The Evolv­ing Over­all Sur­vival Ex­pec­ta­tions of Pa­tients with Re­lapsed or Re­frac­to­ry Mul­ti­ple Myelo­ma

Every March, the blood can­cer com­mu­ni­ty rec­og­nizes Mul­ti­ple Myelo­ma Aware­ness Month – an op­por­tu­ni­ty to en­cour­age the pub­lic to raise aware­ness of mul­ti­ple myelo­ma, a form of blood can­cer that starts in the plas­ma cells in the bone mar­row and in­ter­feres with the im­mune sys­tem’s abil­i­ty to fight in­fec­tion.

When plas­ma cells be­come can­cer­ous, they mul­ti­ply quick­ly, crowd­ing out the healthy blood cells and hin­der­ing the pa­tient’s abil­i­ty to fight in­fec­tion, some­times lead­ing to un­time­ly death.

Dr. Ruben Niesvizky

Mul­ti­ple myelo­ma was ex­pect­ed to im­pact ap­prox­i­mate­ly 30,000 pa­tients in the US in 2017. Un­for­tu­nate­ly, the dis­ease re­mains in­cur­able, with pa­tients fac­ing ever-tight­en­ing cy­cles of suc­cess and fail­ure on treat­ment. Four out of 10 pa­tients who start treat­ment af­ter their first re­lapse may not start their next ther­a­py.

“There are sev­er­al chal­lenges and op­por­tu­ni­ties in treat­ing a pa­tient with mul­ti­ple myelo­ma,” said Ruben Niesvizky, MD, di­rec­tor of the Mul­ti­ple Myelo­ma Cen­ter at Weill Cor­nell Med­i­cine and New York-Pres­by­ter­ian/Weill Cor­nell Med­ical Cen­ter.

Treat­ing Mul­ti­ple Myelo­ma

While mul­ti­ple myelo­ma re­mains in­cur­able, pa­tients’ out­come ex­pec­ta­tions have im­proved sig­nif­i­cant­ly in re­cent years. In the 1990s, pa­tients typ­i­cal­ly lived two to three years fol­low­ing a mul­ti­ple myelo­ma di­ag­no­sis. Now, pa­tients are liv­ing sev­en to 10 years, and some­times longer.

“Once the dis­ease re­turns we strive to of­fer the longest sur­vival with the least amount of tox­i­c­i­ty,” said Dr. Niesvizky. “For­tu­nate­ly, we have seen dra­mat­ic changes in the out­comes over the last five years, and we are now ob­tain­ing long and durable re­spons­es.”

This change in sur­vival ex­pec­ta­tions is di­rect­ly linked to the ar­ray of nov­el ther­a­peu­tic reg­i­mens that have be­come avail­able. Up un­til a decade ago, cy­to­tox­ic chemother­a­py-based reg­i­mens were the main op­tions for pa­tients. To­day, mul­ti­ple myelo­ma is com­mon­ly treat­ed us­ing mul­ti­ple modal­i­ties, in­clud­ing cy­to­tox­ic chemother­a­py, im­munomod­u­la­tors, cor­ti­cos­teroids, etc. Mul­ti­ple treat­ments are used in com­bi­na­tion that at­tack the dis­ease in dif­fer­ent ways and are tai­lored to the in­di­vid­ual pa­tient’s needs, with the goal of get­ting them in­to re­mis­sion and keep­ing them there as long as pos­si­ble.

One class of agents used to treat mul­ti­ple myelo­ma, known as pro­tea­some in­hibitors, leads to ac­cu­mu­la­tion of ab­nor­mal pro­teins with­in the cell and even­tu­al­ly cell death. Myelo­ma cells are par­tic­u­lar­ly de­pen­dent on pro­tea­somes to sur­vive.

“Pro­tea­some in­hibitors are of­ten used as a cor­ner­stone in the treat­ment of myelo­ma,” said Dr. Niesvizky. While mul­ti­ple myelo­ma can be treat­ed with a sin­gle agent, more of­ten dif­fer­ent kinds of drugs are used in com­bi­na­tion.

