OTHER AGENTS

AKT / PI3K INHIBITORS

Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.
J Clin Oncol. 2011 Nov 10;29(32):4243-9.
Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, Densmore J, Krishnan A, Raje N, Bar M, Martin T, Schlossman R, Ghobrial IM, Munshi N, Laubach J, Allerton J, Hideshima T, Colson K, Poradosu E, Gardner L, Sportelli P, Anderson KC.
Perifosine is an alkylphospholipid that inhibits both Akt and PI3K. In this study, 84 patients with relapsed/refractory myeloma were treated with perifosine 50 mg/day + bortezomib, with or without dexamethasone. Response rate was 41%, and median progression-free survival was 6.4 months.

ARSENIC TRIOXIDE

Arsenic trioxide has no role in the routine management of relapsed myeloma.

Clinical activity of arsenic trioxide for the treatment of multiple myeloma.
Leukemia. 2002 Sep;16(9):1835-7.
Munshi NC, Tricot G, Desikan R, Badros A, Zangari M, Toor A, Morris C, Anaissie E, Barlogie B.
This is a phase II trial of arsenic trioxide in 14 patients with relapsed/refractory MM. Responses were seen in 3 patients, and prolonged stable disease in 1 patient. The longest response lasted 6 weeks.

Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2004 May;125(4):470-6.
Hussein MA, Saleh M, Ravandi F, Mason J, Rifkin RM, Ellison R.
This is a phase II study of arsenic trioxide in 24 patients with relapsed or refractory MM. Patients received arsenic trioxide 0.25 mg/kg/day for 5 days/week during the first 2 weeks of a 28-day cycle. 8 of 24 patients (33%) had reductions in serum M protein levels by at least 25%, and 6 patients (25%) had stable disease. The median duration of response was 130 days.

A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients.
Leukemia. 2004 Sep;18(9):1518-21.
Rousselot P, Larghero J, Arnulf B, Poupon J, Royer B, Tibi A, Madelaine-Chambrin I, Cimerman P, Chevret S, Hermine O, Dombret H, Claude Brouet J, Paul Fermand J.
In this study, 12 patients with relapsing or refractory MM patients were treated with arsenic - 10 patients with arsenic trioxide (ATO), and 2 with melarsoprol, an organic compound of arsenic. The melarsoprol arm was prematurely closed due to toxicity. In the ATO arm, median duration of treatment was 38 days (9-54). Results:
  - No complete or partial remission was observed
  - 3 patients had a minor response, i.e., a 25-49% reduction of serum M protein
  - 4 patients had a stabilization of the serum M protein level
Responses were of short duration in all cases.

The efficacy of arsenic trioxide for the treatment of relapsed and refractory multiple myeloma: a systematic review.
Cancer Treat Rev. 2009 Aug;35(5):425-30.
Röllig C, Illmer T.
[Review]

ASPIRIN

Does low-dose aspirin have antineoplastic effects in multiple myeloma?
Baz R, Hussein MA.
Br J Haematol. 2006 Aug;134(3):349-50.
These authors suspected that low-dose aspirin may have antineoplastic properties in MM. They retrospectively reviewed the outcomes of 84 MM patients who received aspirin and 19 who did not receive it. RR was 81% in the aspirin group and 63% in the no-aspirin group. The 1-year survival was 89% in the aspirin group and 68% in the no-aspirin group.

AURORA KINASES

A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191.
Leuk Lymphoma. 2016 Jun;57(6):1463-6.
Hay AE, Murugesan A, DiPasquale AM, Kouroukis T, Sandhu I, Kukreti V, Bahlis NJ, Lategan J, Reece DE, Lyons JF, Sederias J, Xu H, Powers J, Seymour LK, Reiman T.
AT9283 is a multi-targeted inhibitor of Aurora kinases A and B, as well as JAK2 and JAK3. The trial was closed due to slow accrual and toxicity (myelosuppression). The results were disappointing, because no responses were observed among the 8 patients enrolled.

BCL-2 INHIBITORS

Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients.
J Clin Oncol. 2005 Jun 20;23(18):4089-99.
Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B, Takebe N, Heyman M, Zwiebel J, Streicher H, Gocke CD, Tomic D, Flaws JA, Zhang B, Fenton RG.
In this study, 33 patients with MM received G3139, a Bcl-2 antisense oligonucleotide targeting the Bcl-2 mRNA. G3139 was administered as continuous IV infusion for 7 days. Thalidomide and dexamethasone were added on day 4, with 21-day cycles. RR: 55%. There were 6 minimal responses, 12 PR, 4 near CR (positive immunofixation), and 2 CR. The median duration of response was 13 months. PFS: 12 months. OS: 17.4 months.

