AUTOLOGUS STEM CELL TRANSPLANTATION

 

 

Transplant is one of the standard therapeutic approaches for patients with multiple myeloma, because it increases the duration of disease remission. As of 2010, historical data showed a median survival of myeloma patients of only 3-4 years with conventional treatments, whereas it is extended to 5-7 years with autologous stem cell transplantation. In most patients, transplant is not curative, but it prolongs life, and a minority of patients reach remissions lasting >10 years (25% as of 2008).

There are 2 main types of transplant: autologous and allogeneic.

In autologous transplant, stem cells are taken from the patient himself, usually a few days after chemotherapy is given, and after the administration of growth factors such as G-CSF. The collection is a relatively simple procedure that involves an apheresis machine attached to a central venous catheter, extracting the stem cells from the peripheral blood. Collections directly from the bone marrow are now obsolete.

A stem cell transplant can be done in approximately 4 weeks, usually 10-14 days for the collection process and about 2 weeks for the actual transplant.

As compared with standard chemotherapy, dose intensification with autologous PBSCT improves results:
 - Response rate (80% vs 60%)
 - 5-year event-free survival (30% vs 10%)
Median survival is approximately 5 years without maintenance (as of 2005).
In newly diagnosed patients, autologous stem cell transplantation produces CR in approximately 50% of cases (as of 2005).

The standard conditioning regimen before autologous stem cell transplantation is melphalan 200 mg/m2.
Melphalan 180 mg/m2 is myeloablative, whereas 140 mg/m2 is not (as blood counts would recover within 1 month even without stem cell rescue).

Autologous transplant can be performed:
 - "Early": after induction therapy
 - "Late": as salvage therapy, in case of relapsing or refractory disease
A "late" transplant carries some disadvantages, including the possibility of poor performance status or complications (e.g., renal failure, plasma cell leukemia) in case of disease progression which may limit the feasibility of the transplant.

The first allogeneic stem cell transplant in myeloma was done in 1957.
The first autologous stem cell transplant in myeloma was done in 1983.

 

Hematopoietic stem cell transplantation in multiple myeloma.
Biol Blood Marrow Transplant. 2007 Aug;13(8):877-85.
Pant S, Copelan EA.
[Review]

Current status of autologous hematopoietic stem cell transplantation in myeloma.
Bone Marrow Transplant. 2008 Aug;42 Suppl 1:S28-S34.
Mehta J, Singhal S.
[Review]

 

 

Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.
Blood. 1995 Jan 15;85(2):588-96.
Tricot G, Jagannath S, Vesole D, Nelson J, Tindle S, Miller L, Cheson B, Crowley J, Barlogie B.

Autotransplants in multiple myeloma: what have we learned?
Blood. 1996 Aug 1;88(3):838-47.
Vesole DH, Tricot G, Jagannath S, Desikan KR, Siegel D, Bracy D, Miller L, Cheson B, Crowley J, Barlogie B.
This review of 496 myeloma patients treated with tandem transplants conclude that tandem transplants achieved CR in one third of patients, and median overall survival was greater than 5.5 years, if the first transplant was done within 12 months from diagnosis, and the second transplant within 6 months from the first one.

Age is not a prognostic variable with autotransplants for multiple myeloma.
Blood. 1999 Jan 1;93(1):51-4.
Siegel DS, Desikan KR, Mehta J, Singhal S, Fassas A, Munshi N, Anaissie E, Naucke S, Ayers D, Spoon D, Vesole D, Tricot G, Barlogie B.
This study compared the outcomes of 49 myeloma patients older than 65 years (range: 65-76 years) with the outcomes of 49 younger patients (range: 37-64 years). Hematopoietic recovery after autologous stem cell transplantation and rate of toxicities were similar in the two groups. Transplant-related mortality was 2% in the younger group and 8% in the older group. No difference was seen between the two groups in terms of event-free survival and overall survival. In conclusion, in patients with multiple myeloma receiving autologous stem cell transplantation, age per se was not a biologically adverse factor.

High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.
N Engl J Med. 2003 May 8;348(19):1875-83.
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party.
407 patients with newly diagnosed myeloma were randomly assigned to standard chemotherapy or high-dose therapy + autologous stem-cell transplant. Results:
  - Complete response was 44% with transplant vs 8% without transplant
  - Overall survival was higher in the transplant group. Median survival was 54.1 months with transplant vs 42.3 months without transplant

An elective single autograft with high-dose melphalan: single-center study of 451 patients.
Bone Marrow Transplant. 2005 Jul;36(1):19-24.
Sirohi B, Powles R, Mehta J, Rudin C, Kulkarni S, Horton C, Saso R, Singhal S, Treleaven J.
This is one of the largest studies of autologous stem cell transplant in multiple myeloma, with long-term follow-up. 451 patients, 51% with newly diagnosed disease, underwent a single autologous transplant with melphalan 200 mg/m2. Interferon-alpha2b was given as post-transplant maintenance. Median follow-up was 65 months (range: 0.5-17.7 years). Results:
  - Transplant-related mortality was 6%
  - Response rate was 91%, with 59% complete or near-complete responses
  - Median overall survival was 5.9 years
  - Median event-free survival was 2.4 years
  - Probability of overall survival at 10 years was 31.4%
  - Probability of event-free survival at 10 years was 16.5%

Long-term follow-up of gene-marked CD34+ cells after autologous stem cell transplantation for multiple myeloma.
Cancer Gene Ther. 2007 Mar;14(3):227-32.
Alici E, Björkstrand B, Treschow A, Aints A, Smith CI, Gahrton G, Dilber MS.
This study indicates that relapse of myeloma after autologous transplant is likely not related to the presence of contaminating tumor cells in the apheresis products. The authors used gene marking with integrated retroviral vectors in autologous CD34+ enriched BM or peripheral blood cell grafts from 8 myeloma patients. The transgene product was detected for up to 5 years post-transplant. Interestingly, there were no marked myeloma cells in patients with relapsed myeloma, supporting the hypothesis that relapse was related to the inability of high-dose chemotherapy to eradicate the original myeloma clone.