The Gold Stan­dard End­point

While there’s been a sig­nif­i­cant in­crease in the num­ber of avail­able mul­ti­ple myelo­ma ther­a­pies over the past five years, few have proven in clin­i­cal tri­als to im­prove over­all sur­vival (OS), or the to­tal length of a per­son’s life af­ter be­gin­ning treat­ment.

Pro­gres­sion-free sur­vival (PFS), the mea­sure­ment of the time a per­son lives with­out their dis­ease get­ting worse, is by far the most com­mon pri­ma­ry end­point in Phase 3 mul­ti­ple myelo­ma clin­i­cal tri­als. Pro­gres­sion-free sur­vival is con­sid­ered a sur­ro­gate end­point for OS, which takes a longer time to mea­sure.

While PFS of­ten cor­re­lates with an im­prove­ment in OS, this is not al­ways the case. Over­all sur­vival re­mains the gold stan­dard of end­points be­cause it clear­ly demon­strates a drug’s val­ue in ex­tend­ing the pa­tient’s life.

“There are many fac­tors that are con­sid­ered in tai­lor­ing treat­ment pro­grams for a par­tic­u­lar pa­tient,” said Dr. Niesvizky. “But cer­tain­ly, over­all sur­vival ap­pears to be one of the most pow­er­ful ar­gu­ments in fa­vor of a drug or drug com­bi­na­tion.”

Quite an EN­DEAV­OR

Ear­li­er this year, the U.S. Food and Drug Ad­min­is­tra­tion (FDA) an­nounced the ap­proval of a sup­ple­men­tal New Drug Ap­pli­ca­tion to add over­all sur­vival da­ta for the Kd vs Vd in­di­ca­tion to the Pre­scrib­ing In­for­ma­tion for KYPRO­LIS® (carfil­zomib).

Orig­i­nal­ly ap­proved by the FDA in 2012, KYPRO­LIS is ap­proved for use in com­bi­na­tion with dex­am­etha­sone or with lenalido­mide plus dex­am­etha­sone, which are oth­er med­i­cines used to treat mul­ti­ple myelo­ma. KYPRO­LIS® is a pre­scrip­tion med­ica­tion used to treat pa­tients with re­lapsed or re­frac­to­ry mul­ti­ple myelo­ma who have re­ceived one or more pre­vi­ous treat­ments for mul­ti­ple myelo­ma.

Da­ta added to the la­bel showed KYPRO­LIS and dex­am­etha­sone (Kd) in com­bi­na­tion helped pa­tients with re­lapsed mul­ti­ple myelo­ma live near­ly eight months longer than Vel­cade® (borte­zomib) and dex­am­etha­sone (Vd), a re­cent stan­dard of care.

“For the first time, it was de­ter­mined that carfil­zomib at this [56 mg/m2] dose is su­pe­ri­or to borte­zomib –not on­ly in terms of PFS, but al­so over­all sur­vival,” said Dr. Niesvizky, who was a clin­i­cal in­ves­ti­ga­tor on the Phase 3 EN­DEAV­OR tri­al. “That is high­ly sig­nif­i­cant be­cause mov­ing for­ward, we should con­sid­er us­ing carfil­zomib over borte­zomib in the right clin­i­cal sce­nario.”

In ad­di­tion, the Na­tion­al Com­pre­hen­sive Can­cer Net­work Clin­i­cal Prac­tice Guide­lines in On­col­o­gy (NC­CN Guide­lines®), which clin­i­cians of­ten ref­er­ence to help guide de­ci­sion-mak­ing in the man­age­ment of can­cer, now lists KYPRO­LIS and dex­am­etha­sone as the on­ly pre­ferred dou­blet reg­i­men at re­lapse for mul­ti­ple myelo­ma.

The most com­mon side ef­fects oc­cur­ring in at least 20% of pa­tients re­ceiv­ing KYPRO­LIS in the com­bi­na­tion ther­a­py tri­als are: low red blood cell count, low white blood cell count, di­ar­rhea, dif­fi­cul­ty breath­ing, tired­ness (fa­tigue), low platelets, fever, sleep­less­ness (in­som­nia), mus­cle spasm, cough, up­per air­way (res­pi­ra­to­ry tract) in­fec­tion, and de­creased potas­si­um lev­els.

