POST-TRANSPLANT MAINTENANCE/CONSOLIDATION

 

 

Type and duration of post-transplant maintenance in multiple myeloma is controversial, even among experts.

 

Maintenance treatment in multiple myeloma.
Ann Oncol. 2008 Jun;19 Suppl 4:iv54-5.
Harousseau JL.

[Review]

Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma.
Cancer. 2016 Dec 15;122(24):3831-3837.
Mian I, Milton DR, Shah N, Nieto Y, Popat UR, Kebriaei P, Parmar S, Oran B, Shah JJ, Manasanch EE, Orlowski RZ, Shpall EJ, Champlin RE, Qazilbash MH, Bashir Q.
The optimal duration of maintenance therapy after an autologous stem cell transplant in patients with multiple myeloma is unknown. This retrospective study analyzed clinical outcomes of maintenance therapy with lenalidomide in 464 patients. In the overall group, median PFS was 38 months, and median OS 78 months. An additional 19% of patients achieved CR with the maintenance therapy. Revlimid maintenance had to be discontinued in 20% of patients, due to a variety of reasons, including progression (31%), cytopenias (32%), skin rash (14%), fatigue (9%), and GI toxicities (5%). Multivariate analysis showed that longer survival was observed in those patients who received maintenance for longer than 2 years (HR for PFS 0.13, and HR for OS 0.09), and the effect was seen even in those patients on maintenance for >3 years vs <3 years ((HR for PFS 0.02, and HR for OS 0.05). Secondary malignancies were observed in 3% of patients, and the most common malignancy was MDS. No association was found between incidence of secondary malignancies and duration of the Revlimid maintenance. The authors reminded us that the risk of death from relapsed myeloma is greater than the risk of death from secondary malignancies, and therefore the benefit/risk ratio of Revlimid maintenance vs observation is in favor of maintenance. The conclusion of the study, within the limitation of its retrospective nature, is that Revlimid maintenance should be continued indefinitely, until either disease progression or unacceptable toxicity. The optimal dose of Revlimid for post-transplant maintenance remains unknown. The authors used various doses, between 5 and 15 mg, at the discretion of the treating physician.

Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma.
Biol Blood Marrow Transplant. 2017 Feb;23(2):269-277.
Cornell RF, D'Souza A, Kassim AA, Costa LJ, Innis-Shelton RD, Zhang MJ, Huang J, Abidi M, Aiello J, Akpek G, Bashey A, Bashir Q, Cerny J, Comenzo R, Diaz MA, Freytes C, Gale RP, Ganguly S, Hamadani M, Hashmi S, Holmberg L, Hossain N, Kamble RT, Kharfan-Dabaja M, Kindwall-Keller T, Kyle R, Kumar S, Lazarus H, Lee C, Maiolino A, Marks DI, Meehan K, Mikhael J, Nath R, Nishihori T, Olsson RF, Ramanathan M, Saad A, Seo S, Usmani S, Vesole D, Vij R, Vogl D, Wirk BM, Yared J, Krishnan A, Mark T, Nieto Y, Hari P.
In this retrospective analysis of 693 patients with myeloma transplanted within 12 months of diagnosis, the PFS at 3 year was better in those patients who received maintenance than in those who did not (55% vs 39%). Importantly, for the clinical outcome, the type of induction regimen (for example VD, RD, VRD, CVD) was less important than the use of post-transplant maintenance.

 

 

LENALIDOMIDE

Two important trials have studied the effect of lenalidomide in post-transplant maintenance.
The CALGB trial improved both progression-free survival and overall survival.
The IFM-2005-02 trial improved progression-free survival but not overall survival.
 