The impact of race on outcomes of autologous transplantation in patients with multiple myeloma.
Am J Hematol. 2008 May;83(5):355-8.
Verma PS, Howard RS, Weiss BM.
This is a retrospective analysis of 55 Caucasian and 36 African-American patients with myeloma patients who underwent autologous stem cell transplant. Survival was similar.

 

TRANSPLANT IN THE ERA OF NOVEL AGENTS

Autologous transplantation and maintenance therapy in multiple myeloma.
N Engl J Med. 2014 Sep 4;371(10):895-905.
Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M.
This is a study done in 62 centers in Italy and Israel. It compared 4 tandem autologous transplants (141 patients) and MPR chemotherapy (132 patients), with a second randomization of maintenance with lenalidomide (10 mg) until disease progression vs no maintenance.
MPR was given orally every 28 days, as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
  - Prednisone 2 mg/Kg on days 1-4
Median follow-up was 51 months. The results were better with transplant and with maintenance.
273 patients were treated with induction therapy with lenalidomide and dexamethasone.
  - Median progression-free survival:
    43 months in the transplant group vs 22 months in the MPR group
    42 months in the maintenance group vs 22 months without maintenance
  - Overall survival:
    at 4 years: 82% in the transplant group vs 65% in the MPR group
    at 3 years: 88% in the maintenance group vs 79% without maintenance (statistically not significant)
Of note, the advantage of stem cell transplant was maintained despite the fact that 63% of patients assigned to the MPR group received the transplant at progression. Transplant was not always feasible at the time of relapse, sometimes because of worsening of patients' medical conditions. This study is limited by the fact that it did not include proteasome inhibitors in the induction and maintenance phases.

Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma.
N Engl J Med. 2017 Apr 6;376(14):1311-1320.
Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study.
The aim of this study, IFM 2009, was to establish whether the autologous transplant was still the best approach in the treatment of newly diagnosed myeloma, or combinations of novel chemotherapy agents could supplant or delay its use. 700 patients were randomized to receive either VRD (bortezomib, lenalidomide, and dexamethasone) for 8 cycles (VRD group, 350 patients), or VRD for 3 cycles followed by an autologous stem cell transplant, then 2 cycles of VRD (transplant group, 350 patients). Stem cells were collected with cyclophosphamide and G-CSF. In both groups, patients received 1 year of maintenance therapy with lenalidomide 10-15 mg. After a median follow-up of about 3 and a half years, transplant prolonged remission, but it did not improve overall survival. Results:
  - Rate of complete remission: 48% in the VRD group, and 59% in the transplant group
  - Median progression-free survival: 36 months in the VRD group, and 50 months in the transplant group
  - Overall survival at 4 years: 82% in the VRD group, and 81% in the transplant group
Interestingly, stem cells were collected with cyclophosphamide. Although this was not the intent of the trial, the survival results suggest that chemotherapy for mobilization purposes only does not seem to be necessary in these patients.
It has to be noted that many (79%) of the patients who were assigned to the VRD group did receive a "salvage" transplant at the time of disease progression. Therefore, the conclusion of this study should not be that transplant is not necessary any more, but that it can be delayed until disease progression. Unfortunately, since there is no apparent plateau in the survival curves, it seems that even with the best currently available regimens, the majority of patients with myeloma do not achieve a definitive cure.

 

TRANSPLANT IN ELDERLY PATIENTS

Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis.
Am J Hematol. 2008 Aug;83(8):614-7.
Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Rajkumar SV, Litzow MR, Gertz MA.
This study analyzes outcomes of high-dose chemotherapy and autologous stem cell transplantation in older patients with multiple myeloma, with age 70 or older. 33 older patients (range: 70-75.8 years) were matched to a group of 60 myeloma patients younger than 65. Among the older patients, 23 patients received melphalan 200 mg/m2, and 10 patients received melphalan 140 mg/m2. Hematologic recovery and toxicities of the transplant were comparable to younger patients. 1 patient in the older group died, vs no deaths in the younger group, but the difference was not statistically significant. Response rates, ttime to progression, and overall survival were similar. Therefore, the authors conclude that older patients with multiple myeloma should not be excluded from transplant based only on their chronological age.

Feasibility of autologous hematopoietic stem cell transplant in patients aged ≥70 years with multiple myeloma.
Leuk Lymphoma. 2012 Jan;53(1):118-22.
Bashir Q, Shah N, Parmar S, Wei W, Rondon G, Weber DM, Wang M, Orlowski RZ, Thomas SK, Shah J, Qureshi SR, Dinh YT, Popat U, Anderlini P, Hosing C, Giralt S, Champlin RE, Qazilbash MH.
The authors present data from 84 patients with multiple myeloma aged 70 years and older who underwent autologous stem cell transplant at MD Anderson Cancer Center between 1999 and 2010.