BCL-2 INHIBITORS: VENETOCLAX

Venetoclax is an oral drug that specifically inhibits BCL-2 (B-cell lymphoma 2), a protein that inhibits apoptosis in B cells. Myeloma cells harboring the t(11;14) translocation are particularly sensitive to the treatment with venetoclax.

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.
Blood. 2017 Nov 30;130(22):2401-2409.
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C.
This is a phase I study of 66 patients with relapsed/refractory myeloma treated with single-agent venetoclax. Patients were heavily pretreated, because the median number of prior lines of therapy was 5, and 61% of patients were refractory to both bortezomib and lenalidomide. The overall response rate was 21%, with 15% VGPR or better. In the group with t(11;14), which constituted 46% of cases, the response rate was 40%, with 27% VGPR or better. 86% of responses were seen in patients with the t(11;14) translocation. The safety profile was very good, and the main toxicities were gastrointestinal and hematological.

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM.
Blood. 2017 Nov 30;130(22):2392-2400.
Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, Touzeau C, Punnoose EA, Cordero J, Munasinghe W, Jia J, Salem AH, Freise KJ, Leverson JD, Enschede SH, Ross JA, Maciag PC, Verdugo M, Harrison SJ.
This is a phase I study of 66 patients with relapsed/refractory myeloma treated with venetoclax, in combination with bortezomib and dexamethasone. The median number of prior lines of therapy was 3. The overall response rate was 67%, with 42% VGPR or better. Median progression-free survival was 9.5 months.

CDK INHIBITORS

Dinaciclib

Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma.
Blood. 2015 Jan 15;125(3):443-8.
Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, Fruth B, Roy V, Erlichman C, Stewart AK; Mayo Phase 2 Consortium.
Dinaciclib is a small molecule inhibitor of several cyclin-dependent kinases (CDK1, CDK2, CDK5, and CDK9). Among 27 patients with relapsed myeloma, single agent dinaciclib showed a clinical benefit rate of 19% (3 PR and 2 minor responses.

Palbociclib

Phase 1/2 study of CDK4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.
Leuk Lymphoma. 2015 Mar 27:1-21.
Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan AA, Raab MS, Tarantolo S, Vij R, Zonder JA, Huang X, Jayabalan D, DiLiberto M, Huang X, Jiang Y, Kim ST, Randolph S, Chen-Kiang S.
Palbociclib is a specific inhibitor of the cyclin-dependent kinase (CDK) 4/6. In the phase 2 portion of this study, response rate was 20%, and disease stability was observed in 44% of patients.

FARNESYLTRANSFERASE INHIBITORS

Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma.
Blood. 2004 May 1;103(9):3271-7.
Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, Overton RM, Ahmann G, Bruzek LM, Adjei AA, Kaufmann SH, Wright JJ, Sullivan D, Djulbegovic B, Cantor AB, Greipp PR, Dalton WS, Sebti SM.
This study evaluated the activity of the farnesyltransferase inhibitor tipifarnib (Zarnestra) in 43 patients with MM. Dose: 300 mg PO bid for 3 weeks every 4 weeks. 64% of patients had disease stabilization. The most common toxicity was fatigue (66%).

FILANESIB

A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma.
Cancer. 2017 Dec 1;123(23):4617-4630.
Shah JJ, Kaufman JL, Zonder JA, Cohen AD, Bensinger WI, Hilder BW, Rush SA, Walker DH, Tunquist BJ, Litwiler KS, Ptaszynski M, Orlowski RZ, Lonial S.
In this study, 63 patients with relapsed/refractory myeloma received filanesib (ARRY-520), a selective inhibitor of kinesin spindle protein, either as single agent or in combination with dexamethasone. Patients were heavily pretreated. In the phase I of the study, the most common dose-limiting toxicities were neutropenic fever and mucositis. Among 32 evaluable patients treated in the phase 2 of the study, response rates were 16% as single agent and 15% in combination with dexamethasone.

FLAVOPIRIDOL

Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points.
Haematologica. 2006 Mar;91(3):390-3.
Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Fitch TR, Fenton RG, Fonseca R, Isham CR, Ziesmer SC, Erlichman C, Bible KC.
No responses were observed in 18 myeloma patients treated with flavopiridol, given as IV infusion over 1 hour on days 1-3 every 21 days.

