Thursday was the third day of the Inter­na­tional Myeloma Workshop (IMW) in Paris.  There were pre­sen­ta­tions from early morn­ing through the evening.

Some of the highlights from the first part of Day 3 of the conference are summarized in this article.  Highlights from the sec­ond part of the day are summarized in a separate article (see re­lated Beacon news).

Treating Older, Newly Diagnosed Myeloma Patients

The first session of the morn­ing was about treating newly diag­nosed mul­ti­ple myeloma patients over the age of 65 years, spe­cif­i­cally those who are in­eli­gible for a stem cell trans­plant.  It com­ple­mented the session on Wednesday on treating new patients under the age of 65 years.

First, Dr. Vincent Rajkumar from the Mayo Clinic in Minnesota pre­sented the po­ten­tial treat­ment op­tions for older newly diag­nosed patients, reviewed clin­i­cal trial data relevant to those treat­ments, identified key issues around treating older patients, and spoke about his own personal treat­ment pref­er­ences.

Dr. Rajkumar ex­plained that he chooses a patient’s initial treat­ment based on whether the patient is standard-, intermediate-, or high-risk.

First of all, he mentioned that he prefers not to use melphalan (Alkeran), despite its long history of use in myeloma.  He be­lieves it can reduce the ef­fi­cacy of future treat­ments.

Therefore, in the case of standard-risk patients, he rec­om­mends treat­ment with Revlimid (lena­lido­mide) and low-dose dexamethasone (Decadron) for 18 months.  At that point, he discusses with each patient the op­tion of Revlimid main­te­nance ther­apy.

He be­lieves intermediate-risk patients should be treated with a com­bi­na­tion ther­apy that in­cludes Velcade (bor­tez­o­mib).  His pref­er­ence is Velcade, cyclophosphamide (Cytoxan), and dexa­meth­a­sone – a com­bi­na­tion known as VCd or CyBorD – for one year, followed by Velcade main­te­nance for two years.

For high-risk patients, Dr. Rajkumar typ­i­cally uses Revlimid, Velcade, and dexa­meth­a­sone – known as RVd – until the patient (hopefully) achieves a com­plete re­sponse.  Then they are put on Velcade main­te­nance ther­apy until their dis­ease progresses.

When treating patients with Velcade, Dr. Rajkumar almost always uses sub­cu­tane­ous Velcade, rather than in­fused, admin­istered once a week.  He feels this method and frequency of admin­istra­tion has shown good ef­fi­cacy while also reducing the risk of periph­eral neu­rop­athy (pain and tingling in the extremities), which is a common side effect when Velcade is in­fused or given more fre­quently.

Throughout the rest of the session, re­searchers from a variety of countries discussed what myeloma spe­cialists in their countries see as key issues re­lated to the treat­ment of older, newly diag­nosed patients, and the trials that are planned – or which have started recently – to shed light on the key open questions re­lated to treating this patient group.

From the pre­sen­ta­tions, it was readily apparent that there is an extremely broad range of po­ten­tial treat­ment op­tions being in­ves­ti­gated for older, newly diag­nosed patients.  The speakers mentioned mel­phalan and prednisone in com­bi­na­tion with one or more novel agents, cyclo­phos­pha­mide and dexa­meth­a­sone in com­bi­na­tion with one or more novel agents, as well as Revlimid plus dexa­meth­a­sone possibly with the addi­tion of Velcade.

Many of the trials discussed during the session are carefully analyzing each par­tic­i­pant’s chromosomal ab­nor­mal­i­ties and, in some cases, bone imaging re­­sults.  However, very few of the trials dif­fer­en­ti­ate treat­ment based on a patient’s risk classification like Dr. Rajkumar rec­om­mends.

Several creative trial designs were also discussed.

For instance, Dr. Antonio Palumbo from the Uni­ver­sity of Turin, Italy, sug­gested using standard doses for “standard” patients and then a set of lower doses for patients who may be older or have other co-existing med­i­cal con­di­tions.

