BORTEZOMIB-BASED COMBINATIONS REGIMENS

 

Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens.
J Clin Oncol. 2015 Nov 20;33(33):3921-9.
Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J.
This trail randomized 502 transplant-ineligible patients with multiple myeloma into three bortezomib-based treatments: VD (bortezomib-dexamethasone, 168 patients), VTD (bortezomib-thalidomide-dexamethasone, 167 patients), and VMP (bortezomib-melphalan-dexamethasone, 167 patients). After 24 weeks, patients received maintenance with weekly bortezomib for 25 weeks. The three-drug combinations VTD and VMP did not offer significantly better results compared to the two drug combination. With VD, response rate was 73%, median progression-free survival was 15 months, and median overall survival was 50 months.

 

 

COMBINATIONS WITH MELPHALAN

Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.
J Clin Oncol. 2006 Feb 20;24(6):937-44.
Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R.
35 patients with relapsed or refractory multiple myeloma received melphalan in escalating doses from 0.025 to 0.25 mg/kg PO on days 1-4 + bortezomib 0.7-1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to 8 cycles. The maximum-tolerated dose (MTD) was melphalan 0.10 mg/kg + bortezomib 1.0 mg/m2. Results:
  - RR was 83%, CR was 6%
  - Median progression-free survival was 8 months (range, 2-18 months)
  - The most important toxicity was myelosuppression

Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial.
Lancet Oncol. 2010 Oct;11(10):934-41.
Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF.
260 patients of age 65 and older with newly diagnosed myeloma were randomized in to groups:
  - VMP (Velcade, Melphalan, Prednisone) (130 patients) x6 cycles
  - VTP (Velcade, Thalidomide, Prednisone) (130 patients) x6 cycles
then maintenance therapy with either VP (87 patients) or VT (91 patients).
Results after induction therapy:
  - Rate of partial response or better: 80% with VMP and 81% with VTP (p= 0.90)
  - Rate of complete response: 20% with VMP and 28% with VTP (p= 0.20)
  - Discontinuation of therapy due to toxicity was higher with VTP (17% vs 12%, p= 0.03)
  - Grade III/IV peripheral neuropathy: 9% with VMP and 7% with VTP
Results after maintenance therapy:
  - Rate of complete response: 39% with VP and 42% with VT
At the time of this publication, many myeloma experts believed that bortezomib was able to overcome the negative prognostic impact of adverse cytogenetic features. However, in this study, patients with high-risk disease had worse progression-free survival and overall survival despite bortezomib.

Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial.
J Clin Oncol. 2010 Dec 1;28(34):5101-9.
Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M.
511 patients with newly diagnosed myeloma not eligible for stem cell transplantation were randomized in two groups:
  - VMP (bortezomib-melphalan-prednisone) x 9 cycles
  - VMPT (bortezomib-melphalan-prednisone-thalidomide) x 9 cycles, followed by maintenance with VT (bortezomib-thalidomide)
Results:
  - Complete response rate: 38% with VMP-VT, and 24% with VMP (p <0.001)
  - Progression-free survival at 3 years: 56% with VMP-VT, and 41% with VMP (p= 0.008)
  - Overall survival at 3 years: 89% with VMP-VT, and 87% with VMP (p= 0.008)
  - Thromboembolic events: 5% with VMP-VT, and 2% with VMP (p= 0.08)
  - Treatment-related mortality: 4% with VMP-VT, and 3% with VMP

 

MPV

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.
Blood. 2006 Oct 1;108(7):2165-72.
Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF.
At the time of this trial, the standard first-line treatment for elderly patients multiple myeloma was melphalan and prednisone (MP). In this phase I/II trial, 60 patients with multiple myeloma aged 65 years or older were treated with a combination of bortezomib, melphalan, and prednisone (VMP). Response rate was 89%, including 32% CR. When compared with historical controls from patients treated with MP, VMP produced better results:
  - Response rate: 89% with VMP vs 42% with MP
  - Event-free survival at 16 months: 83% with VMP vs 51% with MP
  - Overall survival at 16 months: 90% with VMP vs 62% with MP

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression.
Haematologica. 2008 Apr;93(4):560-5.
Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF.
This is an updated analysis of a previously reported trial of VMP (bortezomib, melphalan, and prednisone) in elderly patients with newly diagnosed myeloma. After a median follow-up of 26 months:
  - Median time to progression: 27 months with VMP vs 20 months with MP
  - Median overall survival: not reached with VMP vs 26 months with MP
  - 3-year survival: 85% with VMP vs 38% with MP
Since time to progression was not significantly influenced by cytogenetic abnormalities, the authors believed that VMP could overcome the adverse prognostic impact of high-risk cytogenetic abnormalities.

