LENALIDOMIDE

 

 

Lenalidomide (CC-5013, Revlimid ®) is an analogue of thalidomide, approved by the FDA in June 2006.

Due to the same concerns of fetal risks seen with thalidomide, patients are required to enroll in a restricted distribution system. Only prescribers and pharmacists registered with the program can provide the drug.

The standard dose is: 25 mg PO on days 1-21 every 28 days.
Primarily excreted by the kidneys.
Dose reductions are necessary in patients with renal insufficiency or thrombocytopenia:

  - Creatinine Clearance 60-80 (mild renal insufficiency): 25 mg qd
  - Creatinine Clearance 30-60 (moderate renal insufficiency): 10 mg qd
  - Creatinine Clearance <30 (severe renal insufficiency): 15 mg qod
  - Hemodialysis (ESRD): 5 mg qd (on HD days, after HD)

Toxicities include:
 - Neutropenia (= decreased white blood cells, with consequent risk of infections)
 - Thrombocytopenia (= decreased platelets, with consequent risk of bleeding)
 - Venous thromboembolism (less than with thalidomide)
 - Skin rash
 - Muscle cramps
 - Secondary malignancies
   The rate of secondary malignancies is low (~5% instead of ~2%), and benefits outweigh the risks,
   because the risk of developing a second cancer is lower than the risk of dying from myeloma.

Antithrombotic prophylaxis (at least with aspirin) is recommended.

 

 

Recent clinical studies of the immunomodulatory drug (IMiD) lenalidomide.
Br J Cancer. 2005 Sep 19;93(6):613-9.
Bartlett JB, Tozer A, Stirling D, Zeldis JB.
[Review]

Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients.
Blood. 2010 Feb 18;115(7):1343-50.
Gay F, Hayman SR, Lacy MQ, Buadi F, Gertz MA, Kumar S, Dispenzieri A, Mikhael JR, Bergsagel PL, Dingli D, Reeder CB, Lust JA, Russell SJ, Roy V, Zeldenrust SR, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Rajkumar SV.
This study compared efficacy and toxicity of RD (lenalidomide + dexamethasone) vs TD (thalidomide + dexamethasone) in 411 patients with newly diagnosed myeloma. 228 patients received RD and 183 TD. Results:
  - RR: 80% with RD and 61% with TD
  - VGPR: 34% with RD and 12% with TD
  - Median progression-free survival: 26.7 months with RD and 17.1 months with TD (p= 0.036)
  - Median overall survival: not reached with RD and 57.2 months with TD (p= 0.018)
  - At least 1 grade 3 or 4 adverse event: similar (57.5% vs 54.6%, p= 0.57)
  - Peripheral neuropathy: 0.9% with RD and 10.4% with TD
  - Venous thromboembolism: 9.2% with RD and 15.3% with TD (p= 0.058)
  - Main toxicity of RD was neutropenia (grade 3 or 4: 14.6% vs 0.6%)
The conclusion of this case-control study is that lenalidomide is more effective than thalidomide.

 

MECHANISM OF ACTION

Lenalidomide is a ubiquitin-ligase modulator.

Cereblon (CRBN) is a substrate-recognition component of a ubiquitin ligase, called cullin 4 ring ligase complex (CRL4).
The E3 ubiquitin ligase complex includes:
  - Cereblon (CRBN)
  - DNA damage binding protein-1 (DDB1)
  - Cullin-4A (Cul4A)
  - Regulator of cullins (Roc1)
Cereblon binds substrate proteins in the ubiquitin ligase complex. The ubiquitinated substrates are targeted for proteolysis.

Lenalidomide exerts its antimyeloma activity by inducing the degradation of the ikaros proteins IKZF1 (Icaros) and IKZF3 (Aiolos).

Ikaros family zinc finger proteins 1 and 3 are two B cell transcription factors, which can be transcriptional activators or repressors, depending on different cellular settings. The therapeutic activity of lenalidomide is due to a cereblon gain of function: lenalidomide modifies the substrate specificity of cereblon, and lenalidomide-bound cereblon is able to induce the proteasome degradation of IKZF1 and IKZF3.

IRF-4 (interferon regulatory factor-4) is a downstream target of cereblon.

