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Experts Review Current And Future Research Into New Multiple Myeloma Treatments

By: Melissa Cobleigh; Published: October 19, 2011 @ 12:55 pm | Comments Disabled

Earlier this year, an inter­na­tional group of myeloma experts pub­lished a review of ongoing re­search into new myeloma treat­ments.  This review not only described a wide range of po­ten­tial new myeloma treat­ments, but also in­cluded the experts' thoughts on where re­search into new treat­ments should go in the future.

Given the recent new drug appli­ca­tion for car­filz­o­mib [1] and the upcoming annual meeting of the American Society of He­ma­tol­ogy -- which undoubtedly will host dis­cus­sions of many po­ten­tial new myeloma treat­ments -- it seems an appro­pri­ate time to go back to the experts' review from earlier this year and highlight some of its key points.

The experts begin their review by noting that, despite sig­nif­i­cant ad­vances in the treat­ment of mul­ti­ple myeloma during the last decade, it con­tinues to be chal­leng­ing to find ef­fec­tive therapies for patients at high risk for early relapse and for patients resistant to mul­ti­ple drugs or drug com­bi­na­tions.  This makes the search for new treat­ments par­tic­u­larly im­por­tant.

The Next Generation of Novel Agents

Regimens con­taining the novel agents Velcade [2] (bor­tez­o­mib), thalidomide [3] (Thalomid), and Revlimid [4] (lena­lido­mide) have played a key role in im­prov­ing progression-free and over­all sur­vival in multiple myeloma patients.  According to the authors of the review article, new drugs that work similarly as these novel agents, but have im­proved ef­fi­cacy or safety, have been showing par­tic­u­lar prom­ise in clin­i­cal trials over the past sev­er­al years.

Carfilzomib: The Next Generation Velcade

Velcade works by in­hib­iting pro­te­a­some, which is responsible for the break down of pro­teins in both healthy and can­cer­ous cells. Treatment with Velcade re­­sults in the accumulation of pro­teins within the cell, and it is be­lieved that this excess pro­tein leads to cell death, sup­pressing tumor growth.

Carfilzomib [5], which belongs to the same class of drugs as Velcade, has shown high ef­fi­cacy in clin­i­cal trials and may have fewer side effects than Velcade (see re­lated Beacon [6] news). Particularly notable are its lower rates of periph­eral neu­rop­athy (nerve damage in the extremities).

There also are other pro­te­a­some in­hib­i­tors under devel­op­ment for the treat­ment of myeloma, in­clud­ing salinosporamide A [7] (marizomib [8],NPI-0052), and MLN9708 [9]/MLN2238, a chemical cousin of Velcade that can be taken orally.

Pomalidomide: The Next Generation Revlimid

Pomalidomide [10] is closely re­lated to thalido­mide and Revlimid.  Although the exact ways in which this class of drugs works remain unclear, all three are immuno­modu­la­tory agents (drugs that affect the im­mune sys­tem), and they apparently encourage a patient’s im­mune sys­tem to attack and destroy myeloma cells. Clinical trials have shown that poma­lido­mide is ef­fec­tive in patients who are resistant to treat­ment with thalido­mide, Velcade, and Revlimid (see re­lated Beacon [11] news).

Dr. Vincent Rajkumar, a pro­fessor of med­i­cine at the Mayo Clinic, noted in a recent column for The Myeloma Beacon that, of the many drugs cur­rently in devel­op­ment for mul­ti­ple myeloma, only poma­lido­mide and car­filz­o­mib have shown sig­nif­i­cant single-agent ac­­tiv­ity in mul­ti­ple clin­i­cal trials (see re­lated Beacon [12] news).

In addi­tion to the im­prove­ments being made in the cur­rently avail­able mul­ti­ple myeloma drug classes, on­go­ing re­search is being done to identify new classes of drugs.