Older patients with myeloma derive similar benefit from autologous transplantation.
Biol Blood Marrow Transplant. 2014 Nov;20(11):1796-803.
Sharma M, Zhang MJ, Zhong X, Abidi MH, Akpek G, Bacher U, Callander NS, Dispenzieri A, Freytes CO, Fung HC, Gale RP, Gasparetto C, Gibson J, Holmberg LA, Kindwall-Keller TL, Klumpp TR, Krishnan AY, Landau HJ, Lazarus HM, Lonial S, Maiolino A, Marks DI, Mehta P, Mikhael Med JR, Nishihori T, Olsson R, Ramanathan M, Roy V, Savani BN, Schouten HC, Scott E, Tay J, To LB, Vesole DH, Vogl DT, Hari P.

 

INDUCTION THERAPY

Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma.
Bone Marrow Transplant. 2002 Nov;30(10):673-9.
Singhal S, Powles R, Sirohi B, Treleaven J, Kulkarni S, Mehta J.
In this study, 222 myeloma underwent induction chemotherapy with C-VAMP (cyclophosphamide, vincristine, doxorubicin and methylprednisolone), followed by autologous SCT with melphalan 200 mg/m2. 43 patients did not respond to C-VAMP (<50% reduction in paraprotein). The 5-year survival was independent of response to the induction chemotherapy: 74% in the group who responded to C-VAMP, and 79% in the group with primary refractory disease.

Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT.
Bone Marrow Transplant. 2008 Jun;41(12):1013-9.
Kumar SK, Dingli D, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Rajkumar SV, Litzow MR, Gertz MA.
This study assesses the effect of initial therapy on the outcome of 472 patients with multiple myeloma undergoing autologous SCT within 12 months of diagnosis. The induction therapy consisted of: VAD, Dexamethasone, Dexamethasone + Thalidomide, and Dexamethasone + Lenalidomide. There was no difference in the response rates to the autologous SCT. The median time to progression after the SCT was 21-27 months and median overall survival was 62-70 months. The authors conclude that in patients undergoing early autologous SCT, the type of induction therapy has no long-term impact on the outcome of the transplant.

Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation.
Biol Blood Marrow Transplant. 2009 Apr;15(4):463-70.
Kim JS, Kim K, Cheong JW, Min YH, Suh C, Kim H, Jo DY, Ryoo HM, Yoon SS, Lee JH; Korean Multiple Myeloma Working Party.
This study evaluated the prognostic effect of disease status before ASCT. 197 MM patients were treated with induction chemotherapy followed by a single ASCT. CR was defined as the absence of detectable M protein regardless of the result of immunofixation. The median follow-up was 29.2 months from the day of diagnosis. Before ASCT, 63 patients (32%) were in CR, and 134 (68%) were in partial remission (PR). The patients in CR had significantly longer OS compared with those in PR. Patients with CR pre-ASCT and CR post-ASCT had better OS compared with patient with PR pre-ASCT and CR post-ASCT. CR pre-ASCT maintained its prognostic significance in multivariate analysis. These results suggest that patients undergoing ASCT should receive effective induction regimens, aiming at CR.

Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial.
J Clin Oncol. 2010 Oct 20;28(30):4621-9.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P.

Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p).
J Clin Oncol. 2010 Oct 20;28(30):4630-4.
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL.
This is a retrospective study of 507 patients with newly diagnosed myeloma who were treated with either bortezomib-dexamethasone x 4 cycles or VAD, as induction therapy before autologous stem cell transplantation. Results:
  - When compared with VAD chemotherapy, bortezomib improved both EFS and OS in patients with t(4;14), but not in patients with del(17p)
  - del(17p) was an adverse prognostic factor only if present in >60% plasma cells
  - t(4;14) and del(17p-) remained poor prognostic factors, and bortezomib did not overcome their prognostic impact (at least, when given for 4 cycles as induction therapy)

Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma.
Biol Blood Marrow Transplant. 2015 Feb;21(2):335-41.
Vij R, Kumar S, Zhang MJ, Zhong X, Huang J, Dispenzieri A, Abidi MH, Bird JM, Freytes CO, Gale RP, Kindwall-Keller TL, Kyle RA, Landsburg DJ, Lazarus HM, Munker R, Roy V, Sharma M, Vogl DT, Wirk B, Hari PN.
This retrospective study aimed at clarifying whether the use of a second-line different chemotherapy is beneficial in those patient who have a suboptimal response (i.e., less than partial response) to the first-line induction therapy before an autologous stem cell transplant. 539 patients with a suboptimal response to the first-line induction chemotherapy were divided into 2 groups: the group who proceeded directly to the autologous stem cell transplant (group A, 215 patients), and the group who received a second induction therapy (group B, 324 patients). In group B, the second-line chemotherapy was able to deepen the responses in 68% of patients (PR 60%, CR 8%), but there was no difference in progression-free survival or overall survival in the 2 groups. The authors concluded that additional induction chemotherapy in patients with a suboptimal response to first-line chemotherapy deepens the response, but it does not lead to a prolonged remission or a prolonged survival after the stem cell transplant.

Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen.
Haematologica. 2016 Feb;101(2):e69-71.
de Tute RM, Rawstron AC, Gregory WM, Child JA, Davies FE, Bell SE, Cook G, Szubert AJ, Drayson MT, Jackson GH, Morgan GJ, Owen RG.
The MRC Myeloma IX trial randomized 397 patients with newly diagnosed myeloma in one group receiving CTD (cyclophosphamide, thalidomide, and dexamethasone), and another group receiving CVAD (another regimen, currently of historical interest, which consisted of cyclophosphamide, vincristine, doxorubicin, dexamethasone). The induction chemotherapy was given for 4-6 cycles, and it was followed by an autologous stem cell transplant. At the traditional 100-day evaluation post-transplant, the CTD regimen was found to induce a higher response rate (82% vs 71%). However, this difference disappeared when the outcome was assessed according to the minimal residual disease (MRD) status, done by flow cytometry:
  - In patients who were MRD positive, median PFS was 16 months, and OS 59 months
  - In patients who were MRD negative, median PFS was 29 months, and OS 81 months
For MRD-negative patients, median PFS was 29 months with either CTD or CVAD.
The conclusion of the study was that the clinical outcome of myeloma patients is independent of the induction chemotherapy regimen, if a status of MRD is achieved after the autologous transplant. It seems that the level of disease is more important that the type of chemotherapy in determining the prognosis of these patients.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.
Blood. 2016 May 26;127(21):2569-74.
Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M.
In this study, 340 patients with newly diagnosed myeloma were randomized to receive either VTD (bortezomib, thalidomide, and dexamethasone), or VCD (bortezomib, cyclophosphamide, and dexamethasone, also called CyBorD). After 4 cycles of induction therapy, before an autologous stem cell transplant, the results were better with VDT: response rate was 92% with VTD, and 83% with VCD (p=0.01).

The impact of induction regimen on transplant outcome in newly diagnosed multiple myeloma in the era of novel agents.
Bone Marrow Transplant. 2017 Jan;52(1):34-40.
Chakraborty R, Muchtar E, Kumar S, Buadi FK, Dingli D, Dispenzieri A, Hayman SR, Hogan WJ, Kapoor P, Lacy MQ, Leung N, Gertz MA.
This is a retrospective study of 1017 patients with multiple myeloma treated with different induction chemotherapy regimens, followed by an early (within 12 months of diagnosis) autologous stem cell transplant. The regimens used were:
  - VRD (bortezomib, lenalidomide, and dexamethasone) - 126 pts
  - CyBorD (cyclophosphamide, bortezomib, and dexamethasone) - 193 pts
  - VD (bortezomib and dexamethasone) - 64 pts
  - RD (lenalidomide and dexamethasone) - 251 pts
  - TD (thalidomide and dexamethasone) - 155 pts
  - VAD (vincristine, doxorubicin, and dexamethasone) or Dex - 228 pts
After a median follow-up of 67 months, the 5-year overall survival rate was as follows: VRD 79%, CyborD 79%, RD 79%, VD 72%,  TD 57%, VAD/Dex 63%, TD 57%. In a multivariate analysis, after controlling for several patient and tumor characteristics, VRD induced higher response rates and better progression-free and overall survival among the several regimens (HR 0.32 for OS).

Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet. 2017 Feb 4;389(10068):519-527.
Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A.
In this prospective clinical trial, 525 patients with newly diagnosed myeloma in need of induction chemotherapy were randomized in two groups: VRD (bortezomib, lenalidomide, and dexamethasone) vs RD (lenalidomide and dexamethasone. The winner was VRD:
  - Response rate (PR or better): 72% with RD, and 82% with VRD
  - Rate of complete response: 8% with RD, and 16% with VRD
  - Median progression-free survival: 30 months with RD, and 43 months with VRD
  - Median overall survival: 64 months with RD, and 75 months with VRD
Of note, VRD was slightly more toxic, because 23% of patients on VRD had to stop therapy due to adverse events, as opposed to 10% of patients on RD.

 

 


 

RESPONSE BEFORE AUTO SCT

Impact of pre-transplant bone marrow plasma cell percentage on post-transplant response and survival in newly diagnosed multiple myeloma.
Leuk Lymphoma. 2017 Feb;58(2):308-315.
Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, Hayman SR, Hogan WJ, Kapoor P, Lacy MQ, Leung N, Gertz MA.
This is a retrospective study of 1070 patients with newly diagnosed myeloma, who underwent an autologous stem cell transplant as upfront therapy. The authors showed that those patients who had <5% plasma cells in the bone marrow aspirate before the transplant had better clinical outcomes than those who had 5% plasma cells: the chance to achieve complete remission after the transplant was higher (46% vs 16%), and the progression-free survival was longer (115 months vs 31 months). This study may have practical relevance, because a bone marrow biopsy is not always performed before the stem cell transplant (it is routinely done after it, to establish the depth of response, at about day +100). Of note, patients who achieved a stringent complete remission after the stem cell transplant had similar progression-free survival and overall survival, regardless of whether their pre-transplant plasma cells in the bone marrow were lower or higher than 5%.

 

 


 

RESPONSE AFTER AUTO SCT

Effect of complete response on outcome following autologous stem cell transplantation for myeloma.
Bone Marrow Transplant. 2000 Nov;26(9):979-83.
Rajkumar SV, Fonseca R, Dispenzieri A, Lacy MQ, Witzig TE, Lust JA, Larson D, Therneau TM, Kyle RA, Litzow MR, Greipp PR, Gertz MA.
Among 126 myeloma patients treated with stem cell transplant, 33% achieved complete remission. Progression-free survival was 12 months. Median overall survival was 56 months from diagnosis and 22 months from transplant. Interestingly, median overall survival depended more on the biologic nature of cancer (as reflected by the plasma cell labeling index) than the achievement of complete remission. Both progression-free survival and overall survival were not different between those patients who achieved complete remission and those who did not:
  - Median PSF: 15 months with CR and 11 months with non-CR (p= 0.2)
  - Median OS: 25 months with CR and 24 months with non-CR (p= 0.5)

