L-Pam: DL-isomer of phenylalanine mustard.
Melphalan was first synthesized in 1953.
Administered orally or as IV infusion over 15-20 min.
The chronic use of oral melphalan can compromise the ability to collect stem cells, and therefore this drug is used only in patients who are not eligible for a stem cell transplant, due to advanced age or comorbidities.

Chemical structure of melphalan:


Oral melphalan is not commonly used any more as it was in the past, due to the improved efficacy or reduced toxicity of more modern combinations. For example, results of clinical trials showed that RD is superior to MPT, and VD is equivalent to VMP.



Clinical experiences with sarcolysin in neoplastic diseases.
Ann N Y Acad Sci. 1958 Apr 24;68(3):1128-32.
Blokhin N, Larionov L, Perevodchikova N, Chebotareva L, Merkulova N.
This study in 1958 is the first report of the use of melphalan in multiple myeloma.

Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma. IV. L-Phenylalanine mustard (NSC-8806).
Cancer Chemother Rep. 1962 Aug;21:87-99.
Bergsagel DE, Sprague CC, Austin C, Griffith KM.
This is one of the first studies which demonstrated the effectiveness of melphalan in the treatment of multiple myeloma. Objective improvement was seen in 14 of 24 patients.

Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure.
J Nephrol. 2002 Nov-Dec;15(6):684-9.
Vigneau C, Ardiet C, Bret M, Laville M, Fiere D, Tranchand B, Fouque D.
These authors used a single dose of melphalan, 25 mg/m2 IV, in 45 patients with multiple myeloma. 79% patients had renal impairment, and some of them were on dialysis. Results:
  - Overall median survival was 45 +/- 43 months after diagnosis. Survival was no different whether renal insufficiency was present or not.
  - 25 of 34 patients had leukopenia, with a mean of 14 days
  - The most frequent adverse effect was infection

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.

Toxicity in standard melphalan-prednisone therapy among myeloma patients with renal failure: a retrospective analysis and recommendations for dose adjustment.
Br J Haematol. 2005 Mar;128(5):631-5.
Carlson K, Hjorth M, Knudsen LM; Nordic Myeloma Study Group.
272 patients with newly diagnosed myeloma were treated with melphalan + prednisone (MP) without dose adjustment for renal function. The hematological toxicity of melphalan was related to the degree of renal insufficiency. Grade 3-4 hematologic toxicity was:
  - 18% with GFR >50
  - 28% with GFR 30-50
  - 36% with GFR <30
Grades 3-4 infections developed in 6% of patients, and they were not related to the renal function. The authors recommend to decrease the dose of melphalan if the GFR is <30. No recommendations could be made for GFR <10 because only 2% of patients had such a degree of renal insufficiency.



Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma.
Blood. 2002 Jul 1;100(1):224-9.
Spanswick VJ, Craddock C, Sekhar M, Mahendra P, Shankaranarayana P, Hughes RG, Hochhauser D, Hartley JA.
The most important cytotoxic mechanism of melphalan is the formation of DNA adducts with the DNA interstrand crosslink. The authors utilized techniques of molecular biology to show that resistance to melphalan is associated with an impairment of DNA interstrand crosslink repair

The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells.
Blood. 2005 Jul 15;106(2):698-705.
Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS.
This study shows that resistance to melphalan in cell lines is due to the enhancement of the interstrand cross-link repair due to the activity of the the Fanconi Anemia/BRCA pathway.





Dose of cyclophosphamide should be reduced:
  - by 25% if GFR is 10-50 mL/min
  - by 50% if GFR is <10 mL/min


Weekly cyclophosphamide and alternate-day prednisone: an effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation.
Mayo Clin Proc. 2005 Dec;80(12):1578-82.
Trieu Y, Trudel S, Pond GR, Mikhael J, Jaksic W, Reece DE, Chen CI, Stewart AK.

This is a retrospective study of 66 patients with myeloma in relapse after stem cell transplantation. Patients were treated with cyclophosphamide 500 mg PO once weekly + alternate-day prednisone 100 mg PO on alternate days. Among 59 evaluable patients, response rate was 61% (PR 41%), 1-year PFS 66%, median PFS 18.6 months, and median overall survival from the time of initiation of salvage therapy 28.6 months.