Dr. María-Victoria Mateos of the Uni­ver­sity Hospital of Salamanca, Spain, also pre­sented a creative trial design that uses two com­bi­na­tion regi­mens: Velcade, mel­phalan, and pred­ni­sone (VMP) and Revlimid plus low-dose dexa­meth­a­sone (Rd).  One set of patients in her group's study will re­ceive the two regi­mens in sequence: first sev­er­al cycles of VMP, then sev­er­al cycles of Rd.  The other set of patients will re­ceive alternating rounds of the two regi­mens: first a cycle of VMP, then a cycle of Rd, then VMP again, and so on.  Dr. Mateos and her colleagues be­lieve the alternating ap­proach may yield better re­­sults,  but they will have to wait to see what the re­­sults say.

Treatments Under De­vel­op­ment

The next key session of the day was an ex­cit­ing set of pre­sen­ta­tions about new drugs and ap­proaches to treating myeloma.  The focus of these pre­sen­ta­tions was on drugs that are still being re­searched and which, in most cases, are not yet gov­ern­ment approved or generally avail­able to treat myeloma.

Dr. Kenneth Anderson of the Dana Farber Cancer In­sti­tute in Boston gave the session’s introductory pre­sen­ta­tion.  It surveyed the field of myeloma drugs that are still under devel­op­ment.  Much of the pre­sen­ta­tion was similar to one he gave on Day 2 of the Workshop (see re­lated Beacon news).  However, in this pre­sen­ta­tion, he also discussed some promising drugs that are in very early devel­op­ment, in­clud­ing BHQ880, PCI-32765, PD 0032891, everolimus, and WT161.

A bit later in the session, Dr. Anderson also de­liv­ered an addi­tional pre­sen­ta­tion that focused on po­ten­tial new myeloma drugs that are pro­te­a­some in­hib­i­tors, a class of drugs that in­cludes Velcade.

One of the new pro­te­a­some in­hib­i­tors, carfilzomib, is already well known among myeloma re­searchers and patients.  But there are many other po­ten­tial myeloma drugs in this class, and they all appear to be quite promising.  Three that are already in clin­i­cal trials, or will be soon, are CEP-18770, NPI-0052, and P5091.  Three others that have shown prom­ise in the laboratory and may soon start clin­i­cal trial testing in­clude MLN9708, ONX 0912 (PR-047), and PR-924.

Another key pre­sen­ta­tion during this session also focused on car­filz­o­mib.  The pre­sen­ta­tion was given by Dr. Andrzej Jakubowiak of the Uni­ver­sity of Michigan.  He first summarized for the audience the design and re­­sults of earlier clin­i­cal trials involving the drug (see re­lated Beacon articles).  Then he described at length up­dated re­­sults from a trial involving car­filz­o­mib com­bined with Revlimid and dexa­meth­a­sone (CRd) in both trans­plant eli­gible and in­eli­gible newly diag­nosed myeloma patients.  The CRd regi­men is being used both as initial (induction) ther­apy as well as con­sol­i­da­tion and main­te­nance ther­apy.

The re­sponse rates observed with this new com­bi­na­tion ther­apy seem very promising.  A full 97 per­cent of patients achieved at least a partial re­sponse, and 60 per­cent of patients achieved either a near com­plete re­sponse or better.  After nine months, no patients have progressed, and all patients are still alive.  Moreover, the side effect profile of the CRd regi­men looks fa­vor­able, with only 11 per­cent of patients reporting periph­eral neu­rop­athy, and no cases of periph­eral neu­rop­athy have been serious.

Another new myeloma drug that has re­ceived sig­nif­i­cant attention, pomalidomide, was the subject of the session’s next pre­sen­ta­tion, which was given by Dr. Martha Lacy of the Mayo Clinic.

Pomalidomide is a chemical rel­a­tive of both Revlimid and thalidomide.  Like those other two drugs, it is taken orally as a capsule.

During her pre­sen­ta­tion, Dr. Lacy reported data that already had been pre­sented in pub­lished papers or at pre­vi­ous conferences.  Those data primarily come from clin­i­cal trials where poma­lido­mide has been used in re­lapsed / re­frac­tory myeloma patients who have had many dif­fer­en­t pre­vi­ous ther­a­pies.  Even in patients that have re­ceived six or more dif­fer­en­t pre­vi­ous ther­a­pies, more than 25 per­cent of the patients taking poma­lido­mide have achieved at least a partial re­sponse.