A Brighter Fu­ture for Pa­tients

Sev­er­al nov­el agents have re­ceived FDA ap­proval over the past five years for the treat­ment of pa­tients with mul­ti­ple myelo­ma, and drug de­vel­op­ment isn’t slow­ing down any time soon.

For now, the emer­gence of a ther­a­peu­tic reg­i­men that is proven to im­prove over­all sur­vival may pro­vide hope for ap­pro­pri­ate pa­tients.

Im­age: Michele Au­gus­to
USA-171-060934


IM­POR­TANT SAFE­TY IN­FOR­MA­TION
KYPRO­LIS® (carfil­zomib) can cause se­ri­ous side ef­fects:
  • Heart prob­lems: KYPRO­LIS can cause heart prob­lems or wors­en pre-ex­ist­ing heart con­di­tions. Death due to car­diac ar­rest has oc­curred with­in one day of KYPRO­LIS ad­min­is­tra­tion. Be­fore start­ing KYPRO­LIS, you should have a full med­ical work-up (in­clud­ing blood pres­sure and flu­id man­age­ment). You should be close­ly mon­i­tored dur­ing treat­ment.
  • Kid­ney prob­lems: There have been re­ports of sud­den kid­ney fail­ure in pa­tients re­ceiv­ing KYPRO­LIS. Your kid­ney func­tion should be close­ly mon­i­tored dur­ing treat­ment.
  • Tu­mor ly­sis syn­drome (TLS): Cas­es of TLS have been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS, in­clud­ing fa­tal­i­ties. You should be close­ly mon­i­tored dur­ing treat­ment for any signs of TLS.
  • Lung dam­age: Cas­es of lung dam­age have been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS, in­clud­ing fa­tal cas­es.
  • Pul­monary hy­per­ten­sion (high blood pres­sure in the lungs): There have been re­ports of pul­monary hy­per­ten­sion in pa­tients re­ceiv­ing KYPRO­LIS.
  • Lung com­pli­ca­tions: Short­ness of breath was re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS. Your lung func­tion should be close­ly mon­i­tored dur­ing treat­ment.
  • High blood pres­sure: Cas­es of high blood pres­sure, in­clud­ing fa­tal cas­es, have been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS. Your blood pres­sure should be close­ly mon­i­tored dur­ing treat­ment.
  • Blood clots: There have been re­ports of blood clots in pa­tients re­ceiv­ing KYPRO­LIS. If you are at high risk for blood clots, your doc­tor can rec­om­mend ways to low­er the risk.
  • If you are us­ing KYPRO­LIS in com­bi­na­tion with dex­am­etha­sone or with lenalido­mide plus dex­am­etha­sone, your doc­tor should as­sess and may pre­scribe an­oth­er med­i­cine to help low­er your risk for blood clots.
  • If you are us­ing birth con­trol pills or oth­er med­ical forms of birth con­trol as­so­ci­at­ed with a risk of blood clots, talk to your doc­tor and con­sid­er a dif­fer­ent method of birth con­trol dur­ing treat­ment with KYPRO­LIS in com­bi­na­tion with dex­am­etha­sone or with lenalido­mide plus dex­am­etha­sone.
  • In­fu­sion re­ac­tions: Symp­toms of in­fu­sion re­ac­tions in­clud­ed fever, chills, joint pain, mus­cle pain, fa­cial flush­ing and/or swelling, vom­it­ing, weak­ness, short­ness of breath, low blood pres­sure, faint­ing, chest tight­ness, and chest pain. These symp­toms can oc­cur im­me­di­ate­ly fol­low­ing in­fu­sion or up to 24 hours af­ter ad­min­is­tra­tion of KYPRO­LIS. If you ex­pe­ri­ence any of these symp­toms, con­tact your doc­tor im­me­di­ate­ly.
  • Se­vere bleed­ing prob­lems: Fa­tal or se­ri­ous cas­es of bleed­ing prob­lems have been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS. Your doc­tor should mon­i­tor your signs and symp­toms of blood loss.