HEAT SHOCK PROTEINS INHIBITORS

Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study.
Br J Haematol. 2011 Jun;153(6):729-40.
Richardson PG, Chanan-Khan AA, Lonial S, Krishnan AY, Carroll MP, Alsina M, Albitar M, Berman D, Messina M, Anderson KC.
72 patients with relapsed/refractory myeloma were treated with tanespimycin, a HSP90 inhibitor, in combination with bortezomib. RR was 27% (12% minimal responses, 12% partial responses, and 3% complete responses).

IBRUTINIB

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results.
Br J Haematol. 2018 Mar;180(6):821-830.
Richardson PG, Bensinger WI, Huff CA, Costello CL, Lendvai N, Berdeja JG, Anderson LD Jr., Siegel DS, Lebovic D, Jagannath S, Laubach JP, Stockerl-Goldstein KE, Kwei L, Clow F, Elias L, Salman Z, Graef T, Bilotti E, Vij R.
In this clinical trial, 92 patients with relapsed/refractory myeloma received dexamethasone 40 mg once a week, and ibrutinib once a day at various doses. Patients were heavily pretreated, because they received a median of 4 prior chemotherapy regimens. Clinical benefit, defined as at least a minor response, was observed in 28% of patients receiving ibrutinib 840 mg daily. Median progression-free survival was 4.6 months (range, 0.4-17.3).

IAP INHIBITORS

IAP antagonists induce anti-tumor immunity in multiple myeloma.
Nat Med. 2016 Dec;22(12):1411-1420.
Chesi M, Mirza NN, Garbitt VM, Sharik ME, Dueck AC, Asmann YW, Akhmetzyanova I, Kosiorek HE, Calcinotto A, Riggs DL, Keane N, Ahmann GJ, Morrison KM, Fonseca R, Lacy MQ, Dingli D, Kumar SK, Ailawadhi S, Dispenzieri A, Buadi F, Gertz MA, Reeder CB, Lin Y, Chanan-Khan AA, Stewart AK, Fooksman D, Bergsagel PL.
This is a study done in mouse models and patients with relapsed/refractory myeloma. The use of LCL161, a small-molecule IAP antagonist, led to anti-myeloma activity significant remission of the disease. cIAP = cellular inhibitors of apoptosis, 1 and 2.

MEK INHIBITORS

A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma.
Clin Cancer Res. 2016 Mar 1;22(5):1067-75.
Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, Korde N, Lin HY, Chen JQ, Herrmann M, Xi L, Raffeld M, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C, Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M, Roberts JD, Sullivan D, Landgren O, Grant S.
In this study, 36 patients with relapsed/refractory myeloma received treatment with selumetinib 75 mg twice a day. unfortunately, the activity in this heavily pretreated patient population was minimal (response rate was only 6%, and the median progression-free survival was 3.5 months).

MET INHIBITORS

Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma.
Ann Hematol. 2017 Jun;96(6):977-985.
Baljevic M, Zaman S, Baladandayuthapani V, Lin YH, de Partovi CM, Berkova Z, Amini B, Thomas SK, Shah JJ, Weber DM, Fu M, Cleeland CS, Wang XS, Stellrecht CM, Davis RE, Gandhi V, Orlowski RZ.
This is a phase II study of tivantinib, a c-MET inhibitor, in 16 patients with relapsed/refractory myeloma. There was no response, but 4 of 11 evaluable patients (36%) had stable disease.

mTOR INHIBITORS

Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma.
Leuk Res. 2009 Nov;33(11):1475-80.
Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K, Dancey JE, Grever MR.
This is a phase II trial of temsirolimus (25mg IV weekly) in patients with relapsed or refractory myeloma. The activity of temsirolimus was modest: only 1 PR (RR 6%) and 5 minor responses among 16 patients. The median time to progression was about 4.6 months.

Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study.
Lancet Oncol. 2011 Mar;12(3):263-72.
Ghobrial IM, Weller E, Vij R, Munshi NC, Banwait R, Bagshaw M, Schlossman R, Leduc R, Chuma S, Kunsman J, Laubach J, Jakubowiak AJ, Maiso P, Roccaro A, Armand P, Dollard A, Warren D, Harris B, Poon T, Sam A, Rodig S, Anderson KC, Richardson PG.
A total of 63 patients with relapsed/refractory myeloma were treated with bortezomib and temsirolimus. In the phase II portion of the study (43 patients), response rate was 33%.