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.
N Engl J Med. 2008 Aug 28;359(9):906-17.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators.
This is a phase III study (VISTA trial - Velcade as Initial Standard Therapy in multiple myeloma)) comparing MP (melphalan + prednisone) (338 pts) vs MPV (MP + bortezomib) (344 pts) in newly diagnosed multiple myeloma who were ineligible for stem cell transplant.
MPV:
  - Melphalan 9 mg/m2 PO days 1-4
  - Prednisone 60 mg/m2 PO on days 1-4
  - Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, 32 during cycles 1-4 and on days 1, 8, 22, and 29 during cycles 5-9
Cycles were repeated every 6 weeks, x9.
MPV gave superior results:
  - Response rate was 35% with MP and 71% with MPV
  - CR rate was 4% with MP and 30% with MPV
  - Time to progression was 16.6 months with MP and 24 months with MPV
  - Treatment-related mortality was similar (1-2%)
An updated follow-up of the VISTA trial [J Clin Oncol, 2010; 28:2259] found that VMP was more beneficial than therapy with conventional agents followed by bortezomib-based regimens at relapse. Another report on the Vista study showed that patients achieving complete response had superior clinical outcomes [Blood, 2010; 116::3743].

Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case-matched study.
Am J Hematol. 2014 Apr;89(4):355-62.
Morabito F, Bringhen S, Larocca A, Wijermans P, Victoria Mateos M, Gimsing P, Mazzone C, Gottardi D, Omedè P, Zweegman S, José Lahuerta J, Zambello R, Musto P, Magarotto V, Schaafsma M, Oriol A, Juliusson G, Cerrato C, Catalano L, Gentile M, Isabel Turel A, Marina Liberati A, Cavalli M, Rossi D, Passera R, Rosso S, Beksac M, Cavo M, Waage A, San Miguel J, Boccadoro M, Sonneveld P, Palumbo A, Offidani M.
The clinical outcomes of 296 patients treated with MPV (melphalan, prednisone, and bortezomib) were retrospectively compared with those of 294 patients treated with MPT (melphalan, prednisone, and thalidomide). Patients had newly diagnosed myeloma and were older than 65. The results were better with MPV:
  - Complete response rate: 21% with MPV and 13% with MPT
  - Median progression-free survival: 32 months with MPV and 23 months with MPT
  - Median overall survival: 80 months with MPV and 45 months with MPT

 

MEL-DEX-VEL

Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma.
Ann Oncol. 2013 Apr;24(4):1038-44.
Romano A, Chiarenza A, Consoli U, Conticello C, Forte S, Uccello G, Vetro C, Cavalli M, Coppolino F, Palumbo GA, Di Raimondo F.
50 patients with previously treated myeloma received Mel-Dex-Vel. Most patients received all 3 drugs once a week:
  - Melphalan 5 mg/m2 IV
  - Dexamethasone 40 mg IV
  - Bortezomib 1.3 mg/m2 IV
Response rate was 62%, and median progression-free survival was 22 months. Toxicity was acceptable.

 

COMBINATIONS WITH CYCLOPHOSPHAMIDE

Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma.
J Clin Oncol. 2008 Oct 10;26(29):4777-83.
Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, Pantoja M, Xu W, Stewart AK.
This is a phase I-II trial that evaluated the combination of bortezomib, cyclophosphamide, and prednisone in 37 patients with relapsed/refractory MM. Regimen:
  - Bortezomib 1.3-1.5 mg/m2 IV on days 1, 4, 8, 11
  - Cyclophosphamide 300 mg/m2 PO once a week
  - Prednisone PO on alternate days
Results:
  - Response rate was 95%, when including minor responses. CR was reached in >50% of patients.
  - 1-year progression-free survival: 83%
  - 1-year overall survival 100%

