once the DEX patients received low-dose DEX at cycle 5.
A total of 27, 13, 11, and 17 patients in the DEX, THAL 100, THAL 200, and THAL 400 groups, respectively, had confirmed response followed by progression or death and were, therefore, eligible for duration of response analysis. Relatively low numbers were available because of the censoring rule applied in this analysis, according to which duration of response was censored in patients who were considered responders and who had completed treatment, or were ongoing at data cut-off, without any end criteria. The same rule applied to patients who had no end criteria at withdrawal and in those who did not respond (response duration zero). The median duration of response was significantly longer in patients in all the THAL groups than in those in the DEX group (Figure 2B). In the THAL 200 group, for example, the median duration of response was approximately double that in the DEX group (13.1 versus 6.5 months; P=0.005). The median duration of responses was similarly high in the THAL 100 group (12.7 months; P=0.046) and THAL 400 group (11.6 months; P=0.016) versus DEX.
The median progression-free survival was 6.0 months in the DEX group and 6.7, 7.3, and 8.1 months in the THAL 100, THAL 200, and THAL 400 groups, respectively. The difference between the patients in the THAL 400 and DEX groups had a P value of 0.051 and was not, therefore, statistically significant in the intent-to-treat group (HR, 0.74; 95% CI 0.55–1.00; P=0.051). However, it was statistically significant in the per-protocol population (HR, 0.72; P=0.039).
The median overall survival has not been reached in the DEX group and the THAL 400 group (Figure 2C). In the THAL 100 and THAL 200 groups, the median survival was 30.0 and 25.6 months, respectively. There was no significant difference in survival between the DEX group and the individual THAL groups.
Of the 499 patients randomized, 497 received at least one dose of study medication and were, therefore, included in the safety assessment. Overall, 24% of patients completed 12 cycles of therapy; the proportion of patients completing therapy was higher in the THAL groups than in the DEX group. The median number of treatment cycles received was also lower in the DEX group than in the THAL groups (6 versus 7 cycles, respectively). The median average dose intensity was 40 mg/day in the DEX group and 100, 198, and 256 mg/day in the THAL 100, THAL 200, and THAL 400 groups, respectively. The median time to first dose reduction was 2.6 months in the DEX group and 4.0, 2.1, and 1.0 months in the THAL 100, THAL 200, and THAL 400 groups, respectively. Adverse events led to treatment discontinuation in 17% of patients in the DEX group and 12%, 15%, and 18% of patients in the THAL 100, THAL 200, and THAL 400 groups, respectively. The most common treatment-emergent adverse events that led to discontinuation were nervous system disorders (4.0%), renal failure (1.8%) and pneumonia (0.8%) in patients treated with thalidomide, and infections (4.0%) and psychiatric disorders (3.2%) in patients treated with dexamethasone.
In the THAL groups, the most frequently reported treatment-emergent adverse events of any grade were constipation (42.1%), fatigue (23.9%), asthenia (13.9%), anemia (13.1%), dizziness (12.9%), back pain (12.1%), and nausea (11%). The most commonly reported treatment-emergent adverse events in the DEX group were fatigue (22.6%), insomnia (19.4%), constipation (16.1%), peripheral edema (14.5%), diarrhea (14.5%), arthralgia (12.1%), asthenia (12.1%), anemia (11.3%), bone pain (10.5%) and bronchitis (10.5%).
Grade 3 or 4 treatment-emergent adverse events were reported in 38% of patients treated with dexamethasone and 44% of patients treated with thalidomide, and appeared to be dose-related (32% in THAL 100, 38% in THAL 200, and 60% in THAL 400). The incidence of grade 3 or 4 hematologic adverse events was low in all treatment groups (Table 4). The most commonly reported grade 3 or 4 treatment-emergent adverse events were neutropenia (THAL 6% and DEX 0%), anemia (THAL 6% and DEX 4%), fatigue (THAL 5% and DEX 2%), and pneumonia (THAL 4% and DEX 4%). Febrile neutropenia of grade 3 or 4 severity was reported for only one patient in the THAL 100 group. Grade 3 or 4 constipation was reported in 1% of patients in the THAL 200 group and 5% in the THAL 400 group. Severe rash was reported in 2% of patients in the THAL 400 group.