Lenalidomide after stem-cell transplantation for multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1770-81.
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C.
In this double-blinded, placebo-controlled trial, 460 patients with myeloma treated with autologous stem cell transplantation were randomized to receive either lenalidomide 5-15 mg daily (231 patients) or placebo (229 patients). Maintenance therapy was started 100-110 days after transplant, and continued indefinitely, until disease progression. Induction therapy lasted 2-12 months, and it included no more than 2 regimens. Median follow-up period was 34 months.
Results:
  - Median time to progression: 27 months with placebo, and 46 months with lenalidomide
  - 3-year overall survival rate: 80% with placebo, and 88% with lenalidomide
  - Median survival was not reached in either group
  - Rate of second cancers: 3% with placebo, and 8% with lenalidomide (p=0.008)
Of note, benefits of maintenance lenalidomide were observed despite the crossover of patients receiving placebo to lenalidomide therapy.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1782-91.
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators.
This is a placebo-controlled trial of 614 patients with myeloma treated with autologous stem cell transplantation, randomized to receive either lenalidomide 10-15 mg daily (307 patients) or placebo (307 patients). Patients were offered a second autologous transplant if they did not achieve CR or VGPR after the first one. Before starting maintenance, most patients received 2 cycles of post-transplant consolidation therapy with lenalidomide 25 mg daily on days 1-21 every 28 days. Maintenance was started within 6 months from the transplant, and it was continued indefinitely, until disease progression. Thromboprophylaxis was not used. Median follow-up period was 45 months.
Results:
  - Median progression-free survival: 23 months with placebo, and 41 months with lenalidomide
  - 3-year progression free-survival rate: 35% with placebo, and 59% with lenalidomide
  - 4-year overall survival rate: 75% with placebo, and 73% with lenalidomide
  - Median survival was not reached in either group
  - Thromboembolic events: 2% with placebo, and 6% with lenalidomide (p=0.01)
    Based on these results, the authors recommend aspirin prophylaxis with lenalidomide therapy.
  - Patients with second cancers: 4% with placebo, and 8% with lenalidomide
The benefit of lenalidomide seemed to persist despite the risk of second cancers, because the median event-free survival, which included second cancers as events, was 23 months with placebo, and 40 months with lenalidomide.

 

 

THALIDOMIDE

Thalidomide has been used in several studies of post-transplant maintenance, but its use has been limited by poor tolerance.

Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant.
Clin Cancer Res. 2004 Dec 15;10(24):8170-6.
Stewart AK, Chen CI, Howson-Jan K, White D, Roy J, Kovacs MJ, Shustik C, Sadura A, Shepherd L, Ding K, Meyer RM, Belch AR.
This is a randomized phase II trial using thalidomide 200 or 400 mg PO qhs + prednisone 50 mg PO qod as post-transplant maintenance in 77 patients with multiple myeloma. After a median follow-up of 37 months, discontinuation rate for thalidomide was 88% (24% with 200 mg and 59% with 400 mg), even allowing dose reductions. Dose reduction for prednisone were needed in 72% of patients. Median progression-free survival was 32.3 months from the time of transplant, and 42.2 months from the time of diagnosis.

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.
Cancer. 2006 May 15;106(10):2171-80.
Brinker BT, Waller EK, Leong T, Heffner LT Jr, Redei I, Langston AA, Lonial S.
Among 112 myeloma patients treated with autologous stem cell transplant, 76 patients received no maintenance therapy, and 36 patients received thalidomide, either as maintenance or as salvage therapy. After a median follow-up of 58 months:
  - Median survival was 54 months
  - Median survival was better in patients who received thalidomide compared with those who did not (65.5 vs 44.5 months, p= 0.09)
  - Median survival was better in patients who received thalidomide as maintenance compared with those who received it as salvage therapy (65 vs 54 months, p= 0.05)

Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study.
Br J Haematol. 2007 Nov;139(3):429-33.
Feyler S, Rawstron A, Jackson G, Snowden JA, Cocks K, Johnson RJ.
This is a phase II study of post-transplant maintenance with 5 different doses of thalidomide in 100 myeloma patients. After a median follow-up of 32 months:
  - 77% of patients stopped thalidomide, either because of disease progression (23%) or toxicity (54%)
  - 15% of patients converted from PR to CR (at a median of 13.5 months)
  - 3-year overall survival: 76%
  - 3-year progression-free survival: 41%
  - Doses >200 mg were too toxic. Main toxicity was peripheral neuropathy.
  - Increased dosage did not improve outcome but it increased toxicity.