Long-term outcomes of previously untreated myeloma patients: responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments.
Br J Haematol. 2005 Jun;129(5):607-14.
Alvares CL, Davies FE, Horton C, Patel G, Powles R, Sirohi B, Zuha R, Gatt A, Saso R, Treleaven JG, Dearden CE, Potter MN, Ethell ME, Morgan GJ.
This study analyzed outcomes of 383 patients with newly diagnosed myeloma who underwent autologous stem cell transplant. The authors found that survival was predicted by response to induction therapy and also by the response after transplant.
 - Median overall survival was 7.5 years in patients who had early response (PR and CR) after induction therapy, and 4.9 years in non-responders (p= 0.035)
 - Attainment of CR at 3 months after SCT was prognostically important: median PFS was 7.4 years in CR group and 5.3 years in non-CR group (p= 0.023)
This data suggests that complete remission should be the goal of myeloma therapy at every stage of treatment, both pre-SCT and post-SCT.

Impact of additional cytoreduction following autologous SCT in multiple myeloma.
Bone Marrow Transplant. 2008 Aug;42(4):259-64.
Kumar S, Dingli D, Dispenzieri A, Lacy M, Hayman SR, Buadi F, Rajkumar S, Litzow M, Gertz M.

Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival.
J Clin Oncol. 2008 Dec 10;26(35):5775-82.
Lahuerta JJ, Mateos MV, Martínez-López J, Rosiñol L, Sureda A, de la Rubia J, García-Laraña J, Martínez-Martínez R, Hernández-García MT, Carrera D, Besalduch J, de Arriba F, Ribera JM, Escoda L, Hernández-Ruiz B, García-Frade J, Rivas-González C, Alegre A, Bladé J, San Miguel JF.
This study analyzed 632 MM patients treated with induction chemotherapy followed by autologous stem-cell transplantation, and found that post-SCT response markedly influenced outcomes: patients who achieved CR had better median EFS (61 v 40 months) and OS (not reached) than patients who achieved nCR. Similarly, patients who achieved nCR had better median EFS (40 vs 34 months) and OS (not reached vs 61 months) than patients who achieved PR. Trends in the same direction were observed with the pre-SCT response. Therefore, improvements in response were associated with prolonged survival.

Serum free light chain ratio, total kappa/lambda ratio, and immunofixation results are not prognostic factors after stem cell transplantation for newly diagnosed multiple myeloma.
Clin Chem. 2009 Aug;55(8):1510-6.
Giarin MM, Giaccone L, Sorasio R, Sfiligoi C, Amoroso B, Cavallo F, Cipriani A, Palumbo A, Boccadoro M.
These authors evaluated the disease response 3 months after stem cell transplant (both autologous and allogeneic) in 203 patients with multiple myeloma, analyzing serum immunofixation, the total kappa/lambda ratio, and the serum free light chain ratio. Serum IFE was negative in 51 patients (25%), and serum free light chain ratio was normal in 92 patients (45%). None of the tests was associated with overall survival, therefore, in this study, achievement of a stringent CR did not have an impact on patient survival.

Implications of continued response after autologous stem cell transplantation for multiple myeloma.
Blood. 2013 Sep 5;122(10):1746-9.
Gonsalves WI, Gertz MA, Dispenzieri A, Lacy MQ, Lin Y, Singh PP, Gupta V, Hayman SR, Buadi FK, Dingli D, Kapoor P, McCurdy AR, Kumar SK.
Most transplant centers assess the disease response to the transplant 3 months later, at approximately day 100. In this study of 430 patients who underwent an autologous transplant upfront (= within 12 months of diagnosis), the authors found that 39% of patients had a continued response (i.e., a decline in the M component in the serum and/or urine) after day 100, without additional therapy. Compared with the other patients, these patients had a better progression-free survival (35 vs 13 months) and overall survival (96 vs 57 months). The prognostic value of the continued response was maintained after a multivariable analysis.

Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma.
J Clin Oncol. 2013 Dec 20;31(36):4529-35.
Kapoor P, Kumar SK, Dispenzieri A, Lacy MQ, Buadi F, Dingli D, Russell SJ, Hayman SR, Witzig TE, Lust JA, Leung N, Lin Y, Zeldenrust SR, McCurdy A, Greipp PR, Kyle RA, Rajkumar SV, Gertz MA.
This is a study of 445 consecutive patients who underwent an autologous stem cell transplantation for multiple myeloma. The depth of response after transplant influenced their survival. The 5-year survival rate was 47% in patients with near-CR, 53% in patients in CR, and 80% in patients with sCR (= stringent CR, 25% of cases).

Absence of spontaneous response improvement beyond day +100 after autologous stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2017 Apr;52(4):567-569.
Fernández de Larrea C, Dávila J, Isola I, Ocio EM, Rosiñol L, García-Sanz R, Cibeira MT, Tovar N, Rovira M, Mateos MV, Miguel JS, Bladé J.
Among 144 patients with myeloma who did not achieve complete response after an autologous stem cell transplant, 74 (51%) did not receive any maintenance therapy. Improvement of response after day +100 is exceedingly rare, because only 1 of these patients achieved CR.

