In a recent review article pub­lished in the journal Clinical Cancer Re­search, two myeloma experts from the Dana-Farber Cancer In­sti­tute, Dr. Nikhil Munshi and Dr. Kenneth Anderson, review the latest strategies in the treat­ment of mul­ti­ple myeloma.

In their article, the experts discuss newer ther­a­pies that appear to be promising in clin­i­cal and pre­clin­i­cal stud­ies.

According to the physicians, com­bi­na­tion ther­a­pies that spe­cif­i­cally target a patient’s ge­netic form of the dis­ease will be re­quired for long-term dis­ease con­trol and ultimately a cure.

Some Historical Perspective

In their review article, Drs. Munshi and Anderson describe that 50 years ago, the use of melphalan ^[1] (Alkeran) and prednisone ^[2] im­proved the sur­vival of myeloma patients to a median of two to three years.  Following that, the use of high-dose chemo­ther­apy and stem cell trans­plan­ta­tion fur­ther im­proved sur­vival to a median of four to five years.

Furthermore, they state that the novel agents thalidomide ^[3] (Thalomid), Velcade ^[4] (bor­tez­o­mib), and Revlimid ^[5] (lena­lido­mide) have trans­formed how myeloma is treated.

According to Drs. Munshi and Anderson, the median sur­vival for myeloma patients has in­creased to over seven years as a re­­sult of these novel ther­a­pies.

Despite these ad­vances and the recent ap­prov­als of Kyprolis ^[6] (car­filz­o­mib) and Pomalyst ^[7] (poma­lido­mide), they point out that myeloma remains incurable for most patients.

Therefore, they state that fur­ther re­search is needed to de­vel­op addi­tional novel ther­a­pies (including immuno­therapy), to learn how to best use them in com­bi­na­tion, and to better under­stand how genomics (a patient’s DNA) can be used to personalize ther­apy.

Proteasome Inhibitors

Proteasome in­hib­i­tors are a class of drugs that work by preventing the breakdown of pro­tein in cancer cells, triggering their death.

Drs. Munshi and Anderson emphasize in their article that the pro­te­a­some in­hib­i­tor Velcade has been ex­treme­ly beneficial for newly diag­nosed as well as re­lapsed and re­frac­tory myeloma patients.

However, they point out that not all patients respond to Velcade and that those who do respond even­tu­ally relapse.

As a re­­sult, the authors be­lieve that addi­tional pro­te­a­some in­hib­i­tors and com­bi­na­tion ther­a­pies are needed to over­come Velcade re­sis­tance.

Kyprolis, another pro­te­a­some in­hib­i­tor, was approved by the U.S. Food and Drug Admin­istra­tion (FDA) in July 2012 for use in re­lapsed and re­frac­tory myeloma patients.

Specifically, Kyprolis was approved for myeloma patients who have already been treated with at least Vel­cade and either Revlimid or thalido­mide and who have also progressed on or within 60 days of com­plet­ing their last ther­apy (see re­lated Beacon ^[8] news).

According to the experts, Kyprolis im­proves upon Velcade by irreversibly in­hib­iting the pro­te­a­some and by causing less periph­eral neu­rop­athy (pain, tingling, or loss of sensation in the extremities).

They state that re­­sults from a Phase 1/2 trial show that 20 per­cent of re­lapsed and Velcade-resistant myeloma patients responded to Kyprolis for a median of 8 months.  They also state that Kyprolis pro­longed sur­vival (to 15 months) (see re­lated Beacon ^[9] news).

They point out that the re­sponse rate for Kyprolis is at least 40 per­cent in patients who have never been treated with Velcade.

Moreover, they state that the com­bi­na­tion of Kyprolis plus Revlimid and dexamethasone ^[10] (Decadron) appears ef­fec­tive in both re­lapsed and newly diag­nosed patients (see re­lated Beacon news about the com­bi­na­tion for relapsed ^[11] and newly diag­nosed ^[12] patients).

Drs. Munshi and Anderson fur­ther discuss sev­er­al addi­tional pro­te­a­some in­hib­i­tors that are still in clin­i­cal and pre­clin­i­cal devel­op­ment.