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.
Am J Hematol. 2016 Jun;91(4):400-5.
Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, Patel CG, Zohren F, Wolf JL.
In this phase 1 study, 31 patients with relapsed/refractory myeloma received TAK-228, an oral TORC1/2 inhibitor. One patient had a minimal response, and 14 patients had stable disease.

OBLIMERSEN SODIUM

Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma.
Leuk Lymphoma. 2009 Apr;50(4):559-65.
Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S.
Oblimersen sodium is a bcl-2 antisense oligonucleotide which decreases the transcription of the bcl-2 protein. 224 patients with relapsed/refractory myeloma were randomized to receive either dexamethasone (114 pts) or the combination dexamethasone + oblimersen (110 pts). No significant differences between the two groups were seen in RR or TTP.

PENTIXATHER

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.
J Nucl Med. 2016 Feb;57(2):248-51.
Herrmann K, Schottelius M, Lapa C, Osl T, Poschenrieder A, Hänscheid H, Lückerath K, Schreder M, Bluemel C, Knott M, Keller U, Schirbel A, Samnick S, Lassmann M, Kropf S, Buck AK, Einsele H, Wester HJ, Knop S.
Pentixather is a chemokine receptor 4 (CXCR4) inhibitor. The authors studied the effect of 177Lu- and 90Y-labeled pentixather in three patients with aggressive and heavily pretreated multiple myeloma. They used a radiolabeled CXCR4 ligand (pentixafor) for diagnostic receptor targeting. Patients received additional chemotherapy and autologous transplant. A significant therapeutic response was observed in 2 patients.

RESVERATROL

A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma.
Br J Haematol. 2013 Mar;160(5):714-7.
Popat R, Plesner T, Davies F, Cook G, Cook M, Elliott P, Jacobson E, Gumbleton T, Oakervee H, Cavenagh J.
Resveratrol is a phytoalexin, naturally produced by several plants. Despite its demonstrated activity against myeloma cells in vitro, it lacked clinical efficacy (no response was observed) in this phase II trial of 24 patients with relapsed/refractory multiple myeloma.

SELINEXOR

Selinexor is a selective inhibitor of exportin 1 (XPO1), a protein found in the nucleus of cancer cells. It induces apoptosis of cancer cells through the retention of tumor suppressor proteins and the glucocorticoid receptor in the nucleus. Selinexor also reduces the expression of oncogenes such as c-myc and bcl-2.

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia.
Blood. 2018 Feb 22;131(8):855-863.
Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N, Baz R, Mau-Sorensen M, Berdeja JG, Savona M, Savoie L, Trudel S, Areethamsirikul N, Unger TJ, Rashal T, Hanke T, Kauffman M, Shacham S, Reece D.

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma.
J Clin Oncol. 2018 Mar 20;36(9):859-866.
Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK.
 In this trial, 79 patients with relapsed myeloma received selinexor 80 mg and dexamethasone 20 mg, both orally and twice a week. Patients were heavily pretreated: they received a median of 7 prior chemotherapy regimens, and most of them were refractory to available agents. The response rate was 21%, and the median duration of response was 5 months. Among responding patients, 1-year survival was 65%.

SERINE/THREONINE KINASE INHIBITORS

A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma.
Am J Hematol. 2011 Jul;86(7):573-8.
Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R.
Enzastaurin is a serine/threonine kinase inhibitor that inhibits the protein kinase C and AKT pathways. 23 patients with relapsed/refractory myeloma were treated with enzastaurin in combination with bortezomib. In this phase I study, 4 patients showed response to therapy, and 9 additional patients had stable disease.

A multicenter phase II study of single-agent enzastaurin in previously treated multiple myeloma.
Leuk Lymphoma. 2014 Sep;55(9):2013-7.
Jourdan E, Leblond V, Maisonneuve H, Benhadji KA, Hossain AM, Nguyen TS, Wooldridge JE, Moreau P.
Enzastaurin is an oral serine/threonine kinase inhibitor. It was ineffective in this clinical trial, as it produced only 1 minimal response among 14 patients with relapsed/refractory myeloma.

TNF INHIBITORS

Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment.
Leuk Res. 2003 May;27(5):375-80.
Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ.
No responses were observed in 10 patients with refractory myeloma treated with Enbrel, a TNF antagonist fusion protein.

