CONDITIONING REGIMEN

 

Single-agent melphalan 200 mg/m2 IV is the conditioning regimen of choice for autologous stem cell transplant in multiple myeloma.
IV melphalan has poor solubility and limited chemical stability upon reconstitution. Most formulations contain propylene glycol as co-solvent , which can occasionally cause metabolic dysfunction and arrhythmias.

 

Myeloablative treatments for multiple myeloma: update of a comparative study of different regimens used in patients from the Spanish registry for transplantation in multiple myeloma.
Leuk Lymphoma. 2002 Jan;43(1):67-74.
Lahuerta JJ, Grande C, Blade J, Martínez-López J, de la Serna J, Alegre A, Garcia LJ, Caballero D, de la Rubia J, Marín J, Perez-Lopez C, Sureda A, Escudero A, Cabrera R, Conde E, García-Ruiz JC, Pérez-Equiza K, Hernandez F, Palomera L, León A, Giraldo P, Solano C, Bargay J, San MJ; Spanish Multiple Myeloma Group.
This study evaluated outcomes of 4 different conditioning regimen used for autologous SCT in MM:
  - MEL200: Melphalan 200 mg/m2 (472 patients)
  - MEL140+TBI: - Melphalan 140 mg/m2 + Total Body Irradiation (135 patients)
  - BU-MEL: Busulfan 12 mg/Kg + Melphalan 140 mg/m2 (186 patients)
  - BU-CY: Busulphan 14 mg/Kg + Cyclophosphamide 120 mg/Kg (28 patients)
There were no significant differences between the 4 conditioning regimens, in terms of hematological recovery and transplant-related mortality. Response rate was 100% with BU-MEL and 86-93% in the other groups (p<0.05). Differences in event-free survival and overall survival did not reach statistical significance.

Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.
Blood. 2002 Feb 1;99(3):731-5.
Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome.
This is a prospective and randomized trial that compared 2 conditioning regimens:
  - Melphalan 140 mg/m2 + TBI 8 Gy (140 patients)
  - Melphalan 200 mg/m2 (142 patients)
Mel 200 was the winner, because it was less toxic and at least as effective as Mel 140 + TBI.
  - The duration of neutropenia and thrombocytopenia was shorter
  - The transfusion requirements lower
  - The median duration of hospitalization was shorter
  - The incidence of severe mucositis was decreased
  - EFS was similar (20.5 vs 21 months)
  - Overall survival at 45 months was improved (65.8% vs 45.5%, p=0.05)

 

MELPHALAN

Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m2).
Leukemia. 2004 Jan;18(1):133-8.
Palumbo A, Bringhen S, Bertola A, Cavallo F, Falco P, Massaia M, Bruno B, Rus C, Barbui A, Caravita T, Musto P, Pescosta N, Rossini F, Vignetti M, Boccadoro M.
In this study, 90 patients with newly diagnosed myeloma were treated with two autologous transplants using melphalan 100 mg/m2, and their outcomes were compared with those of a control group of 90 patients treated with melphalan 200 mg/m2. Results favored the higher dose:
  - Rate of complete remission was 35% with MEL100 and 48% with MEL200 (p=0.08)
  - Median event-free survival was 32 months with MEL100 and 42 months with MEL200 group (p<0.005)
  - Median overall survival was similar
  - Toxicity was inferior with MEL100, but transplant-related mortality was similar

Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study.
Blood. 2010 Mar 11;115(10):1873-9.
Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, De Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, Boccadoro M.
This is a randomized study of 298 myeloma patients treated with tandem autologous SCT and assigned to either melphalan 200 mg/m2 or melphalan 100 mg/m2. Results:
 - Treatment-related mortality: about 3% in both groups
  - RR was 79% with MEL200 and 72% with MEL100
  - CR was 15% with MEL200 and   8% with MEL100
  - Median PFS: 31 months with MEL200 and 26 months with MEL100
  - Median OS: not significantly different
The authors conclude that MEL200 should be considered the standard conditioning regimen, because it leads to longer remission duration.

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma.
Eur J Haematol, 2012; 89(2):145-50.
Talamo G.
, Rakszawski K.L., Rybka W.B., Dolloff N.G., Malysz J., Berno T., Zangari M.

Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma.
Bone Marrow Transplant. 2014 Jun;49(6):761-6.
Parmar SR, Bookout R, Shapiro JF, Tombleson R, Perkins J, Kim J, Yue B, Tomblyn M, Alsina M, Nishihori T.
The authors retrospectively compared two different conditioning regimens of high-dose melphalan: 100 mg/m2 for 2 days (185 patients) and 200 mg/m2 in 1 day (93 patients). No meaningful differences were observed, in terms of clinical outcomes, with the exception of oral mucositis, which was more pronounced in the 2-days regimen.