Thalidomide maintenance following high-dose melphalan with autologous stem cell support in myeloma.
Clin Lymphoma Myeloma. 2008 Jun;8(3):153-8.
Chang JE, Juckett MB, Callander NS, Kahl BS, Gangnon RE, Mitchell TL, Longo WL.
31 patients with myeloma were treated with autologous stem cell transplant and then thalidomide 50 mg PO qhs, escalated to a maximum dose of 200 mg per day.
  - Treatment was poorly tolerated, mainly because of peripheral neuropathy.
  - Maintenance at the dose of 200 mg was not feasible (goal achieved in 55% of patients). The median tolerated dose was 100 mg.
  - No DVT was observed.
  - CR + VGPR: 65% at 1 year and 42% at 2 years.
  - Median OS: > 60 months. Median PFS: 20.8 months.

Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma.
Bone Marrow Transplant. 2006 May;37(9):825-9.
Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G.
This is a phase II study of 29 myeloma patients treated with maintenance thalidomide after a single autologous stem cell transplant. Thalidomide was started at 50 mg PO qhs, and it was increased to max 400 mg a day. It was continued for 6 months after achievement of CR for a maximum duration of 18 months. Results:
  - Median tolerated dose was 200 mg
  - CR or nCR rate at 6 months was 45%
  - Overall survival at 2 years was 83%
  - Progression-free survival at 2 years was 49%

 

RANDOMIZED TRIALS WITH THALIDOMIDE

Three randomized trials have evaluated thalidomide maintenance after stem cell transplant. All studies demonstrated a clinical benefit from thalidomide maintenance, with improvement of overall survival.

1) Total Therapy II (see tandem transplants)

2) IFM 99-02

Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.
Blood. 2006 Nov 15;108(10):3289-94.
Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM).
This is a trial of 597 myeloma patients randomized to receive the following post-transplant maintenance, starting 2 months after stem cell transplant:
  - No maintenance (arm A)
  - Pamidronate (arm B)
  - Pamidronate + thalidomide (arm C) until relapse or toxicity (median 15 months)
Results:
  - Response rate: 55% in arm A, 57% in arm B, and 67% in arm C (p = 0.03).
  - The EFS at 3 years: 36% in arm A, 37% in arm B, and 52% in arm C (p <0.009)
  - 4-year survival (from the time of diagnosis): 77% in arm A, 74% in arm B, and 87% in arm C (p <0.04)
  - Rate of skeletal events: 24% in arm A, 21% in arm B, and 18% in arm C (p = 0.4).
Therefore, thalidomide maintenance was clinically effective, and pamidronate maintenance did not decrease the incidence of skeletal events.

3) Australian study

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.
J Clin Oncol. 2009 Apr 10;27(11):1788-93.
Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N.
This study evaluated the results of post-transplant maintenance with thalidomide in 269 patients with newly diagnosed myeloma treated with a single autologous stem cell transplant. Patients were randomized to either prednisolone maintenance, indefinitely (control group, 129 patients) or the same + thalidomide for 12 months (thalidomide group, 114 patients). Results:
  - 3-year PFS: 42% in the thalidomide group and 23% in the control group (p <0.001)
  - 3-year OS: 86% in the thalidomide group and 75% in the control group (p= 0.004)
  - No difference in survival 12 months after disease progression (79% vs 77%, p= 0.24)

4) Other

[Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.
Blood. 2008 Feb 15;111(4):1805-10.
Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group.
This study has been retracted in June 2009]

 

 

THALIDOMIDE + CORTICOSTEROIDS

Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.
Ann Oncol. 2002 Jul;13(7):1116-9.
Alexanian R, Weber D, Giralt S, Delasalle K.
21 patients with myeloma in partial remission after stem cell transplantation were given consolidation therapy with thalidomide + dexamethasone, in order to achieve a higher rate of complete remission. Thalidomide was given at a dose of 100-300 mg PO qhs, and dexamethasone at 20 mg/m2 on days 1-4, 9-12, and 17-20, with cycles repeated every 35 days. The combination was started within 15 months after transplant, and continued for at least 3 months. Reduction of myeloma paraprotein by at least 90% occurred in 57% of patients, and 19% of patients converted from partial remission to complete remission. Median duration of remission was 22 months.