Mutations in the CRBN gene can lead to mental retardation (autosomal recessive).

Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.
Blood. 2011 Nov 3;118(18):4771-9.
Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL, Orlowski RZ, Stewart AK.

High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone.
Br J Haematol. 2013 Jun;161(5):695-700.
Heintel D, Rocci A, Ludwig H, Bolomsky A, Caltagirone S, Schreder M, Pfeifer S, Gisslinger H, Zojer N, Jäger U, Palumbo A.

Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.
Science. 2014 Jan 17;343(6168):301-5.
Krönke J1, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL.

The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.
Science. 2014 Jan 17;343(6168):305-9.
Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr.

 

INDUCTION THERAPY

Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.
Blood. 2005 Dec 15;106(13):4050-3.
Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA.
This is a phase 2 trial of lenalidomide + dexamethasone in 34 patients with newly diagnosed myeloma. Lenalidomide was given at a dose of 25 mg daily on days 1-21, and dexamethasone was given at a dose of 40 mg daily on days 1-4, 9-12, and 17-20, with cycles repeated every 28 days. Response rate was 91%, including 6% CR and 32% VGPR + nCR.

Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma.
Mayo Clin Proc. 2007 Oct;82(10):1179-84.
Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Bergsagel PL, Stewart AK, Rajkumar SV.
This study reports the long-term results of the phase II study of 34 patients with newly diagnosed myeloma treated with lenalidomide + dexamethasone, previously published in Blood in December 2005. After 4 cycles of therapy, patients could either continue lenalidomide or proceed to autologous stem cell transplantation. 13 patients proceeded to transplant and they were censored at that time. Results:
  - The 2-year PFS was 83% in patients who had SCT and 59% in patients who remained on Rev-Dex
  - The 3-year OS was 92% in patients who had SCT and 85% in patients who remained on Rev-Dex

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.
Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21.
Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group.
445 patients with newly diagnosed multiple myeloma were randomized to two groups:
  - Lenalidomide + high-dose dexamethasone: 40 mg on days 1-4, 9-12, and 17-20, every 28 days (223 patients)
  - Lenalidomide + low-dose dexamethasone: 40 mg on days 1, 8, 15, and 22, every 28 days (222 patients)
After 4 cycles, patients could continue with the same therapy or proceed with stem cell transplantation. After 4 cycles:
  - RR: 79% with high-dose dexamethasone and 68% with low-dose dexamethasone
  - Overall survival at 1 year: 87% with high-dose dexamethasone and 96% with low-dose dexamethasone (p= 0.0002)
  - Grade III-IV toxicity: 52% with high-dose dexamethasone and 35%with low-dose dexamethasone
  - Mortality in the first 4 months: 12 of 222 patients with high-dose dexamethasone and 1 of 220 with low-dose dexamethasone (p= 0.003)
The most common grade III-IV toxicities were DVT (26% vs 12%), infections (16% vs 9%), and fatigue (15% vs 9%).
In conclusion, lenalidomide + low-dose dexamethasone provides better survival and less toxicity than lenalidomide + high-dose dexamethasone.

Single agent lenalidomide in newly diagnosed multiple myeloma: a retrospective analysis.
Leuk Lymphoma. 2010 Jun;51(6):1015-9.
Baz R, Patel M, Finley-Oliver E, Lebovic D, Hussein MA, Miller KC, Wood M, Sher T, Lee K, Chanan-Khan AA.
A retrospective analysis of 17 patients with newly diagnosed myeloma treated with single agent lenalidomide showed a response rate of 47%.

Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232).
Blood. 2010 Dec 23;116(26):5838-41.
Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B.
In this randomized trial, 97 patients received lenalidomide + dexamethasone, and 95 patients placebo + dexamethasone. Results:
  - Overall response rate: 78% with lenalidomide + dexamethasone, and 48% with dexamethasone
  - Progression-free survival at 1 year: 78% with lenalidomide + dexamethasone, and 52% with dexamethasone
  - Overall survival at 1 year: similar (94% with lenalidomide + dexamethasone, and 88% with dexamethasone, p= 0.25)
  - Thromboembolic events (despite aspirin prophylaxis): 23.5% with lenalidomide + dexamethasone, and 5% with dexamethasone