A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-SCT.
Bone Marrow Transplant. 2016 Jan;51(1):67-71.
Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, Green DJ, Press OW, Lill M, Ifthikharuddin JJ, Vescio R, Holmberg LA, Phillips GL.
In this study, 131 patients with multiple myeloma underwent an autologous stem cell transplant using high-dose melphalan. They were randomized to receive either the standard dose 200 mg/m2 (Mel200), or a higher dose 280 mg/m2 (Mel280). Melphalan was given IV over 30 minutes on day -2. All patients received cryotherapy and amifostine. Results:
  - nCR + CR: 22% with Mel200 and 39% with Mel280 (p=0.03)
  - Progression-free survival at 1 year: 83% with Mel200 and 78%
  - Progression-free survival at 3 years: 46% with Mel200 and 54% with Mel280
  - Grade 3 mucositis: 0 with Mel200 and 1 with Mel280
  - No patient died in the entire study group
In conclusion, Mel280 was safe and induced a higher rate of deep responses. The size of the trial was judged to be too small to demonstrate a survival advantage for Mel280.

Effect of melphalan 140 mg/m(2) vs 200 mg/m(2) on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation-a single center experience.
Clin Transplant. 2016 Aug;30(8):894-900.
Katragadda L, McCullough LM, Dai Y, Hsu J, Byrne M, Hiemenz J, May S, Cogle CR, Norkin M, Brown RA, Wingard JR, Chang M, Moreb JS.
In this retrospective study, 96 patients with myeloma received an autologous stem cell transplant using melphalan 200 mg/m2, and 33 patients using melphalan 140 mg/m2. After a median follow-up of 74 months, relapse-free survival and overall survival were similar in the two groups.

 

BEAM

BEAM Conditioning Regimen Has Higher Toxicity Compared With High-Dose Melphalan for Salvage Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2015 Sep;15(9):531-5.
Veeraputhiran M, Jain T, Deol A, Ayash L, Kim S, Dyson G, Bhutani D, Lum LG, Ratanatharathorn V, Uberti JP, Abidi MH.
In this study, 43 patients with myeloma received a second autologous stem cell transplant at relapse after the first one. The conditioning regimen was high-dose melphalan with the first transplant, whereas it was either melphalan (19 patients) or BEAM (BCNU, etoposide, cytarabine, and melphalan) with the second one. The results favored melphalan:
  - The median progression free-survival was similar: 12.1 months with melphalan, and 7.7 months with BEAM (p=0.82)
  - BEAM was associated with higher toxicity, especially fever and infections (whereas melphalan was associated with a higher incidence of mucositis)

 

BUSULFAN-CONTAINING REGIMENS

Busulfan, cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma.
Am J Hematol. 2003 Jul;73(3):169-75.
Cogle CR, Moreb JS, Leather HL, Finiewicz KJ, Khan SA, Reddy VS, Wingard JR.
26 patients treated with Bu-Cy-Etoposide. After SCT, median EFS was 24 months, and median OS 43 months.

High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma.
Leuk Res. 2007 Aug;31(8):1069-75.
Benson DM Jr, Elder PJ, Lin TS, Blum W, Penza S, Avalos B, Copelan E, Farag SS.

BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma.
Bone Marrow Transplant. 2009 Aug;44(3):157-61.
Talamo G, Claxton DF, Dougherty DW, Ehmann CW, Sivik J, Drabick JJ, Rybka W.
Clinical outcomes of  busulfan and cyclophosphamide used as conditioning regimen before stem cell transplantation in 79 myeloma patients were not superior to those obtained in historical controls treated with high-dose melphalan.

Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.
Haematologica. 2010 Nov;95(11):1913-20.
Lahuerta JJ, Mateos MV, Martínez-López J, Grande C, de la Rubia J, Rosiñol L, Sureda A, García-Laraña J, Díaz-Mediavilla J, Hernández-García MT, Carrera D, Besalduch J, de Arriba F, Oriol A, Escoda L, García-Frade J, Rivas-González C, Alegre A, Bladé J, San Miguel JF; Grupo Español de MM and Programa para el Estudio de la Terapéutica en Hemopatía Maligna Cooperative Study Groups.
225 patients who underwent transplant using busulfan 12 mg/Kg + melphalan 140 mg/m2 had a longer progression-free survival than 542 patients treated with melphalan 200 mg/m2. However, overall survival was not different, and there were deaths due to sinusoidal obstruction syndrome (veno-occlusive disease).

Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach.
Biol Blood Marrow Transplant. 2013 Jan;19(1):69-74.
Blanes M, Lahuerta JJ, González JD, Ribas P, Solano C, Alegre A, Bladé J, San Miguel JF, Sanz MA, de la Rubia J.
The authors compared outcomes of a conditioning regimen with busulfan 9.6 mg/Kg + melphalan 140 mg/m2 (51 patients) vs the standard melphalan 200 mg/m2 (102 patients). No significant differences were found:
  - Response rates and CR rates were similar
  - Progression-free survival was similar (24 months with MEL vs 33 months with BU-MEL, p=0.1)
  - Transplant-related mortality: 2% with MEL and 4% with BU-MEL

Bortezomib-based induction therapy followed by intravenous busulfan-melphalan as conditioning regimen for patients with newly diagnosed multiple myeloma.
Leuk Lymphoma. 2015 Feb;56(2):415-9.
Blanes M, González JD, Lahuerta JJ, Ribas P, Lorenzo I, Boluda B, Sanz MA, de la Rubia J.

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan.
Lancet Haematol. 2017 Jun;4(6):e283-e292.
Nieto Y, Valdez BC, Pingali SR, Bassett R, Delgado R, Nguyen J, Shah N, Popat U, Jones RB, Andersson BS, Gulbis A, Ahmed S, Bashir Q, Parmar S, Patel K, Myers A, Rondon G, Orlowski RZ, Champlin R, Qazilbash M.
This is a phase II trial of 74 patients with relapsed/refractory myeloma, treated with an autologous stem cell transplant. They used a conditioning regimen with gemcitabine, busulfan, and melphalan instead of the standard single agent melphalan. Results were compared to those of 184 patients who received melphalan alone. Despite similar post-transplant maintenance, the progression-free survival was better with the three drugs instead of one (15 vs 9 months). There were 3 deaths (4%), 2 due to sepsis and 1 due to a cardiac event.

 

OTHER REGIMENS

High-dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment-related mortality in patients with multiple myeloma: results of a randomised study.
Br J Haematol. 2005 Aug;130(4):588-94.
Fenk R, Schneider P, Kropff M, Huenerlituerkoglu AN, Steidl U, Aul C, Hildebrandt B, Haas R, Heyll A, Kobbe G; West German Myeloma Study Group.
This is a randomized trial comparing two conditioning regimens for autologous transplants in 56 patients with myeloma:
  - The standard regimen was melphalan 200 mg/m2
  - The intensified regimen consisted of melphalan 200 mg/m2 + cyclophosphamide 120 mg/kg + idarubicin 42 mg/m2
The study was discontinued early, because the intensified regimen was associated with unacceptable toxicity: treatment-related mortality was 20% (vs 0% with the standard regimen, mainly because of infections.

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation.
Leukemia. 2006 Feb;20(2):345-9.
Comenzo RL, Hassoun H, Kewalramani T, Klimek V, Dhodapkar M, Reich L, Teruya-Feldstein J, Fleisher M, Filippa D, Nimer SD.
In this study, 49 patients with myeloma underwent autologous stem cell transplant using melphalan 200 mg/m2 + carmustine 300 mg/m2. The transplant-related mortality was 2% and the pulmonary toxicity 10%. The rate of CR + nCR was 49%.

Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM).
Blood. 2010 Jan 7;115(1):32-7.
Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM).
In this study, 54 patients with newly diagnosed MM underwent autologous stem cell transplantation with melphalan 200 mg/m2 (standard regimen) + bortezomib 1 mg/m2 x 4, on days -6, -3, +1, +4. Bortezomib did not delay hematologic recovery. At least VGPR was observed in 70% of patients, and CR rate was 32%. When comparing results with a matched group treated with only melphalan, CR was higher (35% vs 11%; p= 0.001).

Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma.
Bone Marrow Transplant. 2011 Apr;46(4):510-5.
Kazmi SM, Saliba RM, Donato M, Wang M, Hosing C, Qureshi S, Anderlini P, Popat U, Champlin RE, Giralt SA, Qazilbash MH.
Median progression-free survival in 60 patients treated with autologous SCT, using topotecan, cyclophosphamide, and melphalan as conditioning regimen, was 18.5 months, similar to the PFS seen with high-dose melphalan.