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.
J Clin Oncol. 2009 Apr 10;27(11):1788-93.
Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N.
In this study, patients with newly diagnosed MM who received a single ASCT with high-dose melphalan were randomized to receive maintenance therapy with prednisolone, indefinitely (control group, 129 patients), or the same + 12 months of thalidomide (thalidomide group, 114 patients). After a median follow-up of 3 years, the 3-year PFS rates were 42% and 23%, and the OS rates were 86% and 75%, in the thalidomide and control groups, respectively. There was no difference between groups for thromboembolic events.

A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial.
Blood. 2013 Feb 28;121(9):1517-23.
Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM.
In this study, 332 patients with newly diagnosed myeloma received an autologous stem cell transplant and they were randomized in two groups, one without maintenance therapy, and the other with maintenance, using thalidomide 200 mg daily and prednisone 50 mg every other day for 4 years or until disease progression.
Median follow-up was 4.1 years. Results:
  - Overall survival was similar (4-year OS was 68% with maintenance and 60% without maintenance, p=0.18)
  - Progression-free survival at 4 years was superior in the maintenance group (32% vs 14%, p<0.0001)
  - Median OS after relapse was 28 months with maintenance and 34 months with maintenance
  - Quality of life was worse in the maintenance group
The authors concluded that the benefit of post-transplant maintenance therapy with thalidomide and prednisone (= longer duration of disease control) was counterbalanced by negative aspects (= worse quality of life and no prolongation of life).

 

THALIDOMIDE + BORTEZOMIB

Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial.
Leukemia. 2017 Sep;31(9):1922-1927.
Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J.
In this phase III trial (GEM05MENOS65), 390 patients with newly diagnosed myeloma (MM), treated with various induction chemotherapy and an autologous stem cell transplantation, were randomized in 3 groups: one treated with thalidomide (T, 88 patients), one with bortezomib and thalidomide (VT, 91 patients), and another one with alfa-2b interferon (IFN, 92 patients). The maintenance therapy was continue for up to 3 years. After a median follow-up of 58.6 months, PFS was significantly longer with TV compared with T and IFN (about 51 vs 40 vs 32 months, p=0.03), but overall survival was not significantly different among the three arms. Of note, at the time of the publication, the type and schedule of induction therapy and maintenance were considered obsolete.

 

BORTEZOMIB

Bortezomib administered pre-auto-SCT and as maintenance therapy post transplant for multiple myeloma: a single institution phase II study.
Bone Marrow Transplant. 2009 May;43(10):793-800.
Uy GL, Goyal SD, Fisher NM, Oza AY, Tomasson MH, Stockerl-Goldstein K, DiPersio JF, Vij R.
In this study, 40 patients with MM were given bortezomib pre-ASCT for 2 cycles, and post-ASCT, as maintenance therapy, weekly for 5 out of 6 weeks for 6 cycles. RR was 83% and CR + VGPR was 50%. At 3 years, disease-free survival and overall survival were 38.2 and 63.1%, respectively.

Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial.
J Clin Oncol. 2012 Aug 20;30(24):2946-55.
Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM.
827 patients with newly diagnosed myeloma were randomized to:
  - VAD (vincristine, doxorubicin, dexamethasone), autologous transplant, maintenance with thalidomide 50 mg daily (group A)
  - PAD (bortezomib, doxorubicin, dexamethasone), autologous transplant, maintenance with PAD every 2 weeks for 2 years
Progression-free survival was 28 months in group A and 35 months in group B.
In patients with 17p-, PFS was 12 months in group A and 22 months in group B.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial.
Blood. 2013 Jun 6;121(23):4647-54.
Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group.
This is a study of 370 myeloma patients treated with an autologous stem cell transplant and randomized to consolidation with 21 weeks of bortezomib vs no consolidation. Bortezomib improved progression-free survival (27 vs 20 months) but not overall survival. Consolidation with bortezomib did not seem to be beneficial for those patients who reached at least a VGPR after the transplant.

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.
Biol Blood Marrow Transplant. 2017 Feb;23(2):262-268.
Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, Long GD, Horwitz ME, Lopez RD, Sullivan KM, Rizzieri DA, Chao NJ, Gasparetto C.
In this retrospective study, 102 patients with myeloma who underwent an autologous stem cell transplant were given maintenance therapy with bortezomib. This was started between 2 and 3 months after the transplant. Lenalidomide was added in 10 patients. Bortezomib was given at the dose of 1.3 mg/m2 every 2 weeks indefinitely, until progression or unacceptable toxicity. Only 2% of patients required discontinuation of bortezomib due to toxicity. The median progression-free survival, calculated from the date of initiation of maintenance, was 36.5 months, and the median overall survival 73 months (6.1 years). Importantly, 42% of patients had high-risk cytogenetics, and the PFS of those patients did not differ from those with standard-risk cytogenetics.

