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March 26, 2018 06:38 AM EDT

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

Amgen Oncology

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

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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.

Author

Amgen Oncology

amgenmediarelations@amgen.com @AmgenOncology
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