There is no single standard of care in the treatment of multiple myeloma, and the type and duration of chemotherapy must be tailored to the specific patient and clinical context. Several standards of care are available. Chemotherapy consists of various single agents and many combination regimens, with variable degrees of efficacy. As a general rule, based on the results of multiple clinical trials, three-drug combinations are associated with better outcomes than two-drug regimens or single agent therapy (the disease response is usually deeper and longer). One of the 3 drugs is usually a corticosteroid, such as prednisone or dexamethasone.

However, several factors must be taken into account before choosing the optimal treatment strategy, in particular:
  - Patient-related factors: e.g., age and comorbidities
  - Myeloma-related factors: e.g., biology and clinical aggressiveness
  - Drug-related factors: e.g., expected toxicities

Moreover, what is the goal of therapy? Cure, prolongation of life, or just palliation of symptoms? Ideally, it should be cure in everybody, but we know this is observed in only a small minority of patients, about 10-15%, so the goal achieved in the vast majority of cases is prolongation of life. The physician must also identify a balance between prolongation of life and palliation on an individual basis, as more aggressive regimens are associated with better responses, but degrees of toxicities that may be acceptable to some patients and not to others (based on cultural, philosophical, and religious attitudes toward life). We must recognize there is often a fine balance between the toxicity of the chemotherapy and the toxicity of the cancer itself. This is especially important in the elderly, as the average life expectancy of normal individuals is about 80 years, and the average age of myeloma patients at diagnosis is about 70.

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 the following:

 - Corticosteroids: dexamethasone, prednisone
 - Traditional chemotherapy: melphalan, cyclophosphamide, doxorubicin, bendamustine
 - IMIDs: thalidomide, lenalidomide, pomalidomide
 - Proteasome inhibitors: bortezomib, carfilzomib
 - Monoclonal antibodies: daratumumab, elotuzumab
 - HDAC inhibitors: panobinostat



Multiple myeloma cured by conventional chemotherapy: a report and a review.
Leuk Lymphoma. 2002 Apr;43(4):907-10.
Notaro R, De Renzo A, De Rosa G, Karadimitris A, Rotoli B.
This is a case report of a 28-year-old man who received cyclophosphamide every 3-4 weeks for about 3 years, and he remained in persistent complete remission for 23 years without further treatment. The authors review 5 other cases of myeloma cured by conventional chemotherapy reported in the medical literature.

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.

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

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


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.

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

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.

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.

Activity of 129 Single-Agent Drugs in 228 Phase I and II Clinical Trials in Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):284-290.
Kortuem KM, Zidich K, Schuster SR, Khan ML, Jimenez-Zepeda VH, Mikhael JR, Fonseca R, Stewart AK.
This study analyzed the efficacy of 129 drugs administered as single agents in 228 clinical trials involving 7421 myeloma patients. The 10 best drugs according to the average response reported in the clinical trials were the following (in order of decreasing efficacy):
  - Melphalan
  - Bortezomib
  - Fotamustine
  - Dexamethasone
  - Thalidomide
  - Carfilzomib
  - Pomalidomide
  - Prednisone
  - Bendamustine
  - Teniposide

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.




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 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.

Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial.
Leukemia. 2017 Nov;31(11):2435-2442.
Bahlis NJ, Corso A, Mugge LO, Shen ZX, Desjardins P, Stoppa AM, Decaux O, de Revel T, Granell M, Marit G, Nahi H, Demuynck H, Huang SY, Basu S, Guthrie TH, Ervin-Haynes A, Marek J, Chen G, Facon T.
This is a subanalysis of the FIRST trial, which randomized patients with newly diagnosed multiple myeloma to receive lenalidomide + dexamethasone indefinitely, until disease progression ("Rd continuous"), vs MPT (melphalan , thalidomide, and prednisone) x 12 cycles, or lenalidomide + dexamethasone x 18 cycles (Rd x18). Patients were ineligible for an autologous stem cell transplant. Rd continuous was the winner, as it improved efficacy outcomes compared with fixed duration therapies. The 4-year overall survival for those patients who achieved a partial response or better was 64.6% with Rd continuous, 62.5% with Rd x18, and 57.2% with MPT.



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%



Commonly used regimens in the past, now of mainly historical interest:

VAD (Obsolete)
   Vincristine 0.4 mg/day IV cont. inf. days 1-4 (use a central vein)
   Adriamycin 9 mg/m2/day IV cont. inf. days 1-4
   Dexamethasone 40 mg PO days 1-4, 9-12, 17-20
Cycle repeated every 4 weeks.
RR: 75%, but the incidence of true CR is <5%

MP (Obsolete)
   Melphalan 10 mg/m2 PO days 1-4
   Prednisone 60 mg/m2 PO days 1-4
Cycle repeated every 4-6 weeks, depending on count recovery.
RR = 55%. MP rarely produces CR (<5%).



Giampaolo Talamo, M.D.