 

SECONDARY MGUS AFTER SCT

Secondary monoclonal gammopathy of undetermined significance is frequently associated with high response rate and superior survival in patients with plasma cell dyscrasias.
Biol Blood Marrow Transplant. 2014 Mar;20(3):319-25.
Zou D, An G, Zhu G, Wang J, Shi L, Meng H, Xu Y, Sui W, Deng S, Zhan F, Qiu L.
Among 438 patients with either myeloma (409) or plasma cell leukemia (29), about 30% of patients after a stem cell transplant developed a secondary MGUS. Patients with secondary MGUS had a higher rate of complete remission (82% vs 22%), better median progression-free survival (52 vs 22.5 months), and better median overall survival ("not reached" vs 35 months).

Oligoclonal and monoclonal bands after single autologous stem cell transplant in patients with multiple myeloma: impact on overall survival and progression-free survival.
Leuk Lymphoma. 2014 Oct;55(10):2284-9.
Jimenez-Zepeda VH, Reece DE, Trudel S, Franke N, Winter A, Chen C, Tiedemann R, Kukreti V.
Ninety-nine patients with myeloma evaluated at day 100 after an autologous stem cell transplant developed oligoclonal bands or monoclonal bands unrelated to the original clone. They had a favorable clinical outcome compared to the rest of the patients, with longer progression-free survival and overall survival.

 

RELAPSE/PROGRESSION AFTER AUTO SCT

Different patterns of relapse after autologous peripheral blood stem cell transplantation in multiple myeloma: clinical results of 280 cases from the Spanish Registry.
Haematologica. 2002 Jun;87(6):609-14.
Alegre A, Granda A, Martínez-Chamorro C, Díaz-Mediavilla J, Martínez R, García-Laraña J, Lahuerta JJ, Sureda A, Bladé J, de la Rubia J, Fernández-Rañada JM, San Miguel J; Spanish Registry of Transplants in Multiple Myelomas; Spanish Group of Hemopoietic Transplant (GETH); PETHEMA.
This retrospective study evaluated the clinical patterns of relapses after autologous transplant in 280 myeloma patients. The patterns of relapse were heterogeneous:
  - Increase of serum/urine paraprotein and various symptoms, mainly new bone lesions (66%)
  - Slow increase of serum/urine paraprotein in asymptomatic patients (18%)
  - Extramedullary disease and minimal or no increase of paraprotein (14%)
  - Secondary plasma cell leukemia (2%)
After relapse, median overall survival was only 14 months.

Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma.
Bone Marrow Transplant. 2014 Feb;49(2):223-7.
Fernández de Larrea C, Jiménez R, Rosiñol L, Giné E, Tovar N, Cibeira MT, Fernández-Avilés F, Martínez C, Rovira M, Bladé J.
This is a study of 211 patients with multiple myeloma who underwent an autologous stem cell transplant and were followed at the time of disease progression/relapse. The authors describe findings that confirmed the practical knowledge of BMT centers following myeloma patients:
  - About half of the patients has an asymptomatic relapse/progression, with the only evidence of disease reactivation being a reappearance or increase of the myeloma markers
    ("serological relapse/progression");
  - Extramedullary disease was a frequent event at relapse/progression (24% of cases);
  - The treatment-free interval (= time spent without retreatment with chemotherapy) was longer in patients who had relapse from complete remission than in those with progression from partial remission;
  - The median overall survival was longer in patients who has an asymptomatic/serological relapse/progression than in those who were symptomatic.

Clinical course and outcomes of patients with multiple myeloma who relapse after autologous stem cell therapy.
Bone Marrow Transplant. 2016 Aug;51(8):1156-8.
Gonsalves WI, Rajkumar SV, Gertz MA, Dispenzieri A, Lacy MQ, Buadi FK, Dingli D, Go RS, Leung N, Kapoor P, Hayman SR, Lust JA, Russell SJ, Zeldenrust SR, Hwa YL, Kourelis TV, Kyle RA, Kumar SK.
This is a retrospective study of 672 patients with myeloma who underwent an autologous stem cell transplant (SCT) at the Mayo Clinic and experienced a disease relapse, between 2000 and 2012. It showed that a subset of patients can have prolonged remissions and survival even after relapse post-SCT. 468 patients received an "upfront" transplant (i.e., within 12 months from the diagnosis of myeloma), and 204 patients received a "delayed" transplant (i.e., done more than 12 months from the diagnosis). Results:
 - Median survival after progression post-SCT was 39 months with upfront transplant, and 27 months with delayed transplant
 - With upfront transplant: median survival after progression post-SCT was 29 months with a relapse within 2 years post-SCT, and 60 months with relapse after 2 years post-SCT
 - With delayed transplant: median survival after progression post-SCT was 23 months with a relapse within 2 years post-SCT, and 66 months with relapse after 2 years post-SCT
 - Median survival after progression post-SCT was 41 months with SCT done before first relapse, and 23 months with SCT done after at least one relapse.

 

 


 

SCT IN REFRACTORY MYELOMA

Myeloma patients who not respond to induction therapy should not be disqualified from an autologous transplant, because a substantial proportion of these patients attain CR after the transplant and enjoy extended survival.

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy.
Bone Marrow Transplant. 2004 Jul;34(2):161-7.
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 study evaluates the efficacy of autologous stem cell transplantation in patients with newly diagnosed MM who fail initial therapy, i.e., primary refractory disease. The authors compared outcomes of 50 patients with primary refractory MM to 101 patients with chemosensitive disease. Results:
  - Response (50% reduction in the M protein) was observed in 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group
  - CR was observed in 10 patients (20%) in the refractory group and 35 (35%) in the chemosensitive group (p=0.06)
  - The 1-year estimated PFS from the time of transplant was 70% in the refractory group and 83% in the chemosensitive group (p=0.65)
The authors concluded that lack of response to initial induction therapy does not preclude a good response to autologous transplant.

Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma.
Bone Marrow Transplant. 2004 Aug;34(3):229-34.
Alexanian R, Weber D, Delasalle K, Handy B, Champlin R, Giralt S.
This study evaluates outcomes of autologous SCT in 89 myeloma patients who did not respond to dexamethasone-based induction therapy.
Response rate: 69%, including 16% CR. CR occurred in 43% of patients with serum M component <1.5 g/dL, and 7% of patients with higher values.
Median survival was:
  - >7.0 years in 14 patients with CR
  - 4.5 years in 47 patients with PR
  - 2.2 years in 28 patients with NR

Autologous Stem Cell Transplantation Is an Effective Salvage Therapy for Primary Refractory Multiple Myeloma.
Biol Blood Marrow Transplant. 2015 Jul;21(7):1330-4.
Parrish C, Rahemtulla A, Cavet J, Pearce RM, Kirkland K, Lee J, Cook M, Wilson K, Cook G; Clinical Trials Committee of the British Society for Blood and Marrow Transplantation.
In this study, 126 patients underwent an autologous stem cell transplant without achieving a partial remission after the induction chemotherapy. Despite the lack of initial response, the transplant was beneficial, because the response rate was 86% (CR 24%), and there were long term survivors. Progression-free survival (PFS) and overall survival (OS) at 5 years were 14% and 42%, respectively. Median PFS and OS were 18 and 51 months, respectively. The authors conclude that patients with primary refractory disease should not be excluded from an autologous transplant.

Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma.
Cancer. 2017 Sep 15;123(18):3568-3575.
Veltri LW, Milton DR, Delgado R, Shah N, Patel K, Nieto Y, Kebriaei P, Popat UR, Parmar S, Oran B, Ciurea S, Hosing C, Lee HC, Manasanch E, Orlowski RZ, Shpall EJ, Champlin RE, Qazilbash MH, Bashir Q.

 

SCT IN HIGH-RISK DISEASE

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.
Biol Blood Marrow Transplant. 2016 Oct;22(10):1893-9.
Scott EC, Hari P, Sharma M, Le-Rademacher J, Huang J, Vogl D, Abidi M, Beitinjaneh A, Fung H, Ganguly S, Hildebrandt G, Holmberg L, Kalaycio M, Kumar S, Kyle R, Lazarus H, Lee C, Maziarz RT, Meehan K, Mikhael J, Nishihori T, Ramanathan M, Usmani S, Tay J, Vesole D, Wirk B, Yared J, Savani BN, Gasparetto C, Krishnan A, Mark T, Nieto Y, D'Souza A.
This is a retrospective study of 715 patients with mutliple myeloma who underwent an upfront autologous stem cell transplant (i.e., within 12 months of diagnosis). In 125 patients (17.5%), the myeloma had high-risk features at cytogenetic analysis/FISH, defined as 17p-, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y), or chromosome 1 abnormalities (1q+ or 1p-). The results showed that the response rates were similar after the transplant (evaluated at day 100): 59% in the high-risk group, and 61% in the other group. However, as expected, those responses were not sustained:
  - Progression-free survival at 3 years: 37% in the high-risk group, and 49% in the other group
  - Overall survival at 3 years: 72% in the high-risk group, and 85% in the other group

Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.
Am J Hematol. 2016 Oct;91(10):E442-7.
Gaballa S, Saliba RM, Srour S, Lu G, Brammer JE, Shah N, Bashir Q, Patel K, Bock F, Parmar S, Hosing C, Popat U, Delgado R, Rondon G, Shah JJ, Manasanch EE, Orlowski RZ, Champlin R, Qazilbash MH.
This is a retrospective study that compared outcomes of an autologous stem cell transplant in 34 patients with high-risk disease due to 17p-, vs 111 control patients, with multiple myeloma but without 17p-.
  - Median progression-free survival: 8 months with 17p-, and 28 months without 17p-
  - Median overall survival: 21 months with 17p-, and 56 months without 17p-

 

SCT IN EXTRAMEDULLARY DISEASE

Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome.
Bone Marrow Transplant. 2017 Oct;52(10):1473-1475.
Kumar L, Gogi R, Patel AK, Mookerjee A, Sahoo RK, Malik PS, Sharma A, Thulkar S, Kumar R, Biswas A, Sharma OD, Gupta R.
This is a retrospective study of 44 myeloma patients with extramedullary disease who underwent an autologous stem cell transplant. After a median follow-up of 7.5 years, 13 patients (30%) were alive, and 9 of them were in CR. As expected, patients with extramedullary disease had lower PFS and OS compared with the rest of myeloma patients. The study did not provide cytogenetic data. The most important predictor for PFS and OS was the achievement of CR after the stem cell transplant. 

 

 


 

SCT IN PATIENTS WITH RENAL INSUFFICIENCY

Patients with multiple myeloma and renal failure have a relatively high transplant-related morbidity (e.g., greater degree of mucositis) and mortality.
In view of greater toxicity and the absence of a clear survival advantage with melphalan 200 mg/m2, the melphalan dose in patients with ESRD requiring dialysis is often reduced to 140 mg/m2.

