TREATMENT

 

 

Multiple myeloma typically follows a relapsing course, and most patients require multiple lines of therapy.

Drugs commonly used in the treatment of multiple myeloma are:

 - Corticosteroids: dexamethasone, prednisone
 - Traditional chemotherapy: melphalan, cyclophosphamide, doxorubicin, bendamustine
 - IMIDs: thalidomide, lenalidomide, pomalidomide
 - Proteasome inhibitors: bortezomib, carfilzomib

Some experts believe that the specific sequence of drugs is not very important in terms of clinical outcomes and overall survival, but this is a highly controversial issue.

 

Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation.
Hematol J. 2003;4(6):379-98.
Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M, Child JA, Comenzo R, Djulbegovic B, Fantl D, Gahrton G, Harousseau JL, Hungria V, Joshua D, Ludwig H, Mehta J, Morales AR, Morgan G, Nouel A, Oken M, Powles R, Roodman D, San Miguel J, Shimizu K, Singhal S, Sirohi B, Sonneveld P, Tricot G, Van Ness B; Scientific Advisors of the International Myeloma Foundation.
[Review]

Cure of myeloma: hype or reality?
Bone Marrow Transplant. 2005 Feb;35(3):215-24.
Fassas A, Shaughnessy J, Barlogie B.
[Review]

Cure of multiple myeloma - more hype, less reality.
Bone Marrow Transplant. 2006 Jan;37(1):1-18.
Hari P, Pasquini MC, Vesole DH.

[Review]

Improved survival in multiple myeloma and the impact of novel therapies.
Blood. 2008 Mar 1;111(5):2516-20.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA.
This study evaluated demonstrated the impact of the new agents (i.e., thalidomide, lenalidomide, or bortezomib) on the clinical outcomes of myeloma patients. In 387 myeloma patients who relapsed after stem cell transplant, patients who relapsed before 2000 had a median overall survival of 12 months, whereas patients who relapsed after 2000 had a median overall survival of 24 months. Patients who were treated with at least one of the new agents had a median survival after relapse longer than those patients who did not receive the new agents (31 vs 15 months). Survival was prolonged not only in relapsed disease, but also in patients with newly diagnosed myeloma: overall survival in 2981 patients with newly diagnosed myeloma diagnosed treated in the last decade was 45 months, whereas it was 30 months in those diagnosed before the last decade.

Individualizing treatment of patients with myeloma in the era of novel agents.
J Clin Oncol. 2008 Jun 1;26(16):2761-6.
San-Miguel J, Harousseau JL, Joshua D, Anderson KC.
[Review]

Treatment of myeloma: cure vs control.
Mayo Clin Proc. 2008 Oct;83(10):1142-5.
Rajkumar SV.
[Review]

Guidelines for the diagnosis and management of multiple myeloma 2011.
Br J Haematol. 2011 Jul;154(1):32-75.
Bird JM, Owen RG, D'Sa S, Snowden JA, Pratt G, Ashcroft J, Yong K, Cook G, Feyler S, Davies F, Morgan G, Cavenagh J, Low E, Behrens J; Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma Forum.
[Review]

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.
Leukemia. 2012 Jan;26(1):149-57.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, LeLeu X, Hulin C, Klein SK, Sonneveld P, Siegel D, Bladé J, Goldschmidt H, Jagannath S, Miguel JS, Orlowski R, Palumbo A, Sezer O, Rajkumar SV, Durie BG; International Myeloma Working Group.
This is a review of 286 patients with multiple myeloma resistant to novel agents (bortezomib and lenalidomide or thalidomide). Salvage therapy included stem cell transplantation in nearly 20% of patients. The overall outcome was poor. Results:
  - Only 32% of patients had a partial response or better
  - Median event-free survival: 5 months
  - Median overall survival: 9 months

Targeted therapy of multiple myeloma.
Adv Exp Med Biol. 2013;779:197-221.
Dolloff NG, Talamo G.
[Review]

Sequence of novel agents in multiple myeloma: an instrumental variable analysis.
Leuk Res. 2013 Sep;37(9):1077-82.
Baz R, Miladinovic B, Patel A, Ho VQ, Shain KH, Alsina M, Nishihori T, Ochoa-Bayona JL, Sullivan DM, Dalton WS, Djulbegovic B.
In this retrospective analysis, outcomes were not affected by the sequence of therapy chosen (lenalidomide vs bortezomib): 97 patients treated with lenalidomide-based regimens first had a similar survival to that of 111 patients treated with a bortezomib-containing regimen first. Patients with renal insufficiency seemed to benefit more from the use of bortezomib-based therapy upfront.

