Within the past nine months, two new agents have been approved for the treat­ment of re­lapsed mul­ti­ple myeloma.

In July 2012, a sec­ond gen­er­a­tion pro­te­a­some in­hib­i­tor, Kyprolis (car­filzomib), was approved for patients with re­lapsed/refractory dis­ease. In Feb­ru­ary of this year, Pomalyst (poma­lido­mide) was approved for use in similar patients.

These two agents, with dexamethasone (Decadron) or in com­bi­na­tion with other drugs, should fur­ther broaden the armamentarium for the treat­ment of myeloma as we con­tinue to strive to make myeloma a chronic dis­ease.

Rather than dwell on the ad­van­tages of these two agents, which are sub­stan­tial, let us examine what is in the future for the treat­ment of mul­ti­ple myeloma.

There are cur­rently three agents being studied for the treat­ment of myeloma that are in Phase 3 clin­i­cal trials, the penultimate clin­i­cal trial format that may lead to ap­prov­al by the U.S. Food and Drug Admin­istra­tion (FDA): elotuzumab, ixazomib (MLN9708), and panobinostat (Farydak).

The most promising on­go­ing Phase 3 trials in myeloma are investigating elo­tuz­u­mab or ix­az­o­mib in com­bi­nation with Revlimid (lena­lido­mide) and dexa­meth­a­sone.

The first of these trials is investigating the mono­clonal anti­body elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone, com­pared to Revlimid and dexa­meth­a­sone alone, in re­lapsed and re­frac­tory myeloma. The study has com­pleted the trial accrual, and we await the pre­lim­i­nary re­­sults.

The side effects of this com­bi­na­tion have been quite minimal, and the Phase 2 re­­sults were very promising. If the Phase 3 re­­sults are pos­i­tive, we may see FDA ap­prov­al of this agent in 2014, which would make elotuzumab the first mono­clonal anti­body to be approved for the treat­ment of myeloma. Monoclonal anti­bodies are a mainstay of treat­ment for lym­phoma and chronic lym­pho­cytic leukemia.

The sec­ond promising trial is investigating the third gen­er­a­tion oral pro­te­a­some in­hib­i­tor ix­az­o­mib plus Revlimid and dexa­meth­a­sone, com­pared to Revlimid and dexa­meth­a­sone alone, in re­lapsed and re­frac­tory myeloma.  Ixazomib allows for an all oral regi­men of a pro­te­a­some in­hib­i­tor, immuno­modu­la­tory drug (Revlimid), and dexa­meth­a­sone. In Phase 2 trials of this com­bi­na­tion, re­sponse rates were robust and the side effect profile of ix­az­o­mib showed less neu­rop­athy (pain, tingling, and loss of sensation in the extrem­i­ties) than Velcade (bor­tez­o­mib).  FDA ap­prov­al of ix­az­o­mib is not pro­jected until 2015.

Panobinostat is a histone deacetylase in­hib­i­tor (HDAC) that in­ter­feres with DNA in tumor cells. It is being studied in com­bi­na­tion with Velcade and dexa­meth­a­sone, com­pared to Velcade and dexa­meth­a­sone alone. It is not clear if the trial will be a pos­i­tive trial.  A recent trial with the same class drug, Zolinza (vorinostat), was not pos­i­tive in Phase 3 testing.

Along with Zolinza, perifosine is another myeloma drug that looked promising in Phase 2 trials but did not prove efficacious in a larger Phase 3 trial. Perifosine is an AKT in­hib­i­tor, which means that it blocks one of the enzyme path­ways in myeloma cells.  The Phase 3 trial of perifosine in com­bi­na­tion with Velcade and dexa­meth­a­sone, com­pared to Velcade and dexa­meth­a­sone alone, was recently closed at the interim analysis for lack of sig­nif­i­cant ef­fi­cacy.

There are some other agents that are not as ad­vanced in clin­i­cal trials. These agents will probably not be con­sidered for ap­prov­al until 2015 or later.

The first is another third gen­er­a­tion oral pro­te­a­some in­hib­i­tor called oprozomib.  This agent is cur­rently in Phase 2 trials and appears to be ef­fec­tive. The earlier trials with this agent dem­onstrated mod­er­ate gastro­intestinal side effects. The drug de­livery sys­tem was modified, and the cur­rent for­mu­la­tion is much better tol­er­ated.

Daratumumab, a mono­clonal anti­body directed against a surface pro­tein on virtually all myeloma cells (CD38), has very high poten­tial. Over the last 20 years, a num­ber of mono­clonal anti­bodies have been devel­oped. However, virtually none of these mono­clonal anti­bodies has anti-myeloma ac­­tiv­ity by itself. Elotuzumab, as mentioned above, is ef­fec­tive in com­bi­na­tion, yet has minimal single-agent ac­­tiv­ity. Dara­tumumab shows ac­­tiv­ity as a single agent in early stud­ies. This would allow for its use alone, with no re­quire­ment for com­bi­na­tion with other agents. This may be an ideal agent for main­te­nance ther­apy after in­duction treat­ment or trans­plant.

Finally, although this dis­cus­sion focuses primarily on these agents in the relapse setting, it should be noted that once eval­u­ated in the relapse setting, these agents will ultimately be eval­u­ated in newly diag­nosed patients. Thus is the case with an on-going Phase 3 clin­i­cal trial of elotuzumab plus Revlimid and dexa­metha­sone, com­pared to Revlimid and dexa­meth­a­sone alone, in the front­line treat­ment of myeloma. Also, once approved, many of these agents have in­creased ef­fi­cacy when com­bined with dif­fer­en­t class drugs.  For example, Kyprolis, Revlimid, and dexa­meth­a­sone is a very potent regi­men for relapse and front­line ther­apy.

In summary, the future pipe­line for myeloma agents is very promising. Although myeloma is only 1 per­cent of all cancers, six of the 21 agents approved over the past 12 years to treat cancer have been for myeloma, and more myeloma agents appear on the horizon. Soon, we truly will be able to state with con­fi­dence that myeloma is a chronic dis­ease with mul­ti­ple treat­ment op­tions that can con­trol the dis­ease for years.

Dr. David H. Vesole is Co-Chief of the Myeloma Division and Director of Myeloma Re­search at The John Theurer Cancer Center at Hackensack Uni­ver­sity Medical Center. Dr. Vesole writes a quar­ter­ly column for The Myeloma Beacon.