The authors of the review article be­lieve that sev­er­al drugs, while not showing po­ten­tial as single agents themselves, may prove to be ef­fec­tive if given in com­bi­na­tion with other cur­rently approved drugs, such as Velcade (see re­lated Beacon [12] news).   These in­clude the histone deacetylase in­hib­i­tors, Zolinza [13] (vorinostat), panobinostat [14] (Farydak [15]) and Istodax [16] (romidepsin), which have shown ac­­tiv­ity when com­bined with Velcade.

The anti CS-1 anti­body, elotuzumab [17] has also been in­cluded in this list. This drug targets pro­teins that are dis­played on the surface of myeloma cells but not on healthy cells.  Clinical trials are cur­rently underway to examine the ac­­tiv­ity of elotuzumab in patients with re­frac­tory or re­lapsed myeloma. It is antic­i­pated that the drug will work best when com­bined with Revlimid and dexamethasone [18] (Decadron), rather than as a single agent.

Other po­ten­tial drugs that may work best in com­bi­na­tion with existing ther­a­pies in­clude heat shock pro­tein in­hib­i­tors (see re­lated Beacon [19] news), phosphoinositide 3-kinase path­way in­hib­i­tors (for example perifosine [20]), and mTOR in­hib­i­tors, such as Torisel [21] (temsirolimus).  At this time, how­ever, none of the drugs in these classes have been approved by the U.S. Food and Drug Admin­istra­tion (FDA) spe­cif­i­cally to treat mul­ti­ple myeloma.

The authors conclude their review of cur­rent re­search on new myeloma treat­ments by touching on an alphabet soup of drugs in early-stage clin­i­cal trials -- drugs such as ACE-011, BHQ880 [22], BI-505, defibrotide [23], GDC-0449, imetelstat [24] (GRN163L), MLN4924 [25], MLN8237, NVP-BEZ235, and siltuximab [26](CNT 328).  In addi­tion, the authors describe sev­er­al po­ten­tial early stage treat­ments that may stimulate the body's im­mune sys­tem to attack myeloma cells.

Improving Clinical Trial Results

According to the authors of the review, a large num­ber of drugs that are being devel­oped for mul­ti­ple myeloma have shown prom­ise in pre­clin­i­cal trials.  These pre­clin­i­cal trials are not carried out in humans, but instead in other models of the dis­ease, such as cells grown in the laboratory setting or small animals (for example mice).  The review authors point out, how­ever, that despite initial prom­ise, fewer than 10 per­cent of cancer drugs that begin testing in humans ever re­ceive ap­prov­al from the FDA for patient use.

The authors therefore stress that more pre­clin­i­cal testing is needed and that the models used during this testing should more closely mimic the dis­ease as it is observed in humans. They emphasize, for example, that the en­viron­ment surrounding the tumor is of equal importance to the tumor itself, and sug­gest that more models take this so-called “microenvirnoment” into more careful con­sid­er­a­tion.

They also rec­om­mend that patients be carefully selected when clin­i­cal trials of a drug begin.  Because some drugs may per­form better in spe­cif­ic patient pop­u­la­tions, these pop­u­la­tions should be estab­lished before the start of clin­i­cal trials, and patients should be screened to ensure they are in this pop­u­la­tion before they are en­rolled.

Personalized Treatment For Multiple Myeloma

The experts conclude their review by noting that, through work carried out over several decades, cancer biologists have discovered that cancer treat­ment cannot be a “one-size-fits-all” solu­tion.  At the same time, determining the best method for treating an in­di­vid­ual patient for their cancer at the correct time during their dis­ease has proven to be the most chal­leng­ing as­pect of re­search.  Many re­searchers be­lieve, how­ever, that this kind of “personalized ther­apy” offers the most hope for cancer patients.

In this regard, the authors note that the Inter­na­tional Staging System, the avail­a­bil­ity of ge­netic testing, and the devel­op­ment of risk classification sys­tems by in­sti­tu­tions such as the Mayo Clinic and the Uni­ver­sity of Arkansa have all con­trib­uted to greater individualization of multiple myeloma treatment.

