Treatment strategies that com­bine Revlimid with newer types of anti-tumor agents may be ef­fec­tive for re­lapsed and re­frac­tory mul­ti­ple myeloma, ac­cord­ing to myeloma experts who reviewed re­­sults from stud­ies of these new com­bi­na­tions.

Refractory and re­lapsed mul­ti­ple myeloma is notoriously dif­fi­cult to treat. For every remission period that is achieved, relapse typ­i­cally arises sooner and with greater re­sis­tance to pre­vi­ously used ther­a­pies. These patients have lim­ited op­tions for ther­apy.

In examining trials that tested new ther­a­pies in com­bi­na­tion with Revlimid ^[1] (lena­lido­mide), the authors of the review hoped to find the po­ten­tial for a greater array of treat­ment op­tions for re­frac­tory and re­lapsed myeloma patients.

Although these re­­sults are based on early stage clin­i­cal trials, the authors of the review describe them as en­cour­ag­ing. However, they point out that it will still take time before these com­bi­na­tions can be assessed for ap­prov­al.

The review was a col­lab­o­rative effort be­tween myeloma re­searchers at Harvard Medical School and the Uni­ver­sity Medical Center in Utrecht in The Netherlands.

Along with thalidomide ^[2] (Thalomid) and the inves­ti­ga­tional drug pomalidomide ^[3], Revlimid belongs to a class of drugs known as immuno­modu­la­tory agents (IMiDs), which induce death in myeloma cells by activating cer­tain self-destruction path­ways. IMiDs also help incite the im­mune sys­tem into attacking tumor cells.

Revlimid is most commonly prescribed in com­bi­na­tion with dexamethasone ^[4] (Decadron). Most side effects are man­ageable, although a few, such as blood clots and low white blood cell counts, can be very serious and make the treat­ment very dif­fi­cult to tolerate.

According to the authors of the review, how­ever, Revlimid has been less suc­cess­ful in re­frac­tory and re­lapsed patients, especially in patients who have undergone pre­vi­ous regi­mens in­clud­ing thalido­mide and Revlimid.

Thus, re­searchers have begun studying the ef­fi­cacy of treat­ments combining Revlimid with new agents under de­vel­op­ment.

The agents – which in­clude histone deacetylase (HDAC) in­hib­i­tors, Akt in­hib­i­tors, and mTor in­hib­i­tors – combat can­cer­ous growth in dif­fer­en­t ways.

In their paper, the re­searchers reviewed the clin­i­cal ac­­tiv­ity of these new agents in com­bi­na­tion with Revlimid.

Histone deacetylase in­hib­i­tors

The histone deacetylase in­hib­i­tor valproic acid ^[5] (Depakote, Depakene) has long been approved and used in neurology and psychiatry to treat epilepsy and to act as a mood stabilizer. Recently, HDAC in­hib­i­tors have been in­ves­ti­gated as po­ten­tial cancer treat­ments.

HDAC in­hib­i­tors work against tumors by stim­u­lating the ac­­tiv­ity and pro­duc­tion of pro­teins that both prevent cell pro­lif­er­a­tion and also promote cell death.

The authors of the review eval­u­ated trials that studied the HDAC in­hib­i­tor Zolinza ^[6] (vorinostat) in com­bi­na­tion with Revlimid.

One of the stud­ies was a Phase 1 trial involving Zolinza in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and re­frac­tory myeloma patients who had, on average, pre­vi­ously undergone four drug ther­a­pies, in­clud­ing 45 per­cent who had pre­vi­ously used Revlimid and 71 per­cent who had pre­vi­ously used thalido­mide.

The re­­sults showed that 53 per­cent of patients achieved at least a partial re­sponse. The median time to pro­gres­sion was roughly five months. The most common side effects reported were fatigue, low blood cell counts, and diarrhea.

The authors of the review also eval­u­ated a trial that used the same regi­men as a “salvage ther­apy” for 29 myeloma patients who had be­come resistant to Revlimid-dexamethasone alone.

Nearly 24 per­cent of these patients achieved at least a partial re­sponse, with a median duration of re­sponse of four months. The most common side effects reported were fatigue, low blood cell counts, and diarrhea.

Zolinza has also been in­ves­ti­gated in com­bi­na­tion with Velcade (bor­tez­o­mib); re­­sults of var­i­ous Phase 3 trials yielded mixed re­­sults (see re­lated Beacon ^[7] news).

Other HDAC in­hib­i­tors cur­rently being in­ves­ti­gated as po­ten­tial myeloma treat­ment in­clude panobinostat ^[8] and Istodax ^[9] (romidepsin).