TRAIL

Phase II open-label study of recombinant circularly permuted TRAIL as a single-agent treatment for relapsed or refractory multiple myeloma.
Chin J Cancer. 2016 Sep 8;35(1):86.
Leng Y, Qiu L, Hou J, Zhao Y, Zhang X, Yang S, Xi H, Huang Z, Pan L, Chen W.
Circulating permutated TRAIL (CPT) is a recombinant form of Apo2L/TRAIL (apoptosis ligand 2/TNF-related apoptosis-inducing ligand), a member of the TNF superfamily that binds to death receptors 4 and 5 (DR4 and DR5), and induces apoptosis. I this study, the authors administered CPT in 27 patients with relapsed/refractory multiple myeloma, and obtained a response rate of 33%.

TYROSINE KINASE INHIBITORS

A phase II trial of imatinib in patients with refractory/relapsed myeloma.
Leuk Lymphoma. 2006 Jan;47(1):39-42.
Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Greipp PR, Rajkumar SV, Kimlinger T, Lust JA, Fonseca R, Allred J, Witzig TE.
Imatinib inhibits not only the bcr-abl protein, but also other receptor tyrosine kinases, such as c-kit. In this study, 23 patients with relapsed/refractory myeloma were treated with imatinib 400 mg daily for a median duration of 48 days (range: 12-349). 52% of cases had positive c-kit staining. Imatinib was inactive, because there were no responses.

Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation.
Eur J Haematol. 2015 Oct;95(4):316-24.
Scheid C, Reece D, Beksac M, Spencer A, Callander N, Sonneveld P, Kalimi G, Cai C, Shi M, Scott JW, Stewart AK.
In this study, 43 patients with relapsed or refractory myeloma were treated with dovitinib, a receptor tyrosine kinase inhibitor that targets FGFR3. Thirteen patients had the t(4;14) translocation. The results were disappointing, because no objective responses were observed.

VEGF INHIBITORS

Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma.
Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):88-95.
Zangari M, Anaissie E, Stopeck A, Morimoto A, Tan N, Lancet J, Cooper M, Hannah A, Garcia-Manero G, Faderl S, Kantarjian H, Cherrington J, Albitar M, Giles FJ.
In this study, 27 patients with advanced MM were treated with SU5416, a VEGF receptor 2 inhibitor. Four patients had disease stabilization for at least 4 months. There were no objective responses.

A phase II study of ZD6474 (Zactima), a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma - NCIC CTG IND.145.
Invest New Drugs. 2006 Nov;24(6):529-35.
Kovacs MJ, Reece DE, Marcellus D, Meyer RM, Mathews S, Dong RP, Eisenhauer E.
This is a phase II trial of ZD6474 (Zactima) given at 100 mg p.o. daily in 18 patients with relapsed multiple myeloma. There was no clinical benefit, because none of the patients had a reduction in the paraprotein level.

Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034).
Blood. 2009 May 7;113(19):4819-20
Prince HM, Hönemann D, Spencer A, Rizzieri DA, Stadtmauer EA, Roberts AW, Bahlis N, Tricot G, Bell B, Demarini DJ, Benjamin Suttle A, Baker KL, Pandite LN.

Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial.
Br J Haematol. 2011 Aug;154(4):533-5.
Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O'Donnell MR, Mohrbacher AF, Forman SJ, Frankel P, Chen HX, Doroshow JH, Gandara DR.
This is a phase II trial, which was closed prematurely due to poor accrual. Results were not encouraging, as median EFS among 12 evaluable patients was less than 2 months.

Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma.
Cancer. 2013 Jan 15;119(2):339-47.
White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE.
Patients with relapsed or refractory myeloma were randomized to receive bortezomib (53 patients) or bortezomib + bevacizumab (49 patients). The addition of bevacizumab did not improve clinical outcomes, because differences of response rate (51% in the bevacizumab-containing arm vs 43% in the bortezomib arm) and PFS (6.2 months in the bevacizumab-containing arm vs 5.1 months in the bortezomib only arm) were not statistically significant.

VEMURAFENIB

Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3.
Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM.

Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
N Engl J Med. 2015 Aug 20;373(8):726-36.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J.
In this study, 122 patients with cancers positive for the BRAF V600 mutation received treatment with vemurafenib. Five of them had myeloma - no responses were observed.

