POMALIDOMIDE

 

Pomalidomide (CC-4047, Pomalyst ®) is a thalidomide analogue (second generation IMiD).
A
pproved by the FDA in February 2013.

It is active even in patients refractory to thalidomide and lenalidomide.

Dose: 4mg PO daily on days 1-21 every 28 days.
Usually given with dexamethasone 40mg weekly (20 mg in patient older than 70-75) and aspirin.

Pomalidomide is metabolized in the liver. The drug and its metabolites are primarily excreted by the kidneys. Median plasma half life is 7-10 hours.

Possible adverse reactions:
  - Myelosuppression (main toxicity): neutropenia, anemia, thrombocytopenia
  - Fatigue, dyspnea, nausea, constipation, diarrhea
  - Peripheral neuropathy: about 10%
  - DVT/PE: about 3%, with anticoagulation
  - Teratogenicity: the drug is only available through the Pomalyst REMS program

REMS = Risk Evaluation and Mitigation Strategy.

Mechanism of action: see lenalidomide.

 

Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro.
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12703-8.
Mahony C, Erskine L, Niven J, Greig NH, Figg WD, Vargesson N.

 

Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation.
Br J Haematol. 2008 Apr;141(1):41-51.
Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA.
This is a phase 1 study of pomalidomide in 20 patients with relapsed myeloma. The maximum tolerated dose (MTD) was defined as 5 mg every other day. No thrombotic events were observed. In 17 patients, pomalidomide was continued beyond the 4 weeks of the phase 1 study, for a median of 14 months. RR was 60%, with 10% CR. Median PFS was 10.5 months and OS was 33 months.

Pomalidomide-Induced Pulmonary Toxicity in Multiple Myeloma.
Am J Med Sci. 2015 Sep;350(3):241-2.
Modi D, Mamdani H, Vettese T.

 

POMALIDOMIDE + LOW-DOSE DEX

Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5008-14.
Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV.
This is the first phase II trial of pomalidomide + dexamethasone in patients with relapsed or refractory. 60 patients received pomalidomide 2 mg PO daily on days 1-28 + dexamethasone 40 mg PO daily on days 1, 8, 15, and 22, with cycles repeated every 28 days. Patients received aspirin 325 mg PO qd for thromboprophylaxis. Results:
  - RR: 63%, CR: 5%. Responses were observed even in patients refractory to lenalidomide (40%) and thalidomide (37%).
  - Median progression-free survival time was 11.6 months.
  - Main toxicity was myelosuppression. Venous thromboembolism was observed in 1 patient (1.6%).

Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM).
Leukemia. 2010 Nov;24(11):1934-9.
Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F.
34 patients with myeloma refractory to lenalidomide were treated with pomalidomide (2 mg PO daily, continuously, every 28 days) + dexamethasone (40 mg PO weekly). Results:
  - Response rate was 47%: stable disease 35%, PR 23%, VGPR 9%, and progressive disease 18%
  - Median time to response: 2 months
  - Median duration of response: 9 months
  - Median overall survival 14 months
  - Main  toxicity was myelosuppression, with grade 3-4 neutropenia in 26% of patients, and grade 3-4 thrombocytopenia in 9% of patients

Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease.
Blood. 2011 Sep 15;118(11):2970-5.
Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR.
Two trials of pomalidomide in 70 patients with myeloma refractory to both lenalidomide and bortezomib showed a clinical benefit of 43-49%. The most common toxicity was myelosuppression.

Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02.
Blood. 2013 Mar 14;121(11):1968-75.
Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome.
Pomalidomide and weekly dexamethasone were given to 84 patients with myeloma refractory to both bortezomib and lenalidomide. Results:
  - Response rate: 35%
  - Median progression-free survival: 4.6 months
  - Median overall survival: 15 months

Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial.
Lancet Oncol. 2013 Oct;14(11):1055-1066.
Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M.
302 patients with relapsed/refractory myeloma, previously treated with both lenalidomide and bortezomib, were randomized to pomalidomide 4 mg PO qd on days 1-21 every 28 days + low-dose dexamethasone (= 40 mg PO once a week) vs high-dose dexamethasone (= 40 mg PO on days 1-4, 9-12, and 17-20). Median follow-up was 10 months. Results:
  - Response rate was 31% in the low-dose Dex arm
  - Median progression-free survival was 4 months with low-dose Dex, and 1.9 months with high-dose Dex
  - Median overall survival was 12.7 months with low-dose Dex, and 8.1 months with high-dose Dex (p= 0.03)

 

COMBINATIONS

VPD

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma.
Blood. 2017 Sep 7;130(10):1198-1204.
Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ.
In this phase I/II trial, 50 patients with relapsed myeloma, refractory to lenalidomide, received combination chemotherapy with VPD:
  - Bortezomib 1.0-1.3 mg/m2 SC/IV once a week
  - Pomalidomide 4 mg PO on days 1-21
  - Dexamethasone 40 mg PO once a week
Cycles were repeated every 28 days. Median follow-up was 42 months. Results:
  - Response rate: 86%. PR 36%, VGPR 28%, CR 10%, sCR 12%
  - Median progression-free survival: about 14 months
  - OS at 42 months: 66%
  - Most common toxicities: mild cytopenias. No significant peripheral neuropathy was observed.

KPD

Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma.
Blood. 2015 Nov 12;126(20):2284-90.
Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG.
In this phase I trial, 32 patients with relapsed or refractory myeloma, all resistant to prior lenalidomide, received CPD, a combination regimen of:
  - Carfilzomib 20/27 mg/m2 IV on days 1,2, 8,9, 15,16
  - Pomalidomide 4 mg PO on days 1-21
  - Dexamethasone 40 mg PO/IV on days 1, 8, 15, 22
Cycles were repeated every 28 days. The regimen was highly active and well tolerated (1 patient died of pneumonia, and another patient dies of pulmonary embolism, but these two events could have occurred even without the chemotherapy), and the the above doses represented the MTD of the CPD regimen.

Pom-Cy-Dex

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.
Blood. 2016 May 26;127(21):2561-8.
Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S.
This study evaluated the addition of cyclophosphamide to the standard combination of pomalidomide and dexamethasone in 80 patients with relapsed/refractory myeloma. In the randomized phase 2 portion of the study, 36 patients received Pom-Dex, and 34 patients Pom-Cy-Dex. Results were better with Pom-Cy-Dex:
  - Response rate: 39% with Pom-Dex, and 65% with Pom-Cy-Dex (p=0.035)
  - Median progression-free survival was 4.4 months with Pom-Dex, and 9.5 months with Pom-Cy-Dex (p=0.106)

PCP

Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study.
Blood. 2013 Oct 17;122(16):2799-806.
Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A.
In this study, 69 patients with relapsed/refractory myeloma received chemotherapy with PCP:
  - Pomalidomide 1-2.5 mg PO daily (maximum tolerated dose was 2.5 mg)
  - Cyclophosphamide 50 mg PO every other day
  - Prednisone 50 mg PO every other day
This chemotherapy was given for 6 cycles of 28 days, followed by maintenance therapy with pomalidomide 1 mg daily and prednisone 25 mg every other day.
Median follow-up was 15 months. Results:
  - PR: 51%
  - Median progression-free survival: 10.4 months (median EFS was 5 months in historical controls)
  - Median overall survival: not reached (median OS was 9 months in historical controls)
  - 1-year survival: 69%

 

 


Giampaolo Talamo, MD