A num­ber of new drugs are on the horizon for re­lapsed and re­frac­tory patients, as discussed by physicians at the 2009 Inter­na­tional Myeloma Workshop (IMW). The dis­cus­sion covered drugs in all stages of devel­op­ment, from those still undergoing initial lab testing to ones already in inter­na­tional clin­i­cal trials.

Overall re­spon­siveness to treat­ment has im­proved dramatically with the recent in­tro­duc­tion of more potent agents such as Revlimid ^[1] (lena­lido­mide) and Velcade ^[2] (bor­tez­o­mib). Doctors are now testing com­bi­na­tions of these two drugs with newer pharma­ceu­ticals. Of the two, Velcade has been shown to synergize or work well with other drugs, each enhancing the pos­i­tive effects of the other.

Although most trials still do not have enough patients to pro­duce conclusive re­­sults, the outlook for the new syn­­er­gis­tic ther­a­pies is decidedly pos­i­tive.

Carfilzomib ^[3], a proteasome in­hib­i­tor like Velcade, has been shown to re­­sult in less, if any, periph­eral neu­rop­athy. It is cur­rently in trials for patients who have failed everything from standard pharma­ceu­ticals to trans­plants and for patients who have failed on Velcade.

"If it's at least as active as [Velcade] and yet does not cause painful periph­eral neu­rop­athy, to me, that is an ad­vancement," said Sundar Jagannath, MD. "And, if it would do a little better, then so be it. That'll be even better for us."

Elotuzumab ^[4], a monoclonal anti­body, is one of myeloma's hopes for a success story like that of Rituxan (rituximab) for lym­phoma. CHOP chemo­ther­apy, a four-drug com­bi­na­tion, achieved a sig­nif­i­cant per­for­mance boost when Rituxan was introduced to the regi­men. Physicans spoke of two on­go­ing clin­i­cal trials for elotuzumab -- one with Velcade and one with Revlimid and low-lose dexamethasone ^[5]. It is predicted that the drugs will have a syn­­er­gis­tic effect on each other.

CD138 anti­body agonist also originates from a suc­cess­ful lym­phoma ther­apy. Anti­body-based ther­apy has not achieved huge success for myeloma patients, how­ever, in part because the im­mune sys­tems of myeloma patients may be more im­paired than those of lym­phoma patients. The latest myeloma ther­apy com­bines chemo­ther­apy and the anti­body in one dose, ef­fec­tively bypassing the anti­body's reg­u­lar function of activating the im­mune sys­tem. Although anti­body-based ther­apy nor­mally needs the help of a fully functional im­mune sys­tem, the chemo­ther­apy allows the drug to run its course in myeloma patients whose im­mune sys­tems may be compromised.

Four histone deacetylase in­hib­i­tor (HDAC) in­hib­i­tors were discussed -- panobinostat ^[6] (LBH 589), Zolinza ^[7] (vorinostat), tipifarnib, and Istodax (romidepsin) ^[8]. All four are being tested in com­bi­na­tion with Velcade, a pro­te­a­some blocker. HDAC inbitors block aggresome function, and may be syn­­er­gis­tic with pro­te­a­some in­hib­ition in kill­ing plasma cells. Notably, Zolinza is cur­rently in a large inter­na­tional Phase 3 clin­i­cal trial to assess whether combining it with Velcade is better than using Velcade alone.

Actimid ^[9] (poma­lido­mide), an immuno­modu­la­tory mol­e­cule, recently achieved re­sponses in 60 per­cent of re­lapsed patients who had pre­vi­ously been treated with Revlimid or thalidomide ^[10] (Thalomid), said Jagannath.

Tanespimycin ^[11], a heat shock pro­tein drug, may be able to in­crease the ac­­tiv­ity of Velcade while slowing the devel­op­ment of periph­eral neu­rop­athy.

Perifosine ^[12], an Akt in­hib­i­tor, is being tested in com­bi­na­tion with Revlimid and dexa­meth­a­sone and with Velcade. Velcade activates Akt signaling, a process in­volved in tumor growth; perifosine blocks this path­way. A Phase 3 trial is cur­rently assessing the ef­fi­cacy of Velcade/dexamethasone versus Velcade/perifosine/dexamethasone.

These devel­op­ments are sig­nif­i­cant to not only future but also cur­rent myeloma patients. Should a patient relapse in just two or three years from now, "at least one pro­te­a­some in­hib­i­tor new drug and one immuno­modu­la­tory mol­e­cule in the pipe­line is likely to be approved by that time," said Jagannath.

For more in­­for­ma­tion, refer to the IMW pre­sen­ta­tion transcript ^[13] (pdf) provided by the MMRF.