 

NUMBER OF CHEMOTHERAPY AGENTS

Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials.
Crit Rev Oncol Hematol. 2017 May;113:249-255.
Sun Z, Zheng F, Wu S, Liu Y, Guo H, Liu Y.
This is a meta-analysis of 3197 patients with relapsed/refractory myeloma enrolled in clinical trials comparing triplet versus doublet combination regimens. The results showed that triplet combinations led to superior clinical outcomes (improved response rates, CR rates, progression-free survival, and overall survival), at the expense of increased toxicities.

 

CONTINUOUS THERAPY VS FIXED DURATION THERAPY

Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma.
J Clin Oncol. 2015 Oct 20;33(30):3459-66.
Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I, Nagler A, Petrucci MT, Hajek R, Pezzatti S, Delforge M, Patriarca F, Donato F, Cerrato C, Nozzoli C, Yu Z, Boccadifuoco L, Caravita T, Benevolo G, Guglielmelli T, Vincelli D, Jacques C, Dimopoulos MA, Ciccone G, Musto P, Corradini P, Cavo M, Boccadoro M.
In many clinical trials, a valuable end point is the progression-free survival (PFS), which is the time from therapy assignment until the first progression or death. These authors explore a new end point, the PFS2, defined as the time from therapy assignment until the second progression of death), with the goal of clarifying whether a continuous first-line therapy would be associated to a shorter second remission, as opposed to a fixed first-line therapy. In fact, some experts expressed the concern that a continuous first-line therapy would lead to drug-resistant myeloma cells, and that the disease could become more aggressive and less responsive to the second-line therapy. In other words, the remission with the second-line chemotherapy would be shorter if the first-line chemotherapy would be continued until progression. However, this study showed that continuous therapy is superior to fixed duration therapy. The authors analyzed data from three trials, including 417 patients who received continuous therapy, and 410 patients who received fixed duration therapy. In this analysis, patients in remission after first-line therapy, as well as patients who progressed after first-line therapy but are in remission after second-line therapy, are censored. Results:
  - Median PFS1: 32 months with continuous therapy, and 16 months with fixed duration therapy
  - Median PFS2: 55 months with continuous therapy, and 40 months with fixed duration therapy
 - Overall survival at 4 years: 69% months with continuous therapy, and 60% with fixed duration therapy
These results suggest that continuing chemotherapy indefinitely, until tumor progression, does not induce significant resistance to an additional line of chemotherapy.

 

SEQUENTIAL THERAPY VS ALTERNATING THERAPY

Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM.
Blood. 2016 Jan 28;127(4):420-5.
Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J.
In this study, 233 patients with newly diagnosed myeloma were randomized into two groups: the first received "sequential" chemotherapy, with VMP (bortezomib, melphalan, prednisone) x 9 cycles, followed by RD (lenalidomide and dexamethasone) x 9 cycles (118 patients). The second group received "alternating" chemotherapy, with VMP x 1 cycle followed by RD x 1 cycke, and so on, up to 18 cycles (115 patients). There were no differences of clinical outcomes between the "sequential" and "alternating" chemotherapy regimens:
  - With the "sequential" regimen:  RR 42%, median PFS 32 months, 3-year OS 72%
   - With the "alternating" regimen: RR 40%, median PFS 34 months, 3-year OS 74%

 

 


 

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, Azaïs 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. Thus, its use is rarely considered, and only in the setting of myeloma refractory to other therapies.

 

 


Giampaolo Talamo, M.D.