Results from clin­i­cal stud­ies of ixazomib ^[13] (MLN9708 ^[14]), an oral pro­te­a­some in­hib­i­tor, show that the drug is ef­fec­tive for re­lapsed and re­frac­tory myeloma patients as well as in com­bi­na­tion with Revlimid and dexa­metha­sone for newly diag­nosed patients (see re­lated Beacon ^[15] news).

Preclinical stud­ies of another pro­te­a­some in­hib­i­tor known as marizomib ^[16] (NPI-0052) in­di­cate that the drug may be ef­fec­tive in patients who no longer respond to Velcade, and early clin­i­cal trial re­­sults show signs of ef­fi­cacy (see re­lated Beacon ^[17] news).

The authors rec­om­mend the devel­op­ment of addi­tional novel drugs that use other methods to block pro­tein degradation.

Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) in­hib­i­tors work by in­creas­ing the pro­duc­tion of pro­teins that slow cell division and cause cell death.

Zolinza ^[18] (vorinostat) is an oral HDAC in­hib­i­tor that is already approved in the United States, Canada, and Australia for a cer­tain type of lym­phoma.  It is not yet avail­able, how­ever, in Europe.

Drs. Munshi and Anderson highlighted re­­sults from a Phase 3 study with myeloma patients that showed the over­all re­sponse rate for Zolinza plus Velcade was 54 per­cent, com­pared to 41 per­cent for Velcade alone.  However, the addi­tion of Zolinza only had a small im­pact on pro­gres­sion-free sur­vival: 7.6 months for the com­bi­na­tion versus 6.8 months for Velcade alone (see re­lated Beacon ^[19] news).

Another Zolinza study that the authors did not mention showed that 53 per­cent of re­lapsed and re­frac­tory myeloma patients responded to treat­ment with Zolinza plus Revlimid and dexa­meth­a­sone (see re­lated Beacon ^[20] news).

Finally, the experts highlighted a study of the HDAC in­hib­i­tor ricolinostat ^[21] (ACY-1215), which has shown initial prom­ise alone and in com­bi­na­tion with Velcade (see re­lated Beacon ^[22] news).

The authors do not, how­ever, discuss the poten­tial of panobinostat ^[23] (Farydak ^[24]), another HDAC in­hib­i­tor that is cur­rently in Phase 3 testing for myeloma.

Immunomodulatory Drugs

Immunomodulatory drugs are a class of drugs that in­clude thalido­mide, Revlimid, and Pomalyst and work by inducing a patient’s im­mune sys­tem to attack and destroy myeloma cells.

Dr. Munshi and Dr. Anderson ex­plain that thalido­mide and Revlimid have be­come commonly used for newly diag­nosed and re­lapsed myeloma patients as well as part of main­te­nance ther­apy.

They describe Pomalyst, which was approved in Feb­ru­ary by the FDA for use in re­lapsed mul­ti­ple myeloma patients, as the most potent of the three, with an over­all re­sponse rate of 30 per­cent to 40 per­cent in patients who are both Revlimid and Velcade resistant.

Specifically, Pomalyst was approved for use in patients with mul­ti­ple myeloma who have re­ceived at least two prior ther­a­pies in­clud­ing Revlimid and Velcade and have demon­strat­ed dis­ease pro­gres­sion on or with­in 60 days of com­ple­tion of the last ther­apy (see re­lated Beacon ^[25] news).

There are many on­go­ing Pomalyst stud­ies, but the authors highlighted in par­tic­u­lar those studying Pomalyst in com­bi­na­tion with a pro­te­a­some in­hib­i­tor, such as Velcade or Kyprolis.

Monoclonal Antibodies

Monclonal anti­bodies teach a patient’s own im­mune sys­tem to attack and elim­i­nate cancer cells.

The authors state that among the many mono­clonal anti­bodies that have been studied in myeloma, elo­tu­zu­mab ^[26] is one of the most promising for the treat­ment of mul­ti­ple myeloma.