Clinical evidence of neuropathy was seen in all THAL groups (34%, 35%, and 41% of patients in the THAL 100, 200, and 400 groups, respectively). The incidence of grade 2 or higher neuropathy increased as the dose of thalidomide increased (12%, 20%, and 22%, for THAL 100, 200, and 400, respectively). Severe (grade 3 or 4) neuropathy occurred in 2% of patients in the THAL 200 group and 1% of patients in the THAL 400 group (Table 4). Patients with preexisting neuropathy were predisposed to either development or aggravation of neuropathy during thalidomide treatment. Clinical evidence of neuropathy was confirmed by electrophysiological studies, such as measurement of sensory nerve action potentials (Table 5).
The incidence of any grade of venous thromboembolism was similar in the THAL groups and the DEX group (3.2% each), and the incidence of grade 3 or 4 venous thromboembolic events was similarly low in all treatment groups (1–2%). Events reported in the THAL groups included deep-vein thrombosis, thrombophlebitis, pulmonary embolism, and retinal vein thrombosis. In the DEX group, events included deep-vein thrombosis and pulmonary embolism. Patients with a history of venous thromboembolism were not predisposed to experience thromboembolic events in any treatment group. There was no evidence of a pattern with regard to the timing of venous thromboembolism. The use of antithrombotic agents such as aspirin was more common in the THAL groups than in the DEX group (36% versus 15%, respectively).
Cardiac arrhythmias were more frequently reported in the THAL groups than in the DEX group (8% versus 2%). In the THAL groups, reported arrhythmias included: bradycardia (3%); syncope (2%); arrhythmia, cardio-respiratory arrest, and palpitations (1% each); sick sinus syndrome (0.5%); and Adams-Stokes syndrome, first degree atrioventricular block, bradyarrhythmia, sinus bradycardia, and tachycardia (0.3% each). In the DEX group, cardiac arrhythmias included syncope, tachycardia, and sudden death (1% each). Compared with the DEX group, more patients in the THAL groups had a history of cardiac arrhythmia and were more likely to be receiving a beta-blocker (26% versus 17%).
The incidence of adverse events was not affected by age or gender. Older patients (aged ≥65 years) treated with thalidomide had a slightly higher incidence of adverse events than younger patients (95% versus 89%), whereas the incidence in older and younger patients treated with dexamethasone was comparable (88% versus 90%). In female patients, the incidence of adverse events was 93% with thalidomide and 91% with dexamethasone. In male patients, the incidence of adverse events was 91% with thalidomide and 88% with dexamethasone.
Since the first recognition by Barlogie et al. that thalidomide has substantial antimyeloma activity,12 several questions have arisen regarding its optimal dose, and its efficacy and safety in this setting. The present study was the first randomized controlled trial to evaluate thalidomide monotherapy in patients with relapsed and/or refractory MM and was designed to answer many of these questions. Although the study did not demonstrate the superiority of thalidomide over dexamethasone in terms of TTP, our results confirm those from previous uncontrolled trials13–16 indicating that thalidomide is an effective treatment option for relapsed and/or refractory MM and has a dose-dependent safety profile.
The median TTP achieved with a starting dose of thalidomide 400 mg/day was 3 months longer than that achieved with dexamethasone (9.1 versus 6.1 months) but the difference did not reach statistical significance (P=0.055). Previous studies had shown that dexamethasone is an acceptable treatment option for patients with MM.6,7 In one study, dexamethasone produced a response rate of approximately 25% and a median duration of tumor control of 9 months in patients with relapsed and/or refractory MM; these results were comparable to those achieved with the combination of dexamethasone, vincristine, and doxorubicin (VAD), suggesting that most of the antimyeloma effects of this standard regimen can be attributed to dexamethasone.6 Our study results show that, in patients with relapsed and/or refractory MM, thalidomide monotherapy is at least as effective as standard dexamethasone.
The observed TTP with dexamethasone in our trial (6.1 months) was longer than expected (5 months). This expectation was based on results from recent phase III studies in which dexamethasone was used as a control; dexamethasone produced a median TTP of 3.49 months in the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial8 and 4.7 months in the MM-009 and MM-010 trials.9,10 One possible reason for the discrepancy may lie in the types of patients enrolled. Compared with the APEX, MM-009, and MM-010 studies, our study had fewer patients who had received two or more prior therapies. This may have been a result of the high proportion of patients in our study (approximately 30%) who were treated at centers outside of Europe, where fewer treatment options may have been available. Our less heavily pretreated population may account for the better-than-expected results in the control arm.