 

Dialysis-dependent renal failure in patients with myeloma can be reversed by high-dose myeloablative therapy and autotransplant.
Bone Marrow Transplant. 2004 Apr;33(8):823-8.
Lee CK, Zangari M, Barlogie B, Fassas A, van Rhee F, Thertulien R, Talamo G, Muwalla F, Anaissie E, Hollmig K, Tricot G.
In this study, 59 myeloma patients on dialysis underwent autologous transplant. 37 patients were on dialysis at least 6 months. The results showed that renal failure can be reversible after transplant. Recovery of renal function depended on time on dialysis and response to transplant. Results:
  - Of 54 evaluable patients,13 (24%) became dialysis independent, after a median of 4 months post-SCT (range: 1-16 months).
  - Recovery of renal function occurred in 12 of 36 patients (33%) on dialysis for <6 months and only 1 of 18 patients (6%) on dialysis for >6 months
  - Recovery of renal function occurred in 12 of 31 patients (39%) in >PR after SCT and only 1 of 21 patients (5%) in PR or less after SCT
  - The 5-year overall survival was 36%, and the 5-year event-free survival was 24%

Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure.
Eur J Haematol. 2005 Jul;75(1):27-33.
Knudsen LM, Nielsen B, Gimsing P, Geisler C.
In this study, 137 myeloma patients who underwent autologous transplant were divided into 3 groups, based on their renal function:
  - Group A (78 patients): normal renal function both at diagnosis and at transplant
  - Group B (30 patients): renal failure (Creat Clear < 60 mL/min) at diagnosis but normal renal function at transplant (n = 30)
  - Group C (29 patients): renal failure both at diagnosis and at transplant
Results:
 - Disease response to transplant was similar in the 3 groups
 - Transplant-related mortality was 1% in Group A, 0% in Group B, and 17% in Group C
 - 4 of 8 patients on dialysis before transplant died within the first 100 days after transplant.
 - Patients of Group C had a longer hospitalization, increased need for transfusions, and more frequent infections
 - In Group C, 10 patients had a normalization of renal function after transplant

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.
Br J Haematol. 2006 Aug;134(4):385-90.
Bird JM, Fuge R, Sirohi B, Apperley JF, Hunter A, Snowden J, Mahendra P, Milligan D, Byrne J, Littlewood T, Fegan C, McQuaker G, Pagliuca A, Johnson P, Rahemtulla A, Morris C, Marks DI; British Society of Blood and Marrow Transplantation.
27 myeloma patients and 4 amyloidosis patients with severe renal insufficiency (23 on dialysis) underwent autologous stem cell transplantation using high-dose melphalan (median 140 mg/m2, range: 60-200 mg/m2). Results:
  - Response rate: 70%
  - 24% (4 of 17) patients became dialysis-independent at a median of 5 months after SCT
  - Transplant-related mortality at day 100: 19% (5 of 27 patients)
  - Median time to disease progression: 32 months (range: 6-54 months)
  - At a median follow-up of about 6 years, 7 of 23 (30%) myeloma patients were alive, 4 (17%) with disease remission

The outcome of autologous stem cell transplantation in patients with plasma cell disorders and dialysis-dependent renal failure.
Haematologica. 2006 Nov;91(11):1555-8.
Raab MS, Breitkreutz I, Hundemer M, Benner A, Klaus J, Hegenbart U, Moehler T, Ho AD, Zeier M, Goldschmidt H.
In this study, 34 myeloma patients on hemodialysis underwent autologous stem transplant with melphalan 100 mg/m2. The authors found no significant differences with other 34 myeloma patients with normal renal function who received melphalan 200 mg/m2, in terms of many parameters, including hematologic toxicity, transplant related mortality, disease response, EFS, and OS. Patients on dialysis required a longer IV antibiotic treatment and longer hospitalization. Therefore, the authors recommend the dose of melphalan of 100 mg/m2 for myeloma patients on dialysis undergoing autologous SCT.

Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure.
Bone Marrow Transplant. 2015 Jan;50(1):95-9.
St Bernard R, Chodirker L, Masih-Khan E, Jiang H, Franke N, Kukreti V, Tiedemann R, Trudel S, Reece D, Chen CI.
In this retrospective study, the authors analyzed the outcomes of 33 patients with mutliple myeloma who underwent an autologous stem cell transplant while on hemodialysis (in Toronto, Canada, 1998-2012). The coinditioning regimen consisted of high-dose melphalan 200 mg/m2 (61%), 140 mg/m2 (36%), or 160 mg/m2 + TBI (3%). Dose were reduced at the treating physician discretion. Results:
  - Median overall survival: 5.6 years (comparable to that of non-dialysis patients)
  - 7 (25%) patients became dialysis-independent
  - Toxicities: increased risk of mucositis, atrial arrhythmias, hemorrhages, and altered mental status
  - Transplant-related mortality was 15% (primarily septic shock), higher than that seen in previous reports of dialysis-dependent patients (3-12%)

Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival.
Bone Marrow Transplant. 2016 Oct;51(10):1337-1341.
Sweiss K, Patel S, Culos K, Oh A, Rondelli D, Patel P.
This is a retrospective study of 46 patients with multiple myeloma and mild or moderate renal insufficiency (creatinine clearance 20-59), who underwent an autologous stem cell transplant. Their clinical outcomes were compared to a group of 103 patients with normal renal function (creatinine clearance 60). Of note, all patients received melphalan 200 mg/m2. Patients with creatinine clearance <60 had a greater rate of grade 4 mucositis (28% vs 16%), TPN use, grade 2-4 diarrhea, and infections. Although median "treatment-free survival" was longer in patients with normal renal function (37 vs 17 months), the overall survival was similar in the two groups.

 

 


Giampaolo Talamo, M.D.