 

 


 

ENGRAFTMENT

After melphalan 200 mg/m2 on day -1, hematopoietic recovery occurs within 2 weeks in >90% of patients: ANC >500 at about day +11, and platelets >20,000 unsupported at about day +13.

The use of G-CSF, to accelerate neutrophil engraftment, is not always necessary. It may anticipate resolution of neutropenia by 1-2 days, but it is associated with several side effects (e.g., fatigue, bone pain, fever, engraftment syndrome, fluid retention, and allergic reactions).

 

Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients.
Eur J Haematol. 2006 Nov;77(5):410-5.
Martino M, Praticò G, Messina G, Irrera G, Massara E, Messina G, Console G, Iacopino P.
37 consecutive patients with myeloma treated with high-dose melphalan and autologous peripheral blood stem cell transplantation were randomly assigned to receive:
  - Filgrastim 5 mcg/kg SC qd starting on day +5 (19 patients)
  - Peg-filgrastim 6 mg SC x1 on day +1 (n = 18 patients)
The median duration of neutropenia in the Filgrastim and Pegfilgrastim groups was similar, but the incidence of febrile neutropenia (100% vs 61%) and the duration of febrile neutropenia (4 days vs 1.5 days) were lower in the Pegfilgrastim arm.

Ideal body weight correlates better with engraftment after PBSC autograft than actual body weight, but is under-estimated in myeloma patients possibly due to disease-related height loss.
Bone Marrow Transplant. 2007 Oct;40(7):665-9.
Maclean PS, Parker AN, McQuaker IG, Clark AD, Farrell E, Douglas KW.

Pegfilgrastim reduces the length of hospitalization and the time to engraftment in multiple myeloma patients treated with melphalan 200 and auto-SCT compared with filgrastim.
Ann Hematol. 2011 Jan;90(1):89-94.
Samaras P, Blickenstorfer M, Siciliano RD, Haile SR, Buset EM, Petrausch U, Mischo A, Honegger H, Schanz U, Stussi G, Stahel RA, Knuth A, Stenner-Liewen F, Renner C.
This is a retrospective comparison of filgrastim (46 patients) vs pegfilgrastim (46 patients) after melphalan 200 mg/m2. results:
  - Median duration of grade 4 neutropenia: 6 days with filgrastim and 5 days with pegfilgrastim (p=0.008)
  - Median duration of hospitalization: 15.5 days with filgrastim and 14.5 days with pegfilgrastim (p=0.024)
  - Cost was reduced with the use of peg-filgrastim

Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis.
Biol Blood Marrow Transplant. 2016 Feb;22(2):226-31.
Shah N, Shi Q, Williams LA, Mendoza TR, Wang XS, Reuben JM, Dougherty PM, Bashir Q, Qazilbash MH, Champlin RE, Cleeland CS, Giralt SA.
In this study, 80 patients 60 year-old and older with either myeloma or amyloidosis were treated with an autologous transplant using melphalan 200 mg/m2. They were randomized to receive either a standard dose of stem cells (median, 5.1 million CD34+ cells/Kg) or a higher dose (median, 10.5 million CD34+ cells/Kg). The results were negative: patients receiving the high dose of stem cell did not experience a more rapid engraftment of neutrophils and platelets, and they did not experience an improvement of their transplant-related symptoms. 

Fractionated stem cell infusions for patients with plasma cell myeloma undergoing autologous hematopoietic cell transplantation.
Leuk Lymphoma. 2016 Aug;57(8):1781-5.
Landau H, Wood K, Chung DJ, Koehne G, Lendvai N, Hassoun H, Lesokhin A, Hoover E, Zheng J, Devlin SM, Giralt S.
In this study, 22 patients with myeloma underwent an autologous stem cell transplant with fractionated stem cell infusions, i.e., with multiple cell infusions at days 0,, +2, +4, and +6. The results were compared to those of 77 patients who received the stem cells in the traditional way, i.e., with all cells on day 0. The results of the study were negative, because the fractionation did not shorten the number of days of neutropenia, the days of fever, infections, antibiotic use, diarrhea, and length of hospital admission.