Although clin­i­cal stud­ies have shown elotuzumab has lim­ited ef­fi­cacy by itself, they have also shown that elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone is par­tic­u­larly ef­fec­tive in re­lapsed myeloma patients.  In par­tic­u­lar, the over­all re­sponse rate for the com­bi­na­tion was 82 per­cent and the median pro­gres­sion-free sur­vival was not yet reached at a median follow-up time of 16.4 months (see re­lated Beacon ^[27] news).

The experts also highlighted daratumumab ^[28], which has shown initial prom­ise in heavily pre­treated myeloma patients (see re­lated Beacon ^[29] news), and BT-062 ^[30], which consists of a chemo­ther­a­peu­tic drug com­bined with an anti­body that helps de­liver the drug to myeloma and other cancer cells (see re­lated Beacon ^[31] news).

They also mentioned siltuximab ^[32], BHQ880 ^[33], tabalumab ^[34], and denosumab ^[35] as having prom­ise for myeloma or myeloma-related bone dis­ease.

Therapeutic Vaccines

Drs. Munshi and Anderson state that, based on the success of donor (allogeneic) stem cell trans­plants in achieving long-term remission, thera­peutic vaccination ap­proaches are being studied for the treat­ment of myeloma.

Therapeutic vaccines ^[36] stim­u­late an im­mune re­sponse against an already estab­lish­ed dis­ease, such as myeloma or other types of cancer.

When devel­op­ing thera­peutic vaccines for myeloma, re­searchers must vaccinate against components (anti­gens) that are present in myeloma cells but not nor­mal cells.

Drs. Munshi and Anderson highlight in their review a num­ber of an­ti­gens that are being targeted by dif­fer­en­t myeloma vaccines and mention that sev­er­al personalized vaccines have shown ben­e­fit fol­low­ing stem cell trans­plan­ta­tion.

The authors sug­gest that vaccination is best used early in the dis­ease course or in the presence of minimal residual dis­ease.

Additional Promising Approaches

Both authors ex­pec­t the treat­ment of myeloma to rapidly change in the com­ing years. They discuss three new targets that have shown promising re­­sults in pre­clin­i­cal trials: BET bromodomains, MMSET, and BTK.

BET bromodomains are in­volved in regulating the cell cycle and cell death. The re­searchers sug­gest that drugs that target bromodomains may be able to trigger death of myeloma cells.  They mention JQ1 as the first drug to target BET bromodomains and to show ac­­tiv­ity in pre­clin­i­cal myeloma stud­ies.

MMSET is a cancer-causing gene asso­ci­ated with the t(4;14) chromosomal ab­nor­mal­ity that is present in about 15 per­cent of myeloma patients. The authors sug­gest that small-molecule drugs could be used to in­hib­it MMSET and spe­cif­i­cally treat myeloma patients with the t(4;14) chromosomal ab­nor­mal­ity.

Finally, BTK is a pro­tein that plays a role in the growth of both myeloma and bone cells. Inhibitors of BTK may be able to slow myeloma cell growth as well as myeloma-associated bone degradation.

In addi­tion, the authors stressed the need to de­vel­op personalized ther­a­pies for myeloma patients based on their spe­cif­ic ge­netic ab­nor­mal­i­ties.

They point out that cer­tain chromosomal ab­nor­mal­i­ties, such as t(4;14), t(14;16), and del(17p13), have been asso­ci­ated with poor prog­nosis in myeloma patients.

They sug­gest that the next step is to de­vel­op treat­ments that target these ab­nor­mal­i­ties as well as ones that cause drug re­sis­tance, especially at early stages of the dis­ease.

In addi­tion, they state that com­bi­na­tion ther­a­pies are key in the longer-term to overcoming drug re­sis­tance and im­prov­ing re­sponse in all patients.

"Ultimately," they conclude, "prolonged dis­ease free sur­vival and cure [are] on the horizon" for mul­ti­ple myeloma.

For more in­­for­ma­tion, please see the review article in the journal Clinical Cancer Re­search ^[37] (abstract).