 

TRANSPLANT-INELIGIBLE PATIENTS

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.
N Engl J Med. 2014 Sep 4;371(10):906-17.
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team.
This study was conducted in 246 centers of 18 countries, and it randomized 1623 myeloma patients ineligible for transplant in 3 groups:
  - Lenalidomide (25 mg) + dexamethasone (40 mg once a week) indefinitely, until tumor progression.
  - Lenalidomide-dexamethasone for 18 cycles (72 weeks)
  - MPT (melphalan-prednisone-thalidomide) for 12 cycles of 42 days (72 weeks)
The best outcome was in the group treated with Len-Dex indefinitely. The improvement was statistically significant, but overall modest.
  - Median progression-free survival: 25.5 months with Len-Dex indefinitely, 21 months with Len-Dex x18, 21 months with MPT
  - Overall survival at 4 years: 59% with Len-Dex indefinitely, 56% with Len-Dex x18, 51% with MPT

 

MAINTENANCE AFTER INDUCTION THERAPY (NO TRANSPLANT)

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

 

RELAPSED/REFRACTORY DISEASE

Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.
Blood. 2002 Nov 1;100(9):3063-7.
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC.
In this phase I study of lenalidomide, 27 patients with relapsed/refractory myeloma received escalating doses of lenalidomide, from 5 mg to 50 mg daily. The most important toxicity was myelosuppression (grade 3 myelosuppression developed after 28 days in all of the 13 patients treated with 50 mg daily). The maximal tolerated dose was found to be 25 mg. Of note, the usual toxicities observed with thalidomide, i.e., somnolence, peripheral neuropathy, and constipation, were not observed. A response, defined as at least a 25% reduction in paraprotein level, was observed 17 of 24 (71%) patients, including 11 (46%) patients who received prior therapy with thalidomide.

A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.
Blood. 2006 Nov 15;108(10):3458-64.
Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC.
This is a randomized phase 2 study that evaluated 2 doses of lenalidomide in 70 patients with relapsed/refractory myeloma. Patients received lenalidomide either 30 mg once a day or 15 mg twice a day on days 1-21 every 28 days. Dexamethasone was added if no response was seen after 2 cycles. Toxicity was increased in the group receiving 15 mg twice a day, because the rate of grade 3-4 myelosuppression in patients was 41% (vs 13%). With 25 mg once a day, response rate (including minor responses) was 25%, median PFS was 7.7 months, and median overall survival was 28 months.

Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma.
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foŕ R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators.
N Engl J Med. 2007 Nov 22;357(21):2123-32.
This phase 3 trial investigated the use of lenalidomide + dexamethasone in 351 patients with relapsed/refractory myeloma. Patients received at least one previous antimyeloma therapy. Patients were randomized to receive lenalidomide (176 patients) or placebo (175 patients) on days 1-21 every 28 days, along with dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in the first 4 cycles and on days 1-4 in the following cycles. Results:
  - Response rate (PR + CR) was 60% in the lenalidomide group and 24% in the placebo group (p <0.001)
  - CR rate was 16% in the lenalidomide group and 3% in the placebo group (p <0.001)
  - Time to progression was 11.3 months in the lenalidomide group and 4.7 months in the placebo group (p <0.001)
  - The most frequent grade 3-4 adverse events were neutropenia (29.5%), thrombocytopenia (11.4%), and venous thromboembolism (11.4% vs 4.6%)

Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.
N Engl J Med. 2007 Nov 22;357(21):2133-42.
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators.
This phase 3 trial investigated the use of lenalidomide + dexamethasone in 353 patients with relapsed/refractory myeloma. Patients received at least one previous antimyeloma therapy. Patients were randomized to receive lenalidomide (177 patients) or placebo (176 patients) on days 1-21 every 28 days, along with dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in the first 4 cycles and on days 1-4 in the following cycles. Results:
  - Response rate (PR + CR) was 61% in the lenalidomide group and 20% in the placebo group (p <0.001)
  - CR rate was 14% in the lenalidomide group and 1% in the placebo group (p <0.001)
  - Time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (p <0.001)
  - Median overall survival was 29.6 months in the lenalidomide group and 20.2 months in the placebo group (p <0.001)
  - Rate of grade 3-4 adverse events was 85% in the lenalidomide group and 73% in the placebo group
  - Rate of venous thromboembolism was 15% in the lenalidomide group and 3% in the placebo group

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma.
Blood. 2009 Jul 23;114(4):772-8.
Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC.
This study evaluated the efficacy and safety of lenalidomide monotherapy (30 mg/day on days 1-21 every 28 days) in 222 patients with relapsed/refractory MM. PR or better was observed in 26% of patients, minimal response in 18%. Median PFS was 4.9 months, and median OS was 23.2 months.

Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
Leukemia. 2009 Nov;23(11):2147-52.
Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM.
This is an update analysis of 2 large randomized trials, MM-009 and MM-010, including 704 patients with relapsed/refractory myeloma treated with lenalidomide + dexamethasone vs placebo + dexamethasone. Results:
  - Overall response was 61% in the lenalidomide group and 22% in the placebo group
  - CR was 15% in the lenalidomide group and 2% in the placebo group
  - Median time to progression was 13.4 months in the lenalidomide group and 4.6 months in the placebo group
  - Median overall survival was 38 months in the lenalidomide group and 31.6 months in the placebo group (p= 0.045) (cross-over: 48%)

EMD

Lenalidomide is effective for extramedullary disease in relapsed or refractory multiple myeloma.
Eur J Haematol. 2011 Sep;87(3):281-4.
Calvo-Villas JM, Alegre A, Calle C, Hernández MT, García-Sánchez R, Ramírez G; GEM-PETHEMA/Spanish Myeloma Group, Spain.
[Letter]
18 patients with extramedullary disease in the setting of advanced myeloma were treated with lenalidomide. Results:
  - Response rate: 61%
  - Median progression-free survival: 10 months
  - Median overall survival: 15 months

 

LENALIDOMIDE AFTER THALIDOMIDE

Previous thalidomide therapy may not affect lenalidomide response and outcome in relapse or refractory multiple myeloma patients.
Eur J Cancer. 2011 Apr;47(6):814-8.
Guglielmelli T, Bringhen S, Rrodhe S, Gay F, Cavallo F, Berruti A, Montefusco V, Piro E, Benevolo G, Petrucci MT, Caravita T, Offidani M, Corradini P, Boccadoro M, Saglio G, Palumbo A.
Among 80 patients with multiple myeloma resistant to thalidomide, treatment with lenalidomide induced a response rate of 56%. Median progression-free survival was 10 months, and median overall survival 17 months.

 

RETREATMENT

Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma.
Blood. 2011 Aug 18;118(7):1763-5.
Madan S, Lacy MQ, Dispenzieri A, Gertz MA, Buadi F, Hayman SR, Detweiler-Short K, Dingli D, Zeldenrust S, Lust J, Greipp PR, Rajkumar SV, Kumar S.
In this retrospective study, 81 patients initially treated with thalidomide and 59 patients initially treated with lenalidomide received again IMIDs as one of the salvages therapies at relapse or progression. Patients received a median of 2 lines of therapy, including stem cell transplantation in 75% of patients. Partial response was seen in 44% of patients after repeat exposure to the IMIDs, and response rate was higher with lenalidomide than thalidomide.

Long-term disease control in patients with newly diagnosed multiple myeloma after suspension of lenalidomide therapy.
Am J Hematol. 2014 Mar;89(3):302-5.
Kourelis TV1, Kumar SK, Srivastava G, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, Zeldenrust SR, Leung N, Kyle RA, Russell SJ, Dingli D, Lust JA, Lin Y, Kapoor P, Go R, Rajkumar SV, Dispenzieri A.
Among 131 patients with newly diagnosed myeloma treated with dexamethasone and lenalidomide, 31 discontinued the treatment for several reasons, while the myeloma was in remission. Median progression-free survival from the time of stopping the lenalidomide was 39 months in those patients who received lenalidomide for 1 year or more. This study shows that the so-called "drug holidays" are feasible in some patients with multiple myeloma. Of note, all patients who had progressive disease responded again to lenalidomide and dexamethasone. 

 

 


Giampaolo Talamo, MD