G-CSF improves safety when you start the day after autologous transplant in multiple myeloma.
Leuk Lymphoma. 2017 May 16:1-5.
Sborov DW, Cho YK, Cottini F, Hade EM, Lamprecht M, Tackett K, Sharma N, Williams N, Li J, Devine S, Poi M, Phelps MA, Hofmeister CC.
This study analyzed outcomes of three different schedules of G-CSF given after an autologous stem cell transplant for multiple myeloma: started on day +1 (43 patients), +5 (75 patients), or +7 (103 patients). Although starting G-CSF on day -7 leads to some cost savings, the administration on day +1 leads to:
  - Shorter duration of severe neutropenia: median number of days to ANC >500 was 10.2, instead of 11.3 with day +5, and 11.8 with day +7
  - Reduced incidence of neutropenic fever: 28%, instead of 49% with day +5, and 91% with day +7
  - Reduced incidence of grade 2-3 mucositis: 2%, instead of 4% with day +5, and 18% with day +7

 

 


 

COMPLICATIONS

 

There are many possible toxicities after high-dose chemotherapy. They include:
  - Neutropenia, with possibility of infections and sepsis
  - Anemia requiring blood transfusions
  - Thrombocytopenia, with possibility of hemorrhages
  - Nausea and vomiting
  - Oral mucositis, which may require opioid analgesia and total parenteral nutrition
  - Intestinal mucositis, with diarrhea
  - Transient alopecia
The mortality of high-dose melphalan approximately 1-2%.

 

 

NAUSEA AND VOMITING

Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial.
J Clin Oncol. 2014 Oct 20;32(30):3413-20.
Schmitt T, Goldschmidt H, Neben K, Freiberger A, Hüsing J, Gronkowski M, Thalheimer M, Pelzl le H, Mikus G, Burhenne J, Ho AD, Egerer G.

In this study, 362 patients with multiple myeloma undergoing autologous stem cell transplant with high-dose melphalan were randomized to either granisetron + dexametasone + placebo (181 patients), or granisetron + dexamethasone + aprepitant (181 patients). Results favored the aprepitant group:
  - Absence of significant nausea within 120 hours of melphalan administration: 88% with placebo, and 94% with aprepitant
  - Absence of vomiting within 120 hours of melphalan administration: 65% with placebo, and 78% with aprepitant

Olanzapine Reduces Chemotherapy-induced Nausea and Vomiting Compared With Aprepitant in Myeloma Patients Receiving High-dose Melphalan Before Stem Cell Transplantation: A Retrospective Study.
Clin Lymphoma Myeloma Leuk. 2017 Sep;17(9):584-589.
Trifilio S, Welles C, Seeger K, Mehta S, Fishman M, McGowan K, Strejcek K, Eiten E, Pirotte C, Lucier E, DeFrates S, Mehta J.

 

 

ORAL MUCOSITIS

Oral mucositis can be mild or severe. In some cases, patients may require the use of narcotic analgesics and total parenteral nutrition (TPN).

WHO oral toxicity scale:
  Grade 0 = no mucositis
  Grade 1 = erythema or pain
  Grade 2 = ulcers
  Grade 3 = Unable to swallow solid food, but able to swallow liquid food
  Grade 4 = Alimentation is not possible

Oral mucositis can be prevented with oral cryotherapy. Example: patients should hold ice chips or cold water inside their mouth for 5 min prior to the melphalan infusion, then during the infusion (20-30 min), and then for an additional 30 minutes after completion of the infusion. Patients are instructed to melt the ice inside the mouth. When ice melts, it is immediately replaced (the duration of the cryotherapy varies among protocols, from 45 minutes to more than 2 hours).

 

In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient's burden.
Bone Marrow Transplant. 2013 Jul;48(7):966-71.
Blijlevens N, de Château M, Krivan G, Rabitsch W, Szomor A, Pytlik R, Lissmats A, Johnsen HE, de Witte T, Einsele H, Ruutu T, Niederwieser D; CLWP of the EBMT.

Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study.
Bone Marrow Transplant. 2017 Jan;52(1):154-156.
Marchesi F, Tendas A, Giannarelli D, Viggiani C, Gumenyuk S, Renzi D, Franceschini L, Caffarella G, Rizzo M, Palombi F, Pisani F, Romano A, Spadea A, Papa E, Canfora M, Pignatelli A, Cantonetti M, Arcese W, Mengarelli A.
In this study, 72 patients with multiple myeloma undergoing an autologous stem cell transplant were randomized in two groups: one (32 patients) received oral cryotherapy with ice chips or cold water during the infusion of melphalan, and the other (32 patients) did not. Oral cryotherapy reduced the incidence of grade 3-4 mucositis to 6% (vs 44% without it), use of opioids, TPN, and IV antibiotics.

