COMBINATIONS WITH LENALIDOMIDE

Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy.
Ann Oncol. 2006 Dec;17(12):1766-71.
Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, Reed J, Faiman B, Ellis Y, Brand C, Srkalovic G, Andresen S, Knight R, Zeldis J, Hussein MA.
62 patients with relapsed/refractory myeloma were treated with lenalidomide + DVd (liposomal doxorubicin 40 mg/m2 IV, vincristine 2 mg IV on day 1, dexamethasone 40 mg PO on days 1-4). Results:
  - Response rate: 75%, with CR/nCR 29%
  - Median progression-free survival: 12 months
  - Median overall survival: not reached, after a median f/u of 7.5 months

Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma.
J Clin Oncol. 2009 Dec 1;27(34):5713-9.
Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, Munshi NC, Ghobrial IM, Doss D, Warren DL, Lunde LE, McKenney M, Delaney C, Mitsiades CS, Hideshima T, Dalton W, Knight R, Esseltine DL, Anderson KC.
In this phase I study of 38 patients with relapsed/refractory myeloma, the maximum-tolerated dose of lenalidomide + bortezomib was found to be lenalidomide 15 mg + bortezomib 1.0 mg/m2. Cytopenias were the most common toxicity. At least minimal response was observed in 61% of cases, and 83% of patients had stable disease or better. Median overall survival: 37 months.

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.
Leukemia. 2010 Jul;24(7):1350-6.
Kumar SK, Flinn I, Noga SJ, Hari P, Rifkin R, Callander N, Bhandari M, Wolf JL, Gasparetto C, Krishnan A, Grosman D, Glass J, Sahovic EA, Shi H, Webb IJ, Richardson PG, Rajkumar SV.
The addition of cyclophosphamide to VRD in 25 patients with newly diagnosed myeloma led to a response rate of 96% (68% with at least a very good partial response), but 3 patients (12%) experienced neutropenic fever, which usually requires hospital admission.

 

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).

 

BIRD

BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma.
Blood. 2008 Feb 1;111(3):1101-9.
Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M.
The BiRD regimen was used as first-line therapy in 72 myeloma patients. RR= 90.3%, CR= 38.9%.
The BiRD regimen consists of:
  - Clarithromycin (Biaxin®) 500 mg PO bid
  - Revlimid 25 mg PO days 1-21
  - Dexamethasone 40 mg PO once weekly
Cycles are repeated every 28 days.
Supportive therapy: ASA 81 mg PO qd, omeprazole 20 mg PO qd, Bactrim DS 1 tab PO bid 3 times/week.
Clarithromycin potentiates the effects of corticosteroids.

Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma.
Am J Hematol. 2010 Sep;85(9):664-9.
Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R.
This is a case-matched study of 72 patients with newly diagnosed myeloma, treated with BiRd or Rd. The retrospective analysis favored BiRd:
  - Rate of complete response: 46% with BiRd and 14% with Rd (p <0.001)
  - Median progression-free survival: 48.3 months with BiRd and 27.5 months with Rd (p= 0.044)
  - Overall survival at 3 years: 90% with BiRd and 73% with Rd (only trend: p 0.17)

Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.
Am J Hematol. 2014 Aug;89(8):E116-20.
Ghosh N, Tucker N, Zahurak M, Wozney J, Borrello I, Huff CA.
This is a retrospective study of 24 patients with multiple myeloma who progressed while on lenalidomide and dexamethasone. The addition of clarithromycin induced disease remission (at least PR) in 10 patients (42%). The median duration of response was approximately 7 months, and the median PFS was 4 months. The mechanism of action of clarithromycin upon the malignant plasma cells is unclear. One possible explanation is that this antibiotic enhances the therapeutic effect of dexamethasone, by inhibiting CYP3A and increasing the area under the curve of dexamethasone.

 

MPR

Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA - Italian Multiple Myeloma Network.
J Clin Oncol. 2007 Oct 1;25(28):4459-65.
Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network.
54 elderly patients with newly diagnosed myeloma were treated with MPR:
  - Melphalan 0.18-0.25 mg/Kg PO on days 1-4
  - Prednisone 2 mg/Kg PO on days 1-4
  - Revlimid 5-10 mg PO on days 1-21
Cycles were repeated every 28 days, x9 cycles, followed by maintenance with lenalidomide alone.
Results:
  - The maximum tolerated dose was melphalan 0.18 mg/Kg and lenalidomide 10 mg
  - Response rate: 81%, with VGPR 48% and CR 24%
  - Event-free survival at 1 year: 92%
  - Overall survival at 11 year: 100%
  - Most common grade 3-4 adverse events: neutropenia, thrombocytopenia, vasculitis (9.5%), and venous thromboembolism (5%)

Continuous lenalidomide treatment for newly diagnosed multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1759-69.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators.
This is a double-blind, placebo-controlled, randomized trial comparing three regimen for the treatment of 459 patients with newly diagnosed multiple myeloma and ineligible for stem cell transplantation:
  - MP (melphalan 0.18 mg/Kg and prednisone 2 mg/Kg on days 1-4 every 28 days x 9 cycles) (154 patients)
  - MPR (MP and lenalidomide 10 mg on days 1-21) (153 patients)
  - MPR-R (MPR x 9 cycles, followed by lenalidomide maintenance) (152 patients)
Patients received aspirin 75-100 mg for thromboprophylaxis during induction therapy. Aspirin was optional during maintenance.
Results:
  - Response rate: 50% with MP, 68% with MPR, 77% with MPR-R
  - Median progression-free survival: 13 months with MP, 14 months with MPR, 31 months with MPR-R
    The benefit of MPR, as compared with MP, occurred in patients 65-75 years of age and not in those older than 75 years of age.
    The benefit of lenalidomide maintenance was observed even in patients older than 75 (median PFS with MPR-R: 19 months).
  - 3-year overall survival rate: 66% with MP, 62% with MPR, 70% with MPR-R
    Of note, the influence of maintenance therapy on overall survival was unclear, because median follow-up period was only 30 months.
  - The most frequent grade 4 toxicity was neutropenia.
  - 3-year rate of second cancers: 3% with MP, 7% with MPR, 7% with  MPR-R

Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma.
Blood. 2015 Sep 10;126(11):1294-301.
Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV.
This study published the results of the ECOG E1A06 protocol, which randomized 306 patients with newly diagnosed multiple myeloma into two groups: one treated with MPT (melphalan, prednisone, and thalidomide - 154 patients), and the second one with MPR (melphalan, prednisone, and lenalidomide - 152 patients). Patients were elderly (median age 76) and transplant-ineligible. Induction therapy consisted of:
  - Melphalan 9 mg/m2 (in the arm with thalidomide) or 5 mg/m2 (in the arm with lenalidomide) PO daily, on days 1-4 every 28 days
  - Prednisone 100 mg PO daily, on days 1-4 every 28 days
  - Thalidomide 100 mg PO daily continuously, or lenalidomide 10 mg daily on days 1-21, every 28 days
After 12 cycles, patients started maintenance therapy with either thalidomide 100 mg or lenalidomide 10 mg, to be continued indefinitely, until progression.
Median follow-up was 41 months. Clinical outcomes were similar, and neither regimen was well tolerated. Results favored the MPR arm, based on quality of life and toxicity profile (mainly neurotoxicity):
  - Response rate was similar: 64% with MPT, and 60% with MPR (p=0.56) (NB: this is lower than with other regimens used in the induction setting)
  - Median progression-free survival was similar: 21 months with MPT, and 19 with MPR (95% CI 0.64-1.09)
  - Median overall survival was similar: 53 months with MPT, and 48 months with MPR (p=0.48)
  - Toxicity of grade 3 or more: 73% with MPT vs 58% with MPR (NB: this is higher than with other regimens used in the induction setting)
  - Non-hematologic toxicities of grade 3 or more: 60% with MPT, and 40% with MPR (p=0.001)
  - Second malignancies: 18 patients with MPT, and 14 patients with MPR

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.
Blood. 2016 Mar 3;127(9):1109-16.
Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A.
These authors randomized 668 patients with newly diagnosed myeloma in two groups, one receiving MPT (318 pts), and the other receiving MPR (319 pts).
MPT was given as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Prednisone 2 mg/Kg on days 1-4
  - Thalidomide 200 mg/day
Cycles were repeated every 4 weeks x9, followed by maintenance with thalidomide 100 mg/day, until progression.
MPR was given as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Prednisone 2 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
Cycles were repeated every 4 weeks x9, followed by maintenance with lenalidomide 10 mg on days 1-21 every 28 days, until progression.
Thrombosis prophylaxis was given during induction, with either aspirin 75 mg daily, or carbasalasate calcium 100 mg daily.
The results of MPT and MPR were equivalent:
  - Response rate, defined as at least a VGPR, was 47% with MPT and 45% with MPR.
  - Progression-free survival was 20 months with MPT, and 23 months with MPR (p=0.12).
As expected, the toxicity profile was different, because of more neuropathy with MPT, and more myelosuppression with MPR.

 

CPR

Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma.
Blood. 2016 Mar 3;127(9):1102-8.
Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A.
This is a phase 3 clinical trial that involved 58 oncology centers in Italy and 9 in the Czech Republic. It included 662 patients with newly diagnosed myeloma, with a median age of 74 years (range, 63-91). There were 3 groups, MPR (melphalan, prednisone, and lenalidomide - 218 patients), CPR (cyclophosphamide, prednisone, and lenalidomide - 222 patients), and RD (lenalidomide and dexamethasone - 222 patients).
MPR:
  - Melphalan 0.18 mg/Kg on days 1-4 (0.3 mg/Kg if age >75)
  - Prednisone 1.5 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
CPR:
  - Cyclophosphamide 50 mg every day or every other day (x 21 days only if age >75)
  - Prednisone 25 mg every other day
  - Lenalidomide 10-25 mg on days 1-21
RD:
  - Lenalidomide 25 mg on days 1-21
  - Dexamethasone 40 mg once a week (20 mg if age >75)
Cycles were repeated every 4 weeks x9, followed by maintenance with either lenalidomide alone 10 mg on days 1-21 every 28 days, or lenalidomide + prednisone 25 mg every other day, continued until progression.
After a median follow-up of 39 months, median survival was not reached, and median progression-free survival was equivalent in the three groups: 22 months with MPR and CPR, and 21 months with RD (p=0.28). Therefore, the authors concluded that triplet (lenalidomide and alkylator-containing) regimens were not superior to doublet (lenalidomide-containing) regimens in newly diagnosed multiple myeloma. Of note, the doublet regimen contained a higher dose of lenalidomide, and dexamethasone instead of prednisone (the latter is a less potent corticosteroid).

 

CRD

Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: Results from a phase 2 trial.
Am J Hematol. 2011 Aug;86(8):640-5.
Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A.
This trial enrolled 53 patients with newly diagnosed myeloma. Treatment consisted of:
  - Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15
  - Revlimid 25 mg PO on days 1-21
  - Dexamethasone 40 mg PO on days 1, 8, 15, 22 (= weekly)
Cycles were repeated every 28 days.
Response rate was 85%, and 47% of patients had VGPR or better. Median PFS was 28 months, and OS at 2 years 87%.

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

 

 


Giampaolo Talamo, MD