CORTICOSTEROIDS

 

Dexamethasone (Decadron ®) is a hormone very effective in killing myeloma cells. It is the most potent corticosteroid.

The usual dose is 40 mg (= 10 pills) taken once a week, or every day for 4 consecutive days, depending on the schedule and need for rapid cytoreduction. Patients older than 70-75 may tolerate only 20 mg PO weekly.
High-dose pulse dexamethasone: 40 mg PO qd days 1-4, 9-12, 17-20.

Side effects are many, and they include:
 - Psychological/mood changes, agitation
 - Elevated blood pressure
 - Hyperglycemia
 - Weight gain
 - Fluid retention
 - Myopathy
 - Avascular necrosis of the bone (which usually manifests with pain in hips or shoulders)
 - Infections. Antibiotic prophylaxis is recommended while on dexamethasone.

 

 

Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients.
Blood. 2002 May 1;99(9):3163-8.
Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE.
This study showed that single agent prednisone 50 mg PO on alternate days is an effective maintenance regimen in multiple myeloma. The authors compared prednisone 10 mg vs 50 mg PO every other day as maintenance therapy after VAD-based induction chemotherapy in 125 patients with newly diagnosed myeloma. Prednisone maintenance was continued until until disease progression. After a median follow-up of 53 months, patients who received prednisone 50 mg qod has superior outcomes compared to the patients treated with prednisone 10 mg qod: from the time of maintenance, the progression-free survival was 14 vs 5 months (p= 0.003), and the overall survival was 37 vs 26 months (p= 0.05). Toxicities were similar in the two groups.

Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma.
Bone Marrow Transplant. 2004 Sep;34(6):485-90.
Kumar S, Lacy MQ, Dispenzieri A, Rajkumar SV, Fonseca R, Geyer S, Allmer C, Witzig TE, Lust JA, Greipp PR, Kyle RA, Litzow MR, Gertz MA.
This is a retrospective study evaluating the effectiveness of single agent dexamethasone as induction therapy for myeloma before stem cell transplantation. A group of 35 patients treated with dexamethasone alone was compared to a group of 72 patients treated with VAD. Results:
  - Response rate before transplant was 63% with dexamethasone and 74% with VAD (p= 0.25)
  - Response rate after transplant was 97% with dexamethasone and 100% with VAD (p= 0.33)
  - Complete response rate after transplant was 26% with dexamethasone and 39% with VAD (p= 0.18)
  - Progression-free survival and overall survival at 1 year after transplant were similar between the two groups
These results showed that single agent dexamethasone had an efficacy similar to VAD for the induction therapy of myeloma before stem cell transplantation.

Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma.
Br J Haematol. 2004 Oct;127(2):159-64.
Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, Soler JA, Gardella S, Carbonell F, Mateo G, San Miguel JF.
This is a randomized trial comparing MP (melphalan + prednisone, the standard arm) vs MD (melphalan + dexamethasone) in 201 myeloma patients 70 years old or older.
  - Response rates after 6 cycles were similar: 67.9% with MP and 64.5% with MD
  - Response rates after 12 cycles were similar: 49.4% with MP and 46.1% with MD
  - Rates of complete response after 12 cycles were higher in the MD arm: 9.1% with MP and 22.4% with MD (p <0.05)
  - Median event-free survival was similar: 15.9 months with MP and 23.3 months with MD
  - Median overall survival was similar: 29.4 months with MP and 27.2 months with MD (p= 0.63)
  - Toxicity was higher in the MD group, specifically the non-hematological toxicity.
At the time of the study, MP remained the standard treatment for myeloma patients not eligible for stem cell transplantation.

Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy.
J Clin Oncol. 2005 Aug 1;23(22):5217-23.
Talamo G, Angtuaco E, Walker RC, Dong L, Miceli MH, Zangari M, Tricot G, Barlogie B, Anaissie E.

In a total of 553 myeloma patients treated with dexamethasone-containing chemotherapy, AVN of the femoral head developed in 49 patients (9%). The median time to onset was 12 months (range, 2 to 41 months). Only 4 patients required hip replacement because of AVN. Higher cumulative doses of dexamethasone increased the risk of AVN.