  • Very low platelet count: Low platelet lev­els can cause un­usu­al bruis­ing and bleed­ing. You should have reg­u­lar blood tests to check your platelet count dur­ing treat­ment.
  • Liv­er prob­lems: Cas­es of liv­er fail­ure, in­clud­ing fa­tal cas­es, have been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS. Your liv­er func­tion should be close­ly mon­i­tored dur­ing treat­ment.
  • Blood prob­lems: Cas­es of a blood dis­ease called throm­bot­ic mi­croan­giopa­thy, in­clud­ing throm­bot­ic throm­bo­cy­topenic pur­pu­ra/he­molyt­ic ure­mic syn­drome (TTP/HUS), in­clud­ing fa­tal cas­es, have been re­port­ed in pa­tients who re­ceived KYPRO­LIS. Your doc­tor should mon­i­tor your signs and symp­toms.
  • Brain prob­lems: A nerve dis­ease called Pos­te­ri­or Re­versible En­cephalopa­thy Syn­drome (PRES), for­mer­ly called Re­versible Pos­te­ri­or Leukoen­cephalopa­thy Syn­drome (RPLS), has been re­port­ed in pa­tients re­ceiv­ing KYPRO­LIS. It can cause seizure, headache, lack of en­er­gy, con­fu­sion, blind­ness, al­tered con­scious­ness, and oth­er vi­su­al and nerve dis­tur­bances, along with high blood pres­sure. Your doc­tor can mon­i­tor your signs and symp­toms.
  • KYPRO­LIS should not be com­bined with mel­pha­lan and pred­nisone: New­ly di­ag­nosed trans­plant in­el­i­gi­ble mul­ti­ple myelo­ma pa­tients have shown an in­creased risk of se­ri­ous and fa­tal side ef­fects when us­ing KYPRO­LIS in com­bi­na­tion with mel­pha­lan and pred­nisone.
  • Pos­si­ble fe­tal harm: KYPRO­LIS can cause harm to a fe­tus (un­born ba­by) when giv­en to a preg­nant woman. Women should avoid be­com­ing preg­nant dur­ing treat­ment with KYPRO­LIS. Men should avoid fa­ther­ing a child dur­ing treat­ment with KYPRO­LIS. KYPRO­LIS can cause harm to a fe­tus if used dur­ing preg­nan­cy or if you or your part­ner be­come preg­nant dur­ing treat­ment with KYPRO­LIS.
You should con­tact your doc­tor im­me­di­ate­ly if you ex­pe­ri­ence any of the fol­low­ing:
  • Short­ness of breath
  • Pro­longed, un­usu­al or ex­ces­sive bleed­ing
  • Yel­low­ing of the skin and/or eyes (jaun­dice)
  • Headaches, con­fu­sion, seizures, or loss of sight
  • Preg­nan­cy (women should not re­ceive KYPRO­LIS if they are preg­nant or breast­feed­ing)
  • Any oth­er side ef­fect that both­ers you or does not go away
What are the pos­si­ble side ef­fects of KYPRO­LIS?
  • The most com­mon side ef­fects oc­cur­ring in at least 20% of pa­tients re­ceiv­ing KYPRO­LIS in the com­bi­na­tion ther­a­py tri­als are: low red blood cell count, low white blood cell count, di­ar­rhea, dif­fi­cul­ty breath­ing, tired­ness (fa­tigue), low platelets, fever, sleep­less­ness (in­som­nia), mus­cle spasm, cough, up­per air­way (res­pi­ra­to­ry tract) in­fec­tion, and de­creased potas­si­um lev­els.
  • The most com­mon side ef­fects oc­cur­ring in at least 20% of pa­tients re­ceiv­ing KYPRO­LIS when used alone (monother­a­py) in tri­als are: low red blood cell count, tired­ness (fa­tigue), low platelets, nau­sea, fever, dif­fi­cul­ty breath­ing, di­ar­rhea, headache, cough, swelling of the low­er legs or hands.
These are not all the pos­si­ble side ef­fects of KYPRO­LIS. For more in­for­ma­tion, ask your doc­tor or phar­ma­cist. Call your doc­tor for med­ical ad­vice about side ef­fects.
You are en­cour­aged to re­port neg­a­tive side ef­fects of pre­scrip­tion drugs to the FDA. Vis­it www.fda.gov/med­watch or call 1-800-FDA-1088.
Please see ac­com­pa­ny­ing Full Prod­uct In­for­ma­tion.