CONSOLIDATION WITH BORTEZOMIB

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.
Br J Haematol. 2017 Jul;178(1):61-71.
Sezer O, Beksac M, Hajek R, Sucak G, Cagirgan S, Linkesch W, Meltem Akay O, Gülbas Z, Nahi H, Plesner T, Snowden JA, Timurağaoğlu A, Dechow T, Lang A, Tuğlular T, Drach J, Armbrecht G, Potamianou A, Couturier C, Olie RA, Feys C, Allietta N, Terpos E.
This is a phase II study which included 104 patients with multiple myeloma treated with an autologous stem cell transplant. Patients were randomized in two groups, one treated with bortezomib as consolidation therapy (51 patients), and another left with observation only (53 patients). Bortezomib was given at 1.6 mg/m2 IV on days 1, 8, 15, 22, every 35 days for 4 cycles. Patients receiving the consolifdation with bortezomib had better outcomes:
  - Rate of CR/sCR: 11% with observation, and 22% with bortezomib (p=0.19)
  - Median progression-free survival: 22 months with observation, and 45 months with bortezomib (p=0.22)

 

VTD

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.
Blood. 2012 Jul 5;120(1):9-19.
Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; for the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network.
This is a phase 3 study which randomized patients with newly diagnosed myeloma treated with tandem autologous transplants into 2 groups:
  - TD group (161 patients) : Thalidomide and Dexamethasone during induction and maintenance therapy
  - VTD group (160 patients): Bortezomib, Thalidomide, and Dexamethasone during induction and maintenance therapy
Patients treated with VTD has better outcomes:
  - CR/nCR rate was 61% with TD and 73% with VDT
  - Progression-free survival at 3 years was 48% with TD and 60% with VDT
  - Overall survival was similar, but this could be due to short follow-up (median follow-up was 30 months), or to the effect of different salvage therapies

CONSOLIDATION WITH VTD

Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma.
J Clin Oncol. 2010 Apr 20;28(12):2077-84.
Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A.
39 myeloma patients treated with autologous stem cell transplantation and in a status of minimal residual disease (= achievement of at least a very good partial response and positive for IgH rearrangement by PCR) received post-transplant consolidation with 4 monthly cycles of VTD:
  - Bortezomib 1.6 mg/m2 IV days 1, 8, 15, 22
  - Thalidomide 200 mg PO qhs
  - Dexamethasone 20 mg PO on days 1-4, 8-11, 15-18
Results:
  - CR with negative immunofixation increased from 15% after transplant to 49% after consolidation therapy with VTD
  - Molecular remissions by PCR increased from 3% after transplant to 18% after consolidation with VTD
  - After a median follow-up of 42 months, no patient in molecular CR relapsed

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma.
Leukemia. 2013 Nov;27(11):2242-4.
Leleu X, Fouquet G, Hebraud B, Roussel M, Caillot D, Chrétien ML, Arnulf B, Szalat R, Garderet L, Benajiba L, Pegourie B, Regny C, Royer B, Caulier A, Stoppa AM, Garciaz S, Touzeau C, Chaleteix C, Fermand JP, Loiseau HA, Facon T, Attal M, Moreau P.
This retrospective study compares outcomes of 96 myeloma patients treated with VTD (bortezomib, thalidomide, and dexamethasone) x 3 cycles + autologous stem cell transplant, with those of 121 patients treated with VTD + autologous stem cell transplant, followed by a consolidation with 2 additional cycles of VTD. None of the patients received maintenance therapy. Median follow-up was 30 months. Results favored the consolidation group:
  - CR: 30% post-transplant, and 52% post-consolidation
  - Median time to progression: 25 months with VTD-SCT and "not reached" with VTD-SCT-VTD
  - Estimated 4-year progression-free survival: 29% with VTD-SCT and 62% with VTD-SCT-VTD