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.
Leukemia. 2016 Jun;30(6):1320-6.
Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A.
In this study, 152 patients with newly diagnosed myeloma, 75 year-old and oler, received treatment with SC bortezomib in one of 3 regimens: bortezomib + prednisone (VP, 51 patients), bortezomib + prednisone + cyclophosphamide (VCP, 51 patients), and bortezomib + prednisone + melphalan (VMP, 50 patients). This was followed by maintenance therapy . Although VMP had slightly better results, it was more toxic, and the authors suggested that frail patients should be treated with a two-drug combination, followed by maintenance.
  - Response rate: 64% with VP, 67% with VCP, 86% with VMP
  - Median progression-free survival: 14 months with VP, 15.2 months with VCP, 17.1 months with VMP
 - Toxicity-related deaths at 6 months: 4% with VP, 4% with VCP, 8% with VMP

 

CVD (also called CyBorD)

The combination of cyclophosphamide, velcade and dexamethasone induces high response rates with comparable toxicity to velcade alone and velcade plus dexamethasone.
Haematologica. 2007 Aug;92(8):1149-50.
Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ.
These authors studied the effects of the CVD combination in 47 patients with relapsed/refractory multiple myeloma.
  - Cyclophosphamide 500 mg PO on days 1, 8, 15
  - Velcade 1.3 mg/m2 IV on days 1, 4, 8, 11 of a 21 day cycle
  - Dexamethasone 40 mg PO on the day of Velcade and the day after
CVD induced high overall response rate (75%) and complete response rate (31%) compared to velcade/dexamethasone (overall response rate 47%, CR rate 5%) and velcade alone (overall response rate 27%, CR rate 0%). Toxicities, including cytopenias and neuropathy, were comparable between the groups.

Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma.
Br J Haematol. 2007 Aug;138(3):330-7.
Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom.
This phase 2 trial studied the combination of bortezomib, intermediate-dose dexamethasone (on the day of bortezomib injection and the day thereafter), and continuous low-dose oral cyclophosphamide (50 mg PO once daily) in 54 patients with relapsed multiple myeloma. Overall response rate was 90%, with CR 16%, PR 66%, and minor responses 8%. Median overall survival was 22 months, and median event-free survival was 12 months.

DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.
Ann Hematol. 2009 Nov;88(11):1125-30.
Kropff M, Liebisch P, Knop S, Weisel K, Wand H, Gann CN, Berdel WE, Einsele H; Deutsche Studiengruppe Multiples Myelom, DSMM.
This is a clinical trial in 30 patients with newly diagnosed myeloma, who received combination chemotherapy with cyclophosphamide, bortezomib, and dexamethasone as induction therapy before stem cell transplantation. Patients received 3 cycles of:
  - Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11
  - Dexamethasone 40 mg on the day of bortezomib and the day after
  - Cyclophosphamide at various doses, 900-1,500 mg/m2 IV on day 1
The maximum tolerated dose of cyclophosphamide was 900 mg/m2. At this dose level, RR was 92%.

A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma.
Br J Haematol. 2012 Feb;156(3):326-33.
Khan ML, Reeder CB, Kumar SK, Lacy MQ, Reece DE, Dispenzieri A, Gertz MA, Greipp P, Hayman S, Zeldenhurst S, Dingli D, Lust J, Russell S, Laumann KM, Mikhael JR, Leif Bergsagel P, Fonseca R, Vincent Rajkumar S, Keith Stewart A.
This is a retrospective analysis of 3 phase II trials, which involved three different induction chemotherapy regimens:
   - RD (34 patients), repeated every 28 days
            - Revlimid 25 mg on days 1-21
            - Dexamethasone 40 mg on days 1-4, 9-12, 17-20
   - CRD (53 patients), repeated every 28 days
            - Cyclophosphamide 300 mg/m2 on days 1, 8 , 15
            - Revlimid 25 mg on days 1-21
            - Dexamethasone 40 mg on days 1, 8, 15, 22
   - CVD, also called CyBorD (63 patients), repeated every 28 days
            - Cyclophosphamide 300 mg/m2 PO on days 1, 8 , 15, 22
            - Velcade 1.3 mg/m2 IV on days 1, 4, 8, 11
            - Dexamethasone 40 mg on days 1-4, 9-12, 17-20
Only 80 of the 150 patients underwent upfront stem cell transplantation.
Results:
   - Rates of near-complete response or better, after 4 cycles of therapy: 41% with CVD, 12% with RD, and 2% with CRD.
   - Rates of VGPR or better, after 4 cycles of therapy: 65% with CVD, 35% with RD, and 30% with CRD
   - Median progression-free survival was similar (2.3-3.2 years, 2.6 years for all 150 patients)
   - 3-year overall survival was similar (79-88%)
   - 4-year overall survival: 80% for all 150 patients

Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.
Blood. 2012 May 10;119(19):4375-82.
Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV.
This study compared three regimens in 140 patients with newly diagnosed multiple myeloma:
  - VDR = Velcade, Dexamethasone, Revlimid
  - VDC = Velcade, Dexamethasone, Cyclophosphamide
  - VDCR = Velcade, Dexamethasone, Cyclophosphamide, Revlimid
All combinations were highly active, with high response rates. The 4-drug combination regimen induced more toxicities, especially myelosuppression, and it did not provide a significant advantage over the 3-drug combinations.

Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma.
Am J Clin Oncol. 2012 Dec;35(6):562-5.
Fu W, Delasalle K, Wang J, Song S, Hou J, Alexanian R, Wang M.
44 patients with relapsed myeloma received CyBorD, with:
  - Cyclophosphamide 70 mg/m2 twice a day on days 1-4
  - Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
  - Dexamethasone 20 mg/m2 PO daily for 4 days beginning on days 1-4, 9-12, and 17-20
Results:
  - Response rate: 73% (PR 59%, CR 14%)
  - Median remission time of responding patients: 10 months
  - Median survival: 33 months in responsive disease, and 12 months with unresponsive disease.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.
Blood. 2016 May 26;127(21):2569-74.
Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M.
In this study, 340 patients with newly diagnosed myeloma were randomized to receive either VTD (bortezomib, thalidomide, and dexamethasone), or VCD (bortezomib, cyclophosphamide, and dexamethasone, also called CyBorD). After 4 cycles of induction therapy, before an autologous stem cell transplant, the results were better with VDT: response rate was 92% with VTD, and 83% with VCD (p=0.01).

 

COMBINATIONS WITH LIPOSOMAL DOXORUBICIN

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
Blood. 2005 Apr 15;105(8):3058-65.
Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, Johri AR, Jones PE, Ivanova A, Van Deventer HW, Gabriel DA, Shea TC, Mitchell BS, Adams J, Esseltine DL, Trehu EG, Green M, Lehman MJ, Natoli S, Collins JM, Lindley CM, Dees EC.
The maximum tolerated dose of bortezomib and pegylated liposomal doxorubicin in combination was found to be bortezomib 1.3 mg/m2 and liposomal doxorubicin 30 mg/m2.

Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression.
J Clin Oncol. 2007 Sep 1;25(25):3892-901.
Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL.
This is a phase III international study which randomized 646 patients with relapsed or refractory myeloma to either bortezomib or the combination bortezomib + pegylated liposomal doxorubicin (30 mg/m2 IV on day 4). Results:
  - Response rate was 41% with bortezomib vs 44% with bortezomib + liposomal doxorubicin (not statistically significant)
  - Median time to progression was 6.5 months with bortezomib vs 9.3 months with bortezomib + liposomal doxorubicin (p= 0.000004)
  - The 15-month survival rate was 65% with bortezomib and 76% with bortezomib + liposomal doxorubicin (p= 0.03)
The group receiving the combination regimen experienced more frequent toxicities, especially cytopenias, diarrhea, and hand-foot syndrome.

Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma.
Cancer. 2016 Jul 1;122(13):2050-6.
Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF.
The original study of 646 patients was published in 2007, and it showed a survival advantage of patients with relapsed/refractory myeloma when treated with bortezomib + liposomal doxorubicin compared to those treated with bortezomib alone. This study has a much longer follow-up, and it showed a similar overall survival in the two groups: 31 months with bortezomib alone, and 33 months with bortezomib + liposomal doxorubicin (p=61). The disappearance of the survival advantage was attributed to the possible effect of the subsequent lines of chemotherapy.

 

PAD

The PAD regimen is the the combination of:
  - Bortezomib (PS341)
  - Doxorubicin (Adriamycin)
  - Dexamethasone.

Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up.
Br J Haematol. 2008 May;141(4):512-6.
Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N, Esseltine DL, Drake M, Morris C, Cavenagh JD.
The PAD regimen was given in patients with newly diagnosed myeloma as induction therapy before stem cell transplantation. Results: rate of CR/VGPR was 62% in patients treated with bortezomib 1.3 mg/m2 and 42% in patients treated with 1.0 mg/m2. PFS and OS favoured bortezomib 1.3 mg/m2, but differences did not reach statistical significance.

Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma.
Ann Oncol. 2008 Jun;19(6):1160-5.
Palumbo A, Gay F, Bringhen S, Falcone A, Pescosta N, Callea V, Caravita T, Morabito F, Magarotto V, Ruggeri M, Avonto I, Musto P, Cascavilla N, Bruno B, Boccadoro M.
In this study, 64 patients with relapsed/refractory myeloma were treated with PAD for a median of four cycles.
  - Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11
  - Doxorubicin 20 mg/m2 IV days 1, 4 or pegylated liposomal doxorubicin 30 mg/m2 IV day 1
  - Dexamethasone 40 mg PO days 1-4
Cycles were repeated every 28 days. 43 patients (67%) achieved at least a PR, including 16 (25%) with at least a VGPR. At 1 year, EFS was 34% and OS 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%), peripheral neuropathy (10%), and CHF (2 patients).

 

COMBINATIONS WITH THALIDOMIDE

The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma.
Br J Haematol. 2008 Jun;141(6):814-9.
Ciolli S, Leoni F, Casini C, Breschi C, Santini V, Bosi A.
This study compared VTD (28 patients) with VTD + Doxil (42 patients) in advanced MM.
  - Velcade 1.0 mg/m2 IV on days 1, 4, 8, 11 in a 28-d cycle
  - Thalidomide 100 mg PO qhs
  - Dexamethasone 24 mg PO on the day of, and the day after Velcade
  - Doxil 50 mg/m2 (30 mg/m2 for patients older than 75 years) IV on day 4, 1 hour after bortezomib infusion
VTD + Doxil produced better results, in terms of overall response rate (81% vs 50%), time to progression (19 vs 11 months), and progression-free survival (15 vs 8 months).

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.
Blood. 2007 Apr 1;109(7):2767-72.
Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologiche dell'Adulto.
This is a multicenter phase I/II trial of 30 patients with relapsed/refractory myeloma treated with VMPT:
  - Velcade 1.0-1.6 mg/m2 IV on days 1, 4, 15, 22
  - Melphalan 6 mg/m2 PO on days 1-5
  - Prednisone 60 mg PO on days 1-5
  - Thalidomide 50 mg PO qhs on days 1-35
Cycles were repeated every 35 days.
Results:
  - Response rate: 67% (79% when used as second line therapy)
  - Progression-free survival at 1 year: 61%
  - Overall survival at 1 year: 84%
  - No grade 4 toxicities were observed, and grade 3 peripheral neuropathy was seen in only 2 patients

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study.
Ann Hematol. 2010 May;89(5):475-82.
Kim YK, Sohn SK, Lee JH, Yang DH, Moon JH, Ahn JS, Kim HJ, Lee JJ; Korean Multiple Myeloma Working Party (KMMWP).
70 patients with relapsed/refractory myeloma were treated with bortezomib + CTD:
  - Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11
  - Cyclophosphamide 150 mg/m2 PO days 1-4
  - Thalidomide 50 mg PO qd
  - Dexamethasone 20 mg IV days 1, 4, 8, 11
Results:
  - Response rate: 88%
  - CR: 46%
  - Median progression-free survival: 14.6 months
  - Median overall survival 31.6 months
  - Grade 3-4 neutropenia was 4%, and grade 3-4 thrombocytopenia was 12%

Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial.
Lancet Oncol. 2010 Oct;11(10):934-41.
Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF.
260 patients of age 65 and older with newly diagnosed myeloma were randomized in to groups:
  - VMP (Velcade, Melphalan, Prednisone) (130 patients) x6 cycles
  - VTP (Velcade, Thalidomide, Prednisone) (130 patients) x6 cycles
then maintenance therapy with either VP (87 patients) or VT (91 patients).
Results after induction therapy:
  - Rate of partial response or better: 80% with VMP and 81% with VTP (p= 0.90)
  - Rate of complete response: 20% with VMP and 28% with VTP (p= 0.20)
  - Discontinuation of therapy due to toxicity was higher with VTP (17% vs 12%, p= 0.03)
  - Grade III/IV peripheral neuropathy: 9% with VMP and 7% with VTP
Results after maintenance therapy:
  - Rate of complete response: 39% with VP and 42% with VT
At the time of this publication, many myeloma experts believed that bortezomib was able to overcome the negative prognostic impact of adverse cytogenetic features. However, in this study, patients with high-risk disease had worse progression-free survival and overall survival despite bortezomib.