How small- to mid-sized biotechs can adopt pa­tient cen­tric­i­ty in their on­col­o­gy tri­als

By Lucy Clos­sick Thom­son, Se­nior Di­rec­tor of On­col­o­gy Pro­ject Man­age­ment, Icon

Clin­i­cal tri­als in on­col­o­gy can be cost­ly and chal­leng­ing to man­age. One fac­tor that could re­duce costs and re­duce bar­ri­ers is har­ness­ing the pa­tient voice in tri­al de­sign to help ac­cel­er­ate pa­tient en­roll­ment. Now is the time to adopt pa­tient-cen­tric strate­gies that not on­ly fo­cus on pa­tient needs, but al­so can main­tain cost ef­fi­cien­cy.

The top 10 block­buster drugs in the late-stage pipeline — Eval­u­ate adds 6 new ther­a­pies to heavy-hit­ter list

Vertex comes in for a substantial amount of criticism for its no-holds-barred tactical approach toward wresting the price it wants for its commercial drugs in Europe. But the flip side of that coin is a highly admired R&D and commercial operation that regularly wins kudos from analysts for their ability to engineer greater cash flow from the breakthrough drugs they create.

Both aspects needed for success in this business are on display in the program backing Vertex’s triple for cystic fibrosis. VX-659/VX-445 + Tezacaftor + Ivacaftor — it’s been whittled down to 445 now — was singled out by Evaluate Pharma as the late-stage therapy most likely to win the crown for drug sales in 5 years, with a projected peak revenue forecast of $4.3 billion.

The latest annual list, which you can see here in their latest world preview, includes a roster of some of the most closely watched development programs in biopharma. And Evaluate has added 6 must-watch experimental drugs to the top 10 as drugs fail or go on to a first approval. With apologies to the list maker, I revamped this to rank the top 10 by projected 2024 sales, instead of Evaluate's net present value rankings.

It's how we roll at Endpoints News.

Here is a quick summary of the rest of the top 10:

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John Reed at JPM 2019. Jeff Rumans for Endpoints News

Sanofi's John Reed con­tin­ues to re­or­ga­nize R&D, cut­ting 466 jobs while boost­ing can­cer, gene ther­a­py re­search

The R&D reorganization inside Sanofi is continuing, more than a year after the pharma giant brought in John Reed to head the research arm of the Paris-based company.
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John Chiminski, Catalent CEO - File Photo

'It's a growth play': Catal­ent ac­quires Bris­tol-My­er­s' Eu­ro­pean launch pad, ex­pand­ing glob­al CD­MO ops

Catalent is staying on the growth track.

Just two months after committing $1.2 billion to pick up Paragon and take a deep dive into the sizzling hot gene therapy manufacturing sector, the CDMO is bouncing right back with a deal to buy out Bristol-Myers’ central launchpad for new therapies in Europe, acquiring a complex in Anagni, Italy, southwest of Rome, that will significantly expand its capacity on the continent.

There are no terms being offered, but this is no small deal. The Anagni campus employs some 700 staffers, and Catalent is planning to go right in — once the deal closes late this year — with a blueprint to build up the operations further as they expand on oral solid, biologics, and sterile product manufacturing and packaging.

This is an uncommon deal, Catalent CEO John Chiminski tells me. But it offers a shortcut for rapid growth that cuts years out of developing a green fields project. That’s time Catalent doesn’t have as the industry undergoes unprecedented expansion around the world.