Continuous administration of low-dose cyclophosphamide and prednisone as a salvage treatment for multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2010 Feb;10(1):51-5.
Zhou F, Guo L, Shi H, Lin C, Hou J.
27 myeloma patients with severe comorbidities or history of recurrent infections wit conventional chemotherapy received salvage chemotherapy with prednisone 15 mg PO qd + cyclophosphamide 50 mg PO qd. The use of continuous low dose chemotherapy is called metronomic chemotherapy. Response rate was 67%. Median time to response was 2 months. Median OS was 22 months in the 18 responding patients, and 7 months in the 9 non-responding patients. The most common adverse events were infection and Cushing syndrome.

Effectiveness and safety of high-dose cyclophosphamide as salvage therapy for high-risk multiple myeloma and plasma cell leukemia refractory to new biological agents.
Am J Hematol. 2011 Aug;86(8):699-701.
Rivell GL, Brunson CY, Milligan L, Stuart RK, Costa LJ.
High-dose cyclophosphamide (1,500 mg/m2 IV for 2 consecutive days) is an effective salvage regimen for patients with myeloma refractory to the novel biologic agents. Among 17 patients with high-risk disease -6 with plasma cell leukemia-, response assessment at 6 weeks showed 9 pts in PR and 8 pts with stable disease. Circulating plasma cells disappeared in all 6 patients with plasma cell leukemia. Despite antibiotic prophylaxis and growth factor support with peg-filgrastim, most patients required hospitalization because of neutropenic fever, and 1 patient died from sepsis.


Randomized Phase II Study of Bortezomib, Thalidomide, and Dexamethasone With or Without Cyclophosphamide As Induction Therapy in Previously Untreated Multiple Myeloma.
J Clin Oncol. 2013 Jan 10;31(2):247-55.
Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL.
This study randomized patients with newly diagnosed myeloma to VTD (bortezomib, thalidomide, dexamethasone; 49 patients) or VTDC (VTD and cyclophosphamide 400 mg/m2) for four 21-day cycles before autologous stem cell transplant. VTDC increased toxicity without a significant improvement of clinical outcomes:
  - Rate of nCR/CR: 51% with VTD and 44% with VTDC
  - Response rate: 100% with VTD and 96% with VTDC
  - Overall survival at 3 years: 80% in both arms
  - Serious adverse events: 22% with VTD and 41% with VTDC





Pegylated liposomal doxorubicin (Doxil ®) is usually given as a 1-hour infusion at a dose of 30 mg/m2 every 3 weeks, as outpatient. It avoids the need for an indwelling catheter, which is necessary with a continuous infusion of standard doxorubicin.


A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients.
Cancer. 2002 Nov 15;95(10):2160-8.
Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM.
This is a phase II study of VAD incorporating pegylated liposomal doxorubicin (40 mg/m2) in 33 patients witth newly diagnosed multiple myeloma. Chemotherapy was given every 28 days for at least 6 cycles, and for 2 cycles after the best response. Results:
  - Response rate: 88% (complete response 12%, major response 55%, minor response 21%)
  - Stable disease: 9%
  - Progressive disease: 3%
  - Median time to progression: 23.1 months
  - Progression-free survival at 2 years: 42%
  - Progression-free survival at 3 years: 23%
  - Overall survival at 3 years: 67%
  - Most common toxicities: hand-foot syndrome, mucositis, and neutropenia. Only 1 patient had cardiac toxicity.
Compared with historical controls, VAD with liposomal doxorubicin has the same efficacy, and improved safety profile and patient convenience.

Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma.
Ann Oncol. 2003 Jul;14(7):1039-44.
Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group.
This study randomized 259 patients with newly diagnosed myeloma into two groups: 127 patients treated with standard VAD (VAD bolus), and 132 patients treated with VAD containing liposomal doxorubicin 40 mg/m2 (VAD Doxil). The chemotherapy was given every 28 days x 4. Results:
  - Response rate was 61% in both arms
  - Toxicities were similar between the two arms, except for alopecia (more common with VAD bolus), and hand-foot syndrome (more common with VAD Doxil)


Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study.
Ann Oncol. 2004 Jan;15(1):134-8.
Zervas K, Dimopoulos MA, Hatzicharissi E, Anagnostopoulos A, Papaioannou M, Mitsouli Ch, Panagiotidis P, Korantzis J, Tzilianos M, Maniatis A; Greek Myeloma Study Group.
39 patients with newly diagnosed myeloma were treated with VAD-Doxil + thalidomide 200 mg PO qhs every 28 days x 4 cycles. Response rate was 74% (CR 10%, PR 64%), minor response 8%, and refractory disease 18%. Most important toxicities were cytopenias, DVT (10%), skin rash (5%), and peripheral neuropathy (5%). 2 patients (5%) died because of infection.


Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma.
Hematol Oncol. 2006 Dec;24(4):205-11.
García-Sanz R, Hernández JM, Sureda A, García-Laraña J, Prósper F, Alegre A, Bárez A, Mateos MV, San Miguel JF.
This is a phase I/II study of 30 patients with newly diagnosed myeloma, age 70 years and older, treated with melphalan, prednisone, and liposomal doxorubicin x 6 cycles. The phase I of the study found that the maximum tolerated dose of liposomal doxorubicin was 30 mg/m2. Complete response was 14%, and partial response 52%. Median progression free survival was 24 months, 3-year OS 52%, and 3-year PFS 37%. No cases of hand-foot syndrome were observed.


Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial.
Cancer. 2006 Feb 15;106(4):848-58.
Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA.
This is a noninferiority trial of 192 patients with newly diagnosed myeloma, randomized to receive:
1) VAd (95 patients): conventional doxorubicin 9 mg/m2/day, vincristine 0.4 mg per day as continuous IV infusion on Days 1-4 + dexamethasone
2) DVd (97 patients): liposomal doxorubicin 40 mg/m2, vincristine 1.4 mg/m2 IV on Day 1 + dexamethasone 40 mg PO on Days 1-4 (DVd)
Treatment was given every 4 weeks, for at least 4 cycles.
  - Clinical efficacy was similar:
       RR: 41% with VAd and 44% with DVd
       CR: 0% with VAd and 3% with DVd
       Progressive disease: 0% with VAd and 2% with DVd
       Need for hospitalization: 36% with VAd and 37% with DVd
       PFS and OS were similar
  - Toxicity was less with DVd:
       Lower incidence of neutropenia and sepsis, reduced need for central venous access and growh factors
       Alopecia: 44% with VAd and 20% with DVd
       Mean changes from baseline LVEF: -4.5 with VAd and -2.3 with DVd
       Hand-foot syndrome was observed in 25% of patients treated with DVd (Grade 1 and 2 in 84% of cases)


Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study.
Haematologica. 2006 Jan;91(1):133-6.
Offidani M, Corvatta L, Marconi M, Visani G, Alesiani F, Brunori M, Galieni P, Catarini M, Burattini M, Centurioni R, Rupoli S, Scortechini AR, Giuliodori L, Candela M, Capelli D, Montanari M, Olivieri A, Piersantelli MN, Leoni P.
This is a phase II study of thalidomide 100 mg PO qhs, dexamethasone, and liposomal doxorubicin 40 mg/m2 every 28 days in 50 patients with advanced myeloma. Response rate was 92% (CR 26%, nCR 6%, VGPR 6%, PR 38%, and minor response 16%), median event-free survival was 17 months, and median overall survival was not reached.

Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma.
Blood. 2006 Oct 1;108(7):2159-64.
Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, Galieni P, Catarini M, Burattini M, Centurioni R, Ferranti M, Rupoli S, Scortechini AR, Giuliodori L, Candela M, Capelli D, Montanari M, Olivieri A, Poloni A, Polloni C, Marconi M, Leoni P.
50 patients older than 65 years with newly diagnosed myeloma were treated with thalidomide 100 mg PO qhs, dexamethasone, and liposomal doxorubicin 40 mg/m2 every 28 days. Response rate was 98% (CR 34%, nCR 14%, VGPR 10%, PR 30%, and minor response 10%). 3-year OS was 74%, and 3-year EFS was 57%.

Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple myeloma.
Eur J Haematol. 2007 Apr;78(4):297-302.
Offidani M, Bringhen S, Corvatta L, Falco P, Marconi M, Avonto I, Piersantelli MN, Polloni C, Boccadoro M, Leoni P, Palumbo A.
In this study, 47 patients with MM received ThaDD therapy: thalidomide 100 mg/d, dexamethasone 40 mg PO on days 1-4 and 9-12, and pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 28 days. Their clinical outcome was compared with that of 47 matched patients treated at relapse with Thal-Dex (thalidomide (100 mg/d and dexamethasone 40 mg PO on days 1-4). Response rates were significantly higher in ThaDD group, including overall response rate (92% vs. 63.5%), partial response rate (75.5% vs. 59.5%), very good partial response (VGPR) rate (36% vs. 15%), and near complete remission (nCR) rate (30% vs. 10.5%). Patients in the ThaDD group had a longer median progression-free survival, event-free survival, and overall survival, than the group treated with Thal-Dex. Non-hematologic toxicity was similar in the 2 groups of patients, but hematologic toxicity and infections were significantly higher in the group of patieents treated with ThaDD.


Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5015-22.
Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS.
This is a phase II trial with VDD in 40 patients with newly diagnosed multiple myeloma:
  - Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
  - Liposomal doxorubicin 30 mg/m2 IV on day 4
  - Dexamethasone 20-40 mg
Cycles were repeated every 21 days, x 6.
Results: RR was 85.0%, CR/nCR 37.5%. 30 patients proceeded with stem cell transplant. 1-year OS 97.5%, 1-year PFS 92.5%.


A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma.
Leukemia. 2012 Jul;26(7):1675-80.
Berenson JR, Yellin O, Kazamel T, Hilger JD, Chen CS, Cartmell A, Woliver T, Flam M, Bravin E, Nassir Y, Vescio R, Swift RA.
This is a phase II trial of 40 patients with relapsed/refractory myeloma patients, treated with:
  - Bortezomib 1.0 mg/m2 IV on days 1, 4, 8, 11
  - Liposomal doxorubicin 4 mg/m2 IV on days 1, 4, 8, 11
  - Dexamethasone 40 mg on days 1, 4, 8, 11
  - Lenalidomide 10 mg on days 1-14
Cycles were repeated every 28 days.
Clinical benefit was about 85%: Minimal response 36%, PR 18%, VGPR 10%, CR 20%.


Phase II study of CLAD (cyclophosphamide, liposomal doxorubicin and dexamethasone) in patients with advanced multiple myeloma and historical comparison to CAD (cyclophosphamide, doxorubicin and dexamethasone).
Hematol Oncol. 2007 Sep;25(3):132-9.
Hütter G, Szélenyi H, Schmittel A, Siehl JM, Thiel E, Keilholz U.
This study evaluates the CLAD regimen in 60 patients with advanced multiple myeloma.
  - Cyclophosphamide 200 mg/m2 IV days 1-4
  - Pegylated liposomal doxorubicin 20 mg/m2 IV day 1
  - Dexamethasone 40 mg PO days 1-4
Efficacy and toxicity was compared to a historical cohort of 46 patients treated with CAD (cyclophosphamide, dexamethasone and conventional doxorubicin). The response rate was similar: 71% with CLAD and 74% with CAD. CLAD showed an advantage in hematological toxicity and lower infectious complications, and presumably lower cardiotoxicity.



Liposomal daunorubicin (DaunoXome) plus dexamethasone for patients with multiple myeloma. A phase II International Oncology Study Group study.
Cancer. 2002 May 15;94(10):2645-52.
Mohrbacher AF, Gregory SA, Gabriel DA, Rusk JM, Giles FJ.
This is a phase II study of liposomal daunorubicin 100 mg/m2 IV every 3 weeks for max 6 cycles in patients with myeloma, either newly diagnosed (4 patients) or with relapsing/refractory disease (37 patients). Results: partial response 17%, stable disease 63%. Median survival 7.6 months. Main toxicity was myelosuppression.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma: the DD Protocol.
Sao Paulo Med J. 2005 Nov 3;123(6):266-70.
Dulley FL, Saboya R, Hungria VT, Bueno ND, Mello FG, Frota MT, Chiattone CS, Barros JC, Mori NS, Sturaro D, Macedo MC, Silva RL, Melo LM, Souza CA.
Liposomal daunorubicin + dexamethasone (DD) was administered to 20 patients with myeloma. Response rate was 30%.



Giampaolo Talamo, M.D.