 

VTD

Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients.
Leuk Lymphoma. 2006 Jan;47(1):171-3.
Ciolli S, Leoni F, Gigli F, Rigacci L, Bosi A.
18 patients with relapsed/refractory myeloma were treated with VTD:
  - Velcade 1.0 mg/m2 IV on days 1, 4, 8, 11
  - Thalidomide 100 mg PO qhs
  - Dexamethasone 24 mg PO on the same day and the day after Velcade
Cycles were repeated every 28 days x6.
Response rate was 53%, despite the fact that patients had previously received a median of 4 lines of therapy.

VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma.
Leukemia. 2008 Jul;22(7):1419-27.
Pineda-Roman M, Zangari M, van Rhee F, Anaissie E, Szymonifka J, Hoering A, Petty N, Crowley J, Shaughnessy J, Epstein J, Barlogie B.
This is a phase I/II trial of the VTD regimen in 85 patients with refractory multiple myeloma.
  - Velcade, started at 1.0 mg/m2 IV days 1, 4, 8, 11, increased to 1.3 mg
  - Thalidomide, started at 50 mg and increased to a maximum dose of 200 mg, added from cycle 2
  - Dexamethasone, added with cycle 4 in the absence of PR
Cycles were repeated every 21 days.
Results:
  - MTD was reached at Velcade 1.3 mg/m2 and Thalidomide 50 mg
  - Partial response rate: 63% (nCR 22%)
  - Event-free survival at 4 years: 6%
  - Overall survival at 4 years: 23%

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
J Clin Oncol. 2012 Jul 10;30(20):2475-82.
Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G.
The triple combination Bortezomib + Thalidomide + Dexamethasone (VTD) was superior to Thalidomide + Dexamethasone (TD) in 296 patients with myeloma relapsing after autologous stem cell transplantation:
  - Rate of CR/nCR: 45% with VTD and 25% with TD
  - Median progression-free survival was 19.5 months with VTD and 13.8 months with TD
  - 2-year survival: 71% with VTD and 65% with TD
The editorial article accompanying this study underscores the fact that these results are the best seen among all phase III studies for refractory myeloma, because the progression-free survival of all previously published studies was less than 12 months.

 

VRD

Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.
Blood. 2010 Aug 5;116(5):679-86.
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC.
This is a phase I/II study of VRD in 66 patients with newly diagnosed myeloma. MTD was found to be:
  - Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
  - Lenalidomide 25 mg PO qd on days 1-14
  - Dexamethasone 20 mg PO on days 1,2, 4,5, 8,9, 11,12
Cycles were repeated every 21 days.
Results:
  - Response rate was 100%. Complete remission: 57%. 74% of patients achieved VGPR or better.
  - Maximal response was often achieved after 4 cycles
  - Median collection yield was 5.6 million CD34+ cells/Kg (28 patients proceeded to stem cell transplant)
  - After a median follow-up of 21 months, estimated 18-month progression-free survival was 75%, and overall survival 97%.
  - Most common toxicities were peripheral neuropathy (80%) and fatigue (64%)
  - Painful sensory neuropathy: 32%
  - DVT rate was 6%
  - 40%  of patients required dose reductions, interruptions, or discontinuation of therapy because of toxicity

Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma.
Leuk Lymphoma. 2013 Mar;54(3):555-60.
Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Tiedemann R, Kukreti V.
In this retrospective study, VRD was administered in 30 patients with relapsed/refractory myeloma. Response rate was 47% (PR 37%, VGPR 10%). In 21 patients, disease progressed at a median of 3 months (range: 1.4-4.6 months).

Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet. 2017 Feb 4;389(10068):519-527.
Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A.
In this prospective clinical trial, 525 patients with newly diagnosed myeloma in need of induction chemotherapy were randomized in two groups: VRD (bortezomib, lenalidomide, and dexamethasone) vs RD (lenalidomide and dexamethasone. The winner was VRD:
  - Response rate (PR or better): 72% with RD, and 82% with VRD
  - Rate of complete response: 8% with RD, and 16% with VRD
  - Median progression-free survival: 30 months with RD, and 43 months with VRD
  - Median overall survival: 64 months with RD, and 75 months with VRD
Of note, VRD was slightly more toxic, because 23% of patients on VRD had to stop therapy due to adverse events, as opposed to 10% of patients on RD.

 

 


Giampaolo Talamo, M.D.