Variability of high-dose melphalan exposure on oral mucositis in patients undergoing prophylactic low-level laser therapy.
Lasers Med Sci. 2017 Jul;32(5):1089-1095.
Rodrigues GH, Jaguar GC, Alves FA, Guollo A, Camandoni VO, Damascena AS, Lima VCC.

 

 

INFECTIONS

Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients.
Bone Marrow Transplant. 2015 Apr;50(4):573-8.
Kamber C, Zimmerli S, Suter-Riniker F, Mueller BU, Taleghani BM, Betticher D, Zander T, Pabst T.
In this study, reactivation of the varicella zoster virus (VZV) developed in 57 (30%) of 191 patients with myeloma. The VZV reactivation occurred during the induction chemotherapy (8.5% of patients), or after the autologous stem cell transplant (ASCT) (21.5% of patients). Interestingly, for unclear reasons, there was an association between the VZV reactivation after the ASCT and a better median overall survival ("not reached" vs 87 months). Patients received acyclovir 400 mg twice a day for 3 weeks after the ASCT. The incidence of VZV reactivation after the ASCT was about 10% at 1 year, about 15% at 2 years, and about 20% at 4 years.

Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma.
Transpl Infect Dis. 2015 Oct;17(5):679-87.
Park S, Jung CW, Jang JH, Kim SJ, Kim WS, Kim K.
This is a retrospective study of 162 patients with myeloma who underwent an autologous stem cell transplant. The prophylactic use of IVIG did not seem to reduce the incidence of infections (35% without IVIG, and 31% with IVIG, p=0.63), and the incidence of infections requiring hospitalization.

 

 

ENGRAFTMENT SYNDROME

Engraftment syndrome is a frequent complication of autologous stem cell transplant. It manifests with noninfectious fever, skin rash, diarrhea, and noncardiogenic pulmonary edema. The vast majority of cases occur during or after neutrophil engraftment (between 3 days before and 7 days after ANC is 0.5). Most cases resolve spontaneously. Treatment with corticosteroids (e.g., methylprednisolone 1-1.5 mg/Kg/day) is usually effective in improving the symptoms.

 

 

MYELODYSPLASIA

Myelodysplastic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma.
Bone Marrow Transplant. 2007 Oct;40(8):759-64.
Przepiorka D, Buadi F, McClune B, Franz G, Walsh W, White F.
Among 82 myeloma patients who underwent autologous stem cell transplantation, the rate of myelodysplastic syndrome was 12% (10 patients). High-dose melphalan was the conditioning regimen received by 83% of patients. Of note, most patients received other forms of chemotherapy, and 34% received radiation therapy as well. Median overall survival after the diagnosis of myelodysplastic syndrome was 18 months.

 

 

SECOND CANCERS

New cancers after autotransplantations for multiple myeloma.
Biol Blood Marrow Transplant. 2015 Apr;21(4):738-45.
Mahindra A1, Raval G, Mehta P, Brazauskas R, Zhang MJ, Zhong X, Bird JM, Freytes CO, Hale GA, Herzig R, Holmberg LA, Kamble RT, Kumar S, Lazarus HM, Majhail NS, Marks DI, Moreb JS, Olsson R, Saber W, Savani BN, Schiller GJ, Tay J, Vogl DT, Waller EK, Wiernik PH, Wirk B, Lonial S, Krishnan AY, Dispenzieri A, Brandenburg NA, Gale RP, Hari PN.
This study reviews incidence of second cancers among 4161 patients with multiple myeloma treated with an autologous stem cell transplant. Follow-up identified 163 cases of new cancers, with a cumulative incidence of 6.1% at 7 years after transplant. The incidence of new cancers in these patients was similar to that in matched U.S. population, with the exception of AML and melanoma, which were more frequent. Multivariate analysis showed that factors associated to an increased risk of second cancers were obesity, older age, and male gender.

 

 

IMMUNE RECOVERY AFTER TRANSPLANT

Antigen-specific T-cell immunity in multiple myeloma patients is restored following high-dose therapy: implications for timing of vaccination.
Scand J Immunol. 2007 Oct;66(4):465-75.
Svane IM, Nikolajsen K, Johnsen HE.
This study evaluates the recovery of natural and vaccine induced immunity after autologous stem cell transplantation in patients with multiple myeloma. The authors serially measured the T-cell responses to CMV, VZV, and tetanus toxoid, and found that most patients regained specific T-cell immunity to those infections as early as 3 months after transplantation. After transplant, the CD4/CD8 ratio decreases, but antigen specific CD4+ T-cells recover prior to CD8+ T-cells.

 

 


Giampaolo Talamo, M.D.