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Arc­turus ex­pands col­lab­o­ra­tion, adding $30M cash; Ku­ra shoots for $100M raise

→  Rare dis­ease play­er Ul­tragenyx $RARE is ex­pand­ing its al­liance with Arc­turus $ARCT, pay­ing $24 mil­lion for eq­ui­ty and an­oth­er $6 mil­lion in an up­front as the two part­ners ex­pand their col­lab­o­ra­tion to in­clude up to 12 tar­gets. “This ex­pand­ed col­lab­o­ra­tion fur­ther so­lid­i­fies our mR­NA plat­form by adding ad­di­tion­al tar­gets and ex­pand­ing our abil­i­ty to po­ten­tial­ly treat more dis­eases,” said Emil Kakkis, the CEO at Ul­tragenyx. “We are pleased with the progress of our on­go­ing col­lab­o­ra­tion. Our most ad­vanced mR­NA pro­gram, UX053 for the treat­ment of Glyco­gen Stor­age Dis­ease Type III, is ex­pect­ed to move in­to the clin­ic next year, and we look for­ward to fur­ther build­ing up­on the ini­tial suc­cess of this part­ner­ship.”

UP­DAT­ED: Chica­go biotech ar­gues blue­bird, Third Rock 'killed' its ri­val, pi­o­neer­ing tha­lassemia gene ther­a­py in law­suit

Blue­bird bio $BLUE chief Nick Leschly court­ed con­tro­ver­sy last week when he re­vealed the com­pa­ny’s be­ta tha­lassemia treat­ment will car­ry a jaw-drop­ping $1.8 mil­lion price tag over a 5-year pe­ri­od in Eu­rope — mak­ing it the plan­et’s sec­ond most ex­pen­sive ther­a­py be­hind No­var­tis’ $NVS fresh­ly ap­proved spinal mus­cu­lar at­ro­phy ther­a­py, Zol­gens­ma, at $2.1 mil­lion. A Chica­go biotech, mean­while, has been fum­ing at the side­lines. In a law­suit filed ear­li­er this month, Er­rant Gene Ther­a­peu­tics al­leged that blue­bird and ven­ture cap­i­tal group Third Rock un­law­ful­ly prised a vi­ral vec­tor, de­vel­oped in part­ner­ship with the Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter (MSK), from its grasp, and thwart­ed the de­vel­op­ment of its sem­i­nal gene ther­a­py.

Neil Woodford. Woodford Investment Management via YouTube

Wood­ford braces po­lit­i­cal storm as UK fi­nan­cial reg­u­la­tors scru­ti­nize fund sus­pen­sion

The shock of Neil Wood­ford’s de­ci­sion to block with­drawals for his flag­ship fund is still rip­pling through the rest of his port­fo­lio — and be­yond. Un­der po­lit­i­cal pres­sure, UK fi­nan­cial reg­u­la­tors are now tak­ing a hard look while in­vestors con­tin­ue to flee.

In a re­sponse let­ter to an MP, the Fi­nan­cial Con­duct Au­thor­i­ty re­vealed that it’s opened an in­ves­ti­ga­tion in­to the sus­pen­sion fol­low­ing months of en­gage­ment with Link Fund So­lu­tions, which tech­ni­cal­ly del­e­gat­ed Wood­ford’s firm to man­age its funds.

Gilead baits new al­liance with $45M up­front, div­ing in­to the busy pro­tein degra­da­tion field

Gilead is jump­ing on board the pro­tein degra­da­tion band­wag­on. And they’re turn­ing to a low-pro­file Third Rock start­up for the ex­per­tise. But if you were look­ing for a trans­for­ma­tion­al deal to kick up fresh en­thu­si­asm for Gilead, you’ll have to re­main pa­tient.

This one will have a long way to go be­fore they get in­to the clin­ic.

The big biotech said Wednes­day morn­ing that it is pay­ing $45 mil­lion up­front and re­serv­ing a whop­ping $2.3 bil­lion in biotech bucks if San Fran­cis­co-based Nurix can point the way to new can­cer ther­a­pies, as well as drugs for oth­er, un­spec­i­fied dis­eases.

A new num­ber 1 drug? Keytru­da tapped to top the 10 biggest block­busters on the world stage by 2024

Analysts may be fretting about Keytruda’s longterm prospects as a host of rival therapies elbow their way to the market. But the folks at Evaluate Pharma are confident that last year’s $7 billion earner is headed for glory, tapping it to beat out the current #1 therapy Humira as AbbVie watches that franchise swoon over the next 5 years.

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