The one po­ten­tial chal­lenge poma­lido­mide may face is its side effect profile.  In many of the trials Dr. Lacy reviewed, about a third of the patients taking poma­lido­mide ex­peri­enced serious re­duc­tions in their white blood cell counts (also known as neu­tro­penia).

After Dr. Lacy finished her pre­sen­ta­tion, Dr. Enrique Ocio of the Uni­ver­sity Hospital of Salamanca, Spain, pre­sented in­­for­ma­tion about a po­ten­tial new class of myeloma drugs, histone deacetylase (HDAC) in­hib­i­tors.  Two drugs in this class – panobinostat (Farydak) and Zolinza (vorinostat) – are re­ceiv­ing the most attention in clin­i­cal trials.

After initially showing only lim­ited ef­fi­cacy as stand-alone treat­ments for myeloma, panobinostat and Zolinza are now typ­i­cally being tested in com­bi­na­tion with other myeloma treat­ments.  The initial focus has been on testing these drugs in com­bi­na­tion with Velcade, partly because there is a theoretical rationale for such a com­bi­na­tion.  The re­­sults, mainly from trials in re­lapsed / re­frac­tory myeloma patients, have been promising in terms of ef­fi­cacy, but there have been some issues with the drugs causing low platelet counts (thrombocytopenia) in a num­ber of trial par­tic­i­pants.

Panobinostat and Zolinza also are now being tested in com­bi­na­tion with Revlimid and dexa­meth­a­sone, and initial re­­sults of these trials are promising, both in terms of ef­fi­cacy and side effects.

The final pre­sen­ta­tion during the session on po­ten­tial new myeloma drugs was given by Dr. Sundar Jagannath of the Mt. Sinai School of Medicine in New York City.  He spoke about promising drugs that are monocolonal anti­bodies.

Antibodies are pro­teins used by the im­mune sys­tem to identify and destroy foreign objects like bacteria, viruses, and cancer cells.  Monoclonal anti­bodies are pro­duced from a single type of cell, making them com­pletely uni­form and able to hone in on a spe­cif­ic target, such as myeloma cells.

Dr. Jagannath ex­plained that there are a num­ber of mono­clonal anti­bodies under devel­op­ment as po­ten­tial myeloma treat­ments.  However, as has been the case with the HDAC in­hib­i­tors, clin­i­cal trials have found that mono­clonal anti­bodies are typ­i­cally not ef­fec­tive on their own.  Instead, they have the greatest im­pact when com­bined with another myeloma drug, such as Revlimid or Velcade.

Two mono­clonal anti­bodies that are in late stage devel­op­ment are elotuzumab and siltuximab (CNTO-328).  Elotuzumab has shown good ef­fi­cacy in early trials when com­bined with Velcade in re­lapsed / re­frac­tory myeloma patients, but even better ef­fi­cacy when com­bined with Revlimid and dexa­meth­a­sone.  A Phase 3 trial testing elotuzumab com­bined with Revlimid and dexa­meth­a­sone in newly diag­nosed patients is there­fore planned.

Siltuximab also showed solid ef­fi­cacy when com­bined with Velcade in early clin­i­cal trials, and one Phase 3 trial of the drug in com­bi­na­tion with Velcade and dexa­meth­a­sone in re­lapsed / re­frac­tory patients is already on­go­ing.  Another Phase 3 trial combining the drug with Velcade, mel­phalan, and pred­ni­sone in newly diag­nosed patients is planned.

Monoclonal anti­bodies that are in early-stage clin­i­cal trials for myeloma in­clude BHQ880, BT062, daratumumab (HuMax-CD38), and IMMU-110 (hLL1-DOX).

For more detailed summaries of the day’s sessions, see The Myeloma Beacon’s extensive Day 3 coverage in the Beacon forums.  For links to abstracts of some of the pre­sen­ta­tions given during the day, see the IMW pro­gramme.  News from the final day of the workshop will also be summarized in a daily up­date like this one.