RANDOMIZED TRIALS WITH VTD

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
Lancet. 2010 Dec 18;376(9758):2075-85.
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network.
480 patients with newly diagnosed multiple myeloma were treated with tandem autologous stem cell transplants, randomizing between two types of pre-transplant induction and post-transplant consolidation therapies: thalidomide + dexamethasone (TD, 241 patients) vs bortezomib + thalidomide + dexamethasone (VTD, 239 patients). Patients received maintenance therapy with dexamethasone 40 mg PO qd on days 1-4 every 28 days, until disease progression. Results (after a median follow-up of 36 months):
  - Rates of CR/nCR after induction therapy: 11% with TD, and 31% with VDT
  - Progression-free survival at 3 years was improved: 68% with VTD, and 56% with TD (p= 0.0057)
  - Overall survival was similar: 86% with VTD, and 84% with TD (p= 0.30)
The lack of survival advantage was possibly due to the relatively short follow-up, or maybe because of the use of effective salvage therapies.
This trial supported the use of triple therapy in the induction phase of myeloma treatment in transplant-eligible patients.

 

 

VRD

Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients.
Leukemia. 2014 Mar;28(3):690-3.
Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S.
A total of 45 patients with high-risk myeloma were treated with autologous stem cell transplant followed by VRD maintenance. High-risk was defined by the presence of primary plasma cell leukemia (>20% plasma cells in the peripheral blood at presentation), 17p-, t(4;14), t(14;16), and 1p deletion. VRD consisted of:
  - Bortezomib 1.3 mg/m2 SC/IV once a week
  - Lenalidomide 10 mg PO on days 1-21 every 28 days
  - Dexamethasone 40 mg PO once a week
After 3 years VRD, patients continued maintenance with single-agent lenalidomide.
Median follow-up was 26 months. The results were good, considering the high-risk nature of the patient population:
  - Median progression-free survival: 32 months
  - Overall survival at 3 years: 93%

 

 

CHEMOTHERAPY

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.
Br J Haematol. 2002 Oct;119(1):164-8.
Fassas AB, Spencer T, Desikan R, Zangari M, Anaissie E, Barlogie B, Tricot G.
This study reviewed outcomes of consolidation chemotherapy after tandem transplants in 75 myeloma patients, and compared them with those of 75 matched controls who received dexamethasone and/or interferon. Consolidation chemotherapy provided no event-free nor overall survival advantage.

Autologous stem cell transplantation followed by consolidation chemotherapy for patients with multiple myeloma.
Bone Marrow Transplant. 2006 Jan;37(1):65-72.
Gojo I, Meisenberg B, Guo C, Fassas A, Murthy A, Fenton R, Takebe N, Heyman M, Philips GL, Cottler-Fox M, Sarkodee-Adoo C, Ruehle K, French T, Tan M, Tricot G, Rapoport AP.
103 patients with myeloma patients received autologous stem cell transplantation followed by 2 cycles of DCEP (Dexamethasone, Cyclophosphamide, Etoposide, cisPlatin) +/- gemcitabine) at 3 and 9 months after transplant, and 2 cycles of DPP (Dexamethasone, cisPlatin, Paclitaxel) at 6 and 12 months after transplant. Results:
  - Median event-free survival was 26 months
  - Median overall survival was 54.1 months
  - Event-free survival at 5 years was 23.1%
  - Overall survival at 5 years was 42.5%
Of note, only 50% of patients completed the planned chemotherapy courses.

 

 

OTHER

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.

Sequential, cycling maintenance therapy for post transplant multiple myeloma.
Bone Marrow Transplant. 2006 Jan;37(1):89-94.
Chen CI, Nanji S, Prabhu A, Beheshti R, Yi QL, Sutton D, Stewart AK.
28 patients with myeloma were treated with autologous stem cell transplantation followed by consolidation therapy with a sequential approach:
  - Dexamethasone (months 1-3)
  - Melphalan and prednisone (months 4-5)
  - Cyclophosphamide and prednisone (months 6-7)
  - Alpha-interferon (months 8-10)
  - Drug holiday (months 11-12)
Median event-free survival (from transplant) was 36.9 months.

 

 


Giampaolo Talamo, M.D.