Continuous prednisolone versus conventional prednisolone with VMCP-interferon-alpha2b as first-line chemotherapy in elderly patients with multiple myeloma.
Br J Haematol. 2005 Nov;131(3):329-37.
Ludwig H, Spicka I, Klener P, Greil R, Adam Z, Gisslinger H, Tarkovács G, Linkesch W, Maniatis A, Morant R, Drach J, Kuhn I, Schuster J, Hinke A.
299 elderly patients with newly diagnosed multiple myeloma were randomized to induction therapy with either prednisolone daily conttinuously or prednisolone for 2 weeks/cycle + VMCP (vincristine, melphalan, cyclophosphamide, and prednisolone) and interferon-alpha 2b. Prednisolone given continuously during the induction therapy did not improve outcome:
  - Response rate: 62% in the continuous arm and 60% in the control arm
  - Median progression-free survival: 20 months in the continuous arm vs 19 months in the control (p= 0.97)
  - Median overall survival: 34 months in the continuous arm vs 37 months in the control arm (p= 0.35)
Continuous prednisolone was more toxic, because it was associated with more frequent dyspnea, cardiac impairment, and hyperglycaemia.

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy.
Blood. 2006 Feb 15;107(4):1292-8.
Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaďs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group.
In the IFM 95-01 trial, 488 myeloma patients aged 65-75 years were randomized between 4 different regimens of treatment:
  - MP (melphalan + prednisone)
  - Dexamethasone alone
  - Melphalan + dexamethasone
  - Dexamethasone + interferon alpha
The standard MP remained the best regimen, in terms of efficacy and toxicity. The response rate at 6 months was higher in the group receiving melphalan + dexamethasone. The progression-free survival was longer in the groups receiving melphalan. However, overall survival was similar among the 4 treatment groups. The toxicity of dexamethasone-containing regimens was higher than with MP, particularly because of pyogenic infections, hemorrhage, diabetes, GI, and psychiatric complications.

A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7.
Br J Haematol. 2007 Jan;136(2):203-11.
Shustik C, Belch A, Robinson S, Rubin SH, Dolan SP, Kovacs MJ, Grewal KS, Walde D, Barr R, Wilson J, Gill K, Vickars L, Rudinskas L, Sicheri DA, Wilson K, Djurfeldt M, Shepherd LE, Ding K, Meyer RM.
466 older patients were randomized to either MP (melphalan + prednisone) or M-Dex (melphalan + dexamethasone) as induction therapy, then treated with dexamethasone or observation as maintenance therapy. Dexamethasone did not improve outcomes in induction therapy, when combined with melphalan: MP and M-Dex produced similar outcomes, in terms of median progression-free survival (1.8 vs 1.9 years, p= 0.2] and median overall survival (2.5 vs 2.7 years, p = 0.3). Maintenance therapy with dexamethasone improved progression-free survival but not overall survival: the group treated with maintenance dexamethasone had better PFS (2.8 vs 2.1 years, p= 0.0002), but similar median OS (4.1 vs 3.8 years, p= 0.4).

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.

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma.
Haematologica. 2015 Jan;100(1):100-6.
Dimopoulos MA, Orlowski RZ, Facon T, Sonneveld P, Anderson KC, Beksac M, Benboubker L, Roddie H, Potamianou A, Couturier C, Feng H, Ataman O, van de Velde H, Richardson PG.
This is a retrospective analysis of  109 matched pairs of patients with relapsed myeloma, treated in 3 clinical trials with either single agent bortezomib (V group) or the combination dexamethasone + bortezomib (VD group). Median dose of bortezomib and treatment duration were similar in the two groups. The results favored the addition of dexamethasone to bortezomib:
  -  Response rate: 41% in the V group, and 75% in the VD group
  -  Median progression-free survival: 6.4 months in the V group, and 11.9 months in the VD group
  - Toxicity rates and treatment-related mortality were similar in the two groups (2 patients died in each group)

 

 


INTERFERON ALFA

The effectiveness of interferon alpha in the treatment of myeloma is very modest, in the order of weeks/months instead of years, and it can be associated with significant toxicities. Its use is mainly of historical interest, and it should only be considered in the setting of myeloma refractory to most other therapies.

 

 


Giampaolo Talamo, M.D.