It should be noted that the definition of TTP used in this study differed from that used in other recent phase III studies. In our study, patients who received subsequent antimyeloma therapy before independent review committee-documented progression were followed until progression rather than being censored. Patients without documented progression, including those who received subsequent therapy, were censored at the date of their last disease assessment prior to data cut-off. Sensitivity analyses using TTP revealed a statistically significant improvement in TTP in the THAL 400 group compared to that in the DEX group. It should also be noted that, in the subgroup of patients who had received two or three prior lines of therapy, thalidomide, at all dose levels studied, prolonged TTP significantly compared with dexamethasone.
Response rates were similar in all four treatment groups, but the duration of response was significantly longer with thalidomide (at any dose) than with dexamethasone. Dexamethasone appeared to produce early responses (within 5 months) of short duration. This pattern may correspond with the protocol-specified reduction in dexamethasone dose intensity after the fourth cycle, which was required to conform to other recent phase III trials.8–10 Compared with this dexamethasone regimen, daily thalidomide appeared to provide more durable responses. Moreover, overall survival was similar in all four groups of patients. This comparable overall survival between the groups is likely to be due to two factors. Firstly, as this study focused on efficacy (response rate, TTP, progression-free survival) and safety, the survival data were gathered at a relatively early time-point and patients were not followed for long enough to obtain reasonable overall survival estimates. Secondly, the proportion of censored patients in this analysis was high in all four treatment groups (65–75%), resulting in few observed deaths. This may also have been confounded by the use of subsequent therapy.
The safety data from this study confirm and extend our knowledge of the effects of thalidomide.4 Severe adverse events associated with thalidomide included fatigue, constipation, neutropenia, and anemia. Rates of severe rash, bradycardia, neuropathy, and venous thromboembolism were low. As expected, thalidomide was associated with a higher risk of cardiac arrhythmias, mostly bradycardia and syncope. However, more patients in the THAL groups had a history of arrhythmias and were more likely to have been taking beta-blockers, which may have contributed to the increased incidence of sinus bradycardia. Dose-dependent peripheral neuropathy was observed clinically with thalidomide which, as previously observed,17 correlated with electrophysiological findings. It is of note, however, that among patients with clinical evidence of peripheral neuropathy, concomitant reductions in sensory nerve action potentials of greater than 50% were observed in only around a fourth of patients (Table 5). Hence, in routine practice clinical evidence and symptoms appear to be the most reliable indicators of peripheral neuropathy. Dose reductions for neuropathy allowed for continued thalidomide treatment. For example, in the THAL 400 group, the mean daily dose was 256 mg, but treatment duration was similar to that in the other treatment groups. There was no indication of an increased risk of venous thromboembolism with thalidomide monotherapy at any of the doses studied. A large proportion of patients (36%) treated with thalidomide were also given antithrombotic agents. This was as per-protocol, as investigators were concerned about the prothrombotic effects observed when thalidomide is used in combination with other active agents,18,19 although the risk appears to be reduced when the drug is given as monotherapy.20
Combination therapy regimens are now the standard of care for relapsed and/or refractory MM, and most patients should continue to receive combination therapy. Nevertheless, based on our findings, thalidomide monotherapy represents an effective salvage therapy option, particularly for patients with a good prognosis and those who have already received two or three regimens for relapsed and/or refractory MM. Thalidomide was associated with low rates of hematologic adverse events and a low rate of venous thromboembolism, despite the fact that only about a third of patients received thromboprophylaxis. With regard to the optimal dose of thalidomide, the 400 mg/day dose generally provided better efficacy outcomes than lower doses. Sensitivity analyses also indicated improved TTP in the THAL 400 group versus the DEX group. However, the actual median dose received by patients in the THAL 400 group was 256 mg/day compared with 198 mg/day in the THAL 200 group. Patients in the THAL 200 group also had the longest duration of response and a lower number of serious adverse events. Based on these observations, a starting dose of 400 mg/day could be recommended for optimum efficacy with timely dose reductions for patients who cannot tolerate this treatment.
The authors received editorial support, funded by Celgene Corporation from Excerpta Medica in the preparation of this manuscript. The authors are fully responsible for regarding content and editorial decisions for this manuscript.
Authorship and Disclosures
The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.
Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.
- Received March 21, 2011.
- Revision received October 18, 2011.
- Accepted November 16, 2011.
- Copyright© Ferrata Storti Foundation