The ultimate goal, ac­cord­ing to the review authors, will be to identify subsets of patients that will respond most ef­fec­tively to cer­tain drugs or drug com­bi­na­tions and, thereby, im­prove the pro­gres­sion-free and over­all sur­vival of myeloma patients.  Further in­ves­ti­ga­tion is there­fore needed into the classification of patients and the devel­op­ment of clin­i­cally relevant tests to identify patient classes.

While such stud­ies may not be easy to implement, the authors be­lieve that such issues are likely the next major frontier of myeloma re­search in the com­ing years.

For more in­­for­ma­tion, please see the review in the Journal of Clinical Oncology [27] (abstract).


Article printed from The Myeloma Beacon: https://myelomabeacon.org

URL to article: https://myelomabeacon.org/news/2011/10/19/experts-review-current-and-future-research-into-new-multiple-myeloma-treatments/

URLs in this post:

[1] new drug appli­ca­tion for car­filz­o­mib: https://myelomabeacon.org/news/2011/09/28/beacon-breakingnews-onyx-submits-carfilzomib-for-fda-approval/

[2] Velcade: https://myelomabeacon.org/resources/2008/10/15/velcade/

[3] thalidomide: https://myelomabeacon.org/resources/2008/10/15/thalidomide/

[4] Revlimid: https://myelomabeacon.org/resources/2008/10/15/revlimid/

[5] Carfilzomib: https://myelomabeacon.org/resources/2009/06/04/carfilzomib/

[6] Beacon: https://myelomabeacon.org../search/Carfilzomib

[7] salinosporamide A: https://myelomabeacon.org/resources/2009/11/04/npi-0052/

[8] marizomib: https://myelomabeacon.org/tag/Marizomib/

[9] MLN9708: https://myelomabeacon.org/tag/MLN9708/

[10] Pomalidomide: https://myelomabeacon.org/resources/2008/10/15/pomalidomide/

[11] Beacon: https://myelomabeacon.org../news/2010/12/07/pomalidomide-shows-promising-results-for-multiple-myeloma-patients-resistant-to-revlimid-and-velcade-ash-2010/

[12] Beacon: https://myelomabeacon.org../news/2011/04/15/promising-new-drugs-for-multiple-myeloma-will-the-future-come-soon-enough-by-dr-vincent-rajkumar/

[13] Zolinza: https://myelomabeacon.org/resources/2009/11/04/zolinza/

[14] panobinostat: https://myelomabeacon.org/resources/2009/12/03/panobinostat/

[15] Farydak: https://myelomabeacon.org/tag/farydak/

[16] Istodax: https://myelomabeacon.org/resources/2009/06/04/istodax/

[17] elotuzumab: https://myelomabeacon.org/resources/2009/12/03/elotuzumab/

[18] dexamethasone: https://myelomabeacon.org../resources/2008/10/15/dexamethasone/

[19] Beacon: https://myelomabeacon.org../news/2008/12/07/phase-iii-trials-of-hsp90-inhibitors-in-cancer-patients-underway/

[20] perifosine: https://myelomabeacon.org/resources/2009/11/04/perifosine/

[21] Torisel: https://myelomabeacon.org/resources/2009/12/03/torisel/

[22] BHQ880: https://myelomabeacon.org/tag/bhq880/

[23] defibrotide: https://myelomabeacon.org/resources/2010/02/04/defibrotide/

[24] imetelstat: https://myelomabeacon.org/tag/imetelstat/

[25] MLN4924: https://myelomabeacon.org/tag/MLN4924/

[26] siltuximab : https://myelomabeacon.org/tag/siltuximab/

[27] Journal of Clinical Oncology: http://jco.ascopubs.org/content/early/2011/04/11/JCO.2010.34.0760.abstract

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