Akt in­hib­i­tors

Akt in­hib­i­tors fight against cancer by sup­pressing the function of Akt, a pro­tein that is thought to promote tumor sur­vival, pro­lif­er­a­tion, and metastasis.

So far, perifosine is the only Akt in­hib­i­tor being devel­oped to treat mul­ti­ple myeloma.

The authors of the review eval­u­ated a Phase 1 trial that in­cluded 64 re­frac­tory and re­lapsed myeloma patients who re­ceived treat­ment with perifosine, Revlimid, and dexa­meth­a­sone. Patients had re­ceived a median of two prior lines of ther­apy, and the study excluded patients who were re­frac­tory to Revlimid-dexamethasone alone.

About 50 per­cent of patients ex­peri­enced at least a partial re­sponse, and the median duration of pro­gres­sion-free sur­vival was around 11 months.

Other on­go­ing Phase 3 trials are assessing the ef­fi­cacy of perifosine and Velcade in mul­ti­ple myeloma patients (see re­lated Beacon news).

mTor in­hib­i­tors

mTor in­hib­i­tors prevent the ac­­tiv­ity of "mammalian target of rapamycin" (mTor), a pro­tein that is known to promote tumor cell pro­lif­er­a­tion. mTor in­hib­i­tors are already used to treat other dis­eases, but only recently have they been sought out as a possible method of treating cancer.

The review article examined the trials of two dif­fer­en­t mTor in­hib­i­tors:  Torisel ^[10] (temsirolimus) and Afinitor ^[11] (everolimus).

The authors of the review eval­u­ated a Phase 1 trial that in­cluded 21 re­lapsed and re­frac­tory myeloma patients who re­ceived Revlimid and Torisel. Patients had undergone a median of three prior ther­a­pies before the trial, in­clud­ing 19 per­cent who had pre­vi­ously re­ceived Revlimid.

The re­­sults showed that 10 per­cent of patients achieved a partial re­sponse; an addi­tional 71 per­cent achieved stable dis­ease.

The most common side effects reported were fatigue, low white blood cell counts, anemia, rash, and electrolyte ab­nor­mal­i­ties.

Torisel is also being in­ves­ti­gated in com­bi­na­tion with Velcade and has shown promising re­­sults so far (see re­lated Beacon ^[12] news), after it had shown little ef­fi­cacy as a single agent in myeloma (see re­lated Beacon ^[13] news).

Afinitor is cur­rently used to prevent trans­plant rejection and to treat some types of kidney cancers. Before 2010, there had been no re­search into the ef­fi­cacy of Afinitor in treating mul­ti­ple myeloma.

The authors of the review eval­u­ated a Phase 1 trial that in­cluded 28 re­lapsed and re­frac­tory myeloma patients who re­ceived a Revlimid-Afinitor regi­men. Patients had re­ceived a median of four prior lines of ther­apy, in­clud­ing half who had pre­vi­ously used Revlimid.

Around 11 per­cent of patients achieved at least a partial re­sponse. The most common side effects reported were low white blood cell counts and low platelet counts.

Monoclonal anti­body ther­apy and cancer vaccines

Researchers are also investigating the ef­fi­cacy of mono­clonal anti­bodies and cancer vaccines in com­bi­na­tion with Revlimid for the treat­ment of re­frac­tory and re­lapsed mul­ti­ple myeloma patients.

Monclonal anti­bodies induce the patient’s own im­mune sys­tem into attacking and elim­i­nat­ing tumors.

According to the authors of the review, pre­lim­i­nary reports from on­go­ing Phase 1/2 clin­i­cal trials that com­bine Revlimid with human anti­body drugs elotuzumab ^[14], lorvotuzumab mertansine ^[15], and dacetuzumab ^[16] show promising re­­sults.

Cancer vaccines also work to en­hance the body’s im­mune sys­tem in fighting and preventing can­cer­ous growth.

Results of a pre­clin­i­cal study show that a lym­phoma vaccine com­bined with Revlimid im­proved sur­vival and en­hanced cel­lu­lar immunity, com­pared to either treat­ment alone.

Results of another pre­clin­i­cal study show that Revlimid boosted vaccine re­sponses to a dendritic cell vaccine.

According the authors of the review, these trials in cancer vaccines show that Revlimid may im­prove im­mune dysfunction and may serve as an adjuvant for myeloma vaccines.

For more in­for­ma­tion, please see the review in the journal Cancer Man­age­ment and Re­search ^[17] (pdf).