VITAMINS

RETINOIC ACID

Pilot study of 13cis-retinoic acid+dexamethasone+alpha interferon as maintenance therapy following high-dose chemotherapy and autologous stem cell transplant for multiple myeloma.
Bone Marrow Transplant. 2005 May;35(10):979-84.
Friedman J, Khoury H, Adkins D, Devine S, Nervi B, Edwards T, Dipersio J, Vij R.
33 patients with multiple myeloma treated with autologous stem cell transplantation were given maintenance therapy with 13-cis-retinoic acid, dexamethasone, and interferon alpha. After a median follow-up of 35 months, only 34% of patients were in remission, and 33% died. The median progression-free survival from diagnosis was 35 months.

VITAMIN C

Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells.
Clin Cancer Res. 2006 Jan 1;12(1):273-80.
Zou W, Yue P, Lin N, He M, Zhou Z, Lonial S, Khuri FR, Wang B, Sun SY.
These authors studied the interaction between vitamin C and bortezomib in human cancer cell lines. They found that vitamin C abrogated the ability of bortezomib to inhibit the proteasome activity and induce apoptosis. There was a direct chemical interaction between vitamin C and bortezomib. Vitamin C directly binds to bortezomib and it may suppress the anticancer activity of bortezomib. These findings are relevant because many cancer patients routinely take multivitamins.

VITAMIN D

Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells.
J Natl Cancer Inst. 2003 Jun 18;95(12):896-905.
Kumagai T, O'Kelly J, Said JW, Koeffler HP.

Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myeloma.
Am J Hematol. 2009 Jul;84(7):397-400.
Ng AC, Kumar SK, Rajkumar SV, Drake MT.
These authors evaluated serum levels of 25-hydroxyvitamin D in 148 consecutive patients at baseline, within 14 days of diagnosis. Vitamin D deficiency was found in 16% of patients in stage I, 20% in stage II, and 37% in stage III ISS. Patients with vitamin D deficiency (defined as a level <50 nmol/L or <20 ng/mL) had higher serum creatinine, higher ISS stage at time of diagnosis, and poorer prognosis.

HORMONES

ESTROGENS/ANTIESTROGENS

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells.
Blood. 2002 Sep 15;100(6):2187-94.
Chauhan D, Catley L, Hideshima T, Li G, Leblanc R, Gupta D, Sattler M, Richardson P, Schlossman RL, Podar K, Weller E, Munshi N, Anderson KC.

Promising preclinical activity of 2-methoxyestradiol in multiple myeloma.
Clin Cancer Res. 2002 Dec;8(12):3948-54.
Dingli D, Timm M, Russell SJ, Witzig TE, Rajkumar SV.

Multicenter phase II feasibility trial of high-dose tamoxifen in patients with refractory or relapsed multiple myeloma.
J Natl Cancer Inst. 2004 Apr 21;96(8):636-7.
Decaudin D, Etienne MC, De Cremoux P, Maciorowski Z, Vantelon JM, Voog E, Urien S, Tran-Perennou C, Renée N, Vielh P, Némati F, Pouillart P.
This trial was prematurely stopped after 6 patients were included, because of overall lack of response and neurologic toxicity.

2-Methoxyestradiol at low dose induces differentiation of myeloma cells.
Leuk Res. 2005 Sep;29(9):1059-67.
Hou J, Xiong H, Gao W, Jiang H.
2ME2 induced maturation of myeloma cells and increased the secretion of light chain proteins.

Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma.
Clin Cancer Res. 2007 Oct 15;13(20):6162-7.
Rajkumar SV, Richardson PG, Lacy MQ, Dispenzieri A, Greipp PR, Witzig TE, Schlossman R, Sidor CF, Anderson KC, Gertz MA.
This is the first phase II trial of 2-methoxyestradiol in multiple myeloma. 60 patients were treated. PFS at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. There were no partial responses, and minor response was observed in 2 patients.

SOMATOSTATIN ANALOGS

The somatostatin analog octreotide inhibits growth of interleukin-6 (IL-6)-dependent and IL-6-independent human multiple myeloma cell lines.
Blood. 1999 Mar 1;93(5):1724-31.
Georgii-Hemming P, Strömberg T, Janson ET, Stridsberg M, Wiklund HJ, Nilsson K.

PPAR

Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands.
Clin Immunol. 2004 Nov;113(2):203-13.
Ray DM, Bernstein SH, Phipps RP.

PPARbeta-mediated growth suppression of baicalein and dexamethasone in human myeloma cells.
Leukemia. 2007 Jan;21(1):187-90.
Otsuyama KI, Ma Z, Abroun S, Amin J, Shamsasenjan K, Asaoku H, Kawano MM.

Giampaolo Talamo, M.D.