Pushing the boundaries of drug discovery for myeloma patients

We have made huge progress in find­ing and deliv­er­ing treat­ments for mul­ti­ple myelo­ma – a blood can­cer gen­er­at­ed by faulty plas­ma cells in bone mar­row – and a dis­ease with a very poor prog­no­sis has become a man­age­able, chron­ic con­di­tion.

It is still incur­able, but the aver­age patient can now expect sur­vival of around ten years com­pared to three years thanks to effec­tive treat­ments. Our con­tin­u­ing chal­lenge is to find bet­ter ther­a­pies for a con­di­tion which, although classed as a rare can­cer, affects around 17,500 peo­ple in the UK.

Myelo­ma is a relaps­ing and remit­ting con­di­tion that caus­es renal fail­ure, anaemia, fatigue, hyper­cal­caemia and destruc­tive bone lesions. It is dif­fer­ent for each patient, mak­ing diag­no­sis dif­fi­cult, and ther­a­py regimes need to be tuned to keep­ing the dis­ease at bay and pro­vid­ing good qual­i­ty of life for patients.

Treat­ment has evolved from a sin­gle chemother­a­py drug with poor out­comes and high tox­i­c­i­ty through the use of the drug thalido­mide around 15 years ago, which was the first of a new class of immunomod­u­la­to­ry drugs (IMiDs). We now have two more in that class and pro­tea­some inhibitors, which came along more than ten years ago, help us bet­ter man­age patients and improve sur­vival.

These drugs are well tol­er­at­ed and many patients enjoy a good qual­i­ty of life, rarely being admit­ted to hos­pi­tal. More than 60 per­cent of younger patients have a ten-year sur­vival pro­file, but old­er patients can be more frail at diag­no­sis and we need to under­stand how best to treat them.

The med­ical and sci­en­tif­ic com­mu­ni­ty has made sig­nif­i­cant advances in decod­ing myelo­ma and lab­o­ra­to­ry tests have allowed us to iden­ti­fy the genet­ic mark­ers in the myelo­ma cells so we can choose the appro­pri­ate treat­ment in each case. We expect to derive even fur­ther under­stand­ing from gene-expres­sion pro­fil­ing and next-gen­er­a­tion sequenc­ing plat­forms.

But, unlike with many sol­id tumours, we have been unable to find a spe­cif­ic dri­ver or muta­tion which we can then hit. For instance, in lung can­cer you can iden­ti­fy a muta­tion and use an inhibitor which works very effec­tive­ly, but this sim­ply doesn’t exist in myelo­ma.

It is a com­plex con­di­tion, but there is much hope in a series of clin­i­cal tri­als being under­tak­en glob­al­ly and at Uni­ver­si­ty Col­lege Hos­pi­tal, Lon­don. It has been dis­cov­ered that the drug Vene­to­clax, which is fund­ed and licensed for chron­ic lym­pho­cyt­ic leukaemia, is effec­tive on a sub-group of myelo­ma patients and we are cur­rent­ly engaged in a clin­i­cal tri­al on its use.

We also have two brand-new IMiDs designed to improve on cur­rent ther­a­pies, which are look­ing promis­ing in phase‑1 tri­als and we would hope they could come through for patients next year.

The big chal­lenge we face is that myelo­ma caus­es pro­found immune dereg­u­la­tion, which con­fers resis­tance on these myelo­ma cells. They are able to mutate and mod­i­fy and, despite using estab­lished drugs, resis­tant clones keep appear­ing. So we are com­ing to the view that the only way to achieve long-term con­trol is to invoke the body’s own immune sys­tem because it is the only ele­ment that has the abil­i­ty to adapt and change to cure the can­cer.

There is promise for myelo­ma patients, but this is a com­plex con­di­tion and our efforts must not, and will not, relax

At a recent con­fer­ence, some­one framed the dif­fi­cul­ty suc­cinct­ly by stat­ing that plas­ma cells are designed to stay in your body for 80 years pro­duc­ing anti­bod­ies, so it is not sur­pris­ing it is dif­fi­cult to kill them. Oth­er can­cer cells have a quick­er turnover and die, but there are a mul­ti­tude of ways myelo­ma man­ages to sur­vive from genet­ic abnor­mal­i­ties to inter­ac­tions with­in the bone mar­row micro-envi­ron­ment.

Huge promise is com­ing from the rapid­ly emerg­ing approach of engi­neer­ing a patient’s immune cells to attack the can­cer, known as CAR T‑cell ther­a­py. It has worked well in leukaemia and lym­phoma, but the sto­ry doesn’t seem to be as excit­ing in myelo­ma as with oth­er can­cers, which is dis­ap­point­ing. But there is a lot to learn and over the next five years we will be using a com­bi­na­tion of CAR T‑cells and drugs we know to lever­age long-last­ing impacts.

Wor­ry­ing­ly, the inci­dence of myelo­ma is climb­ing. It has dou­bled to 2 per­cent of all can­cers recent­ly and, although bet­ter diag­no­sis is a fac­tor, we are not com­plete­ly sure why. This makes our research and quest for bet­ter ther­a­pies, and ulti­mate­ly a cure, all the more crit­i­cal.

We know the caus­es of myelo­ma are a com­bi­na­tion of genet­ic and envi­ron­men­tal influ­ences. Pop­u­la­tion research shows a clus­ter­ing of myelo­ma in fam­i­lies, while an inter­est­ing piece of data has emerged recent­ly that the fire­fight­ers who attend­ed the 9/11 World Trade Cen­ter dis­as­ter in New York have a high­er risk of devel­op­ing the pre-can­cer­ous con­di­tion known as MGUS, which shows there is an envi­ron­men­tal ele­ment.

In the near future, our aim is to con­tin­ue to devel­op immunother­a­pies to see the next step change in sur­vival for our patients who can look for­ward to new agents com­ing from clin­i­cal tri­als over the next few years.

Our aim is to pro­vide a good qual­i­ty of life with well-tol­er­at­ed drugs, so peo­ple can con­tin­ue work­ing or, if they are retired, have the free­dom to trav­el and not be stuck in hos­pi­tal.

Myelo­ma is clas­si­fied as a rare can­cer and, con­se­quent­ly, does not get the pro­file of some more emo­tive can­cers. But, even though inci­dence is low, sur­vival has improved, so the num­ber of peo­ple liv­ing with myelo­ma on treat­ment is equal­ly as high as the more com­mon can­cers.

Patients are still pri­mar­i­ly diag­nosed when they attend A&E units and it can take months for a patient to see a haema­tol­o­gist. There­fore, we need to ener­gise edu­ca­tion as well as hav­ing more invest­ment into research so the UK can lead the way to bring new treat­ments to patients.

There is promise for myelo­ma patients, but this is a com­plex con­di­tion and our efforts must not, and will not, relax.

Dr Popat is a Con­sul­tant Haema­tol­o­gist at Uni­ver­si­ty Col­lege Hos­pi­tal, Lon­don and HCA Health­care UK. He is Hon­orary Clin­i­cal Senior Lec­tur­er at the UCL Can­cer Insti­tute, a mem­ber of the Nation­al Can­cer Research Insti­tute myelo­ma sub-group and North Thames Clin­i­cal Research Net­work Spe­cial­i­ty Lead for haema­tol­ogy in the can­cer divi­sion.