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The Future Of Treatment For Multiple Myeloma

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Published: May 24, 2013 4:23 pm

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 (Alkeran) and prednisone 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 (Thalomid), Velcade (bor­tez­o­mib), and Revlimid (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 (car­filz­o­mib) and Pomalyst (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 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 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 (Decadron) appears ef­fec­tive in both re­lapsed and newly diag­nosed patients (see re­lated Beacon news about the com­bi­na­tion for relapsed and newly diag­nosed 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 (MLN9708), 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 news).

Preclinical stud­ies of another pro­te­a­some in­hib­i­tor known as marizomib (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 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 (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 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 news).

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

The authors do not, how­ever, discuss the poten­tial of panobinostat (Farydak), 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 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 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 news).

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

They also mentioned siltuximab, BHQ880, tabalumab, and denosumab 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 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 (abstract).

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8 Comments »

  • rosecitylady said:

    Thank you for this very informative article.

  • Eric said:

    Thanks for the look into myeloma's future. The vaccine approach sounds the most interesting to me. Lets hope it happens quickly.

  • terryl1 said:

    Let's hope their very positive last line comes to fruition soon.

  • Michele Augusto said:

    i go to dana farber...this gives me HOPE...ty so much ...keep working so i get to be a part of this in my lifetime..xo

  • Jan Stafl said:

    This is an excellent review of new approaches for MM treatment, and their targeted action. The next FDA approved med is likely to be a monoclonal antibody, but the exciting part for me is individualized therapy based on documented specific genetic abnormalities. I believe that immunotherapy will be the key to permanent cure for MM.
    One area of research that has received little attention in the US is hyperthermia therapy, in conjunction with the listed therapeutic options. It has been used successfully in various leukemia and lymphoma patients in Europe, and research in MM patients is needed. By inducing a febrile state under controlled conditions, our own immunologic defenses are turned on, with the release of natural killer cells and other endogenous defenses. Many other medications are likely to be more effective with therapeutic controlled hyperthermia. This inexpensive, low tech addition to the armamentarium used in many oncologic therapies is worth researching further.

  • DM Walking said:

    This may sound weird, but for those of us on less agressive but effective treatments - such as revlimid plus dexamethasone - I wonder whether these new approaches will pass us by. We cannnot simply add them to our current regimens. Trials based on such regiments are invariably for relapsed patients - and in some cases the newly diagnosed.

    And if our only access to them is upon relapse, then their efficacy may well be limited.

  • Claudia Tyrrell said:

    Can't find any information on the use of melanoma drugs against myeloma. So far insurance is denying coverage because the drug is approved for another cancer.

  • mike green said:

    dm walkings comment regarding i have also wondered about less aggresive(rev and dex) treatments. Does anyone else have any ideas about new approaches passing us by.