Canterbury DHB

Context

Myeloma

In This Section

International guidelines

Autologous transplant as 1st line consolidation

Tandem autologous transplant as 1st line therapy

Up-front or delayed autologous transplant?

2nd autologous transplant in relapsed myeloma following ASCT1

Allogeneic transplant following ASCT for myeloma in 1st remission

Allogeneic transplant for relapsed myeloma

International guidelines

Shah, N., et al. (2015). "Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation." Biology of Blood and Marrow Transplant 21(7): 1155-1166.

Autologous transplant as 1st line consolidation

Koreth et al undertook a systematic review and meta-analysis of all RCT evaluating unfront HDT in myeloma (Koreth, Cutler et al. 2007). 10 RCT comparing up-front HDT with standard therapy with >2 years follow up were identified. Nine studies comprising 2411 patients were fully analysed. There was significant heterogeneity between studies. The overall risk of death with HDT was 0.92 (0.74-1.13). The combined hazard of progression was 0.75 (0.59-0.96). Sensitivity and sub-group analysis supported the main finding that PFS but not OS was prolonged and also showed that benefit is not restricted to chemo-responsive myeloma.

Myeloma patients should not be disqualified from ASCT based upon a lack of response to induction chemotherapy based on data from six retrospective analyses (Rajkumar, Fonseca et al. 1999; Vesole, Crowley et al. 1999; Singhal, Powles et al. 2002; Alexanian, Weber et al. 2004; Kumar, Lacy et al. 2004; Rosinol, Garcia-Sanz et al. 2012).

Transplant-related mortality has varied widely between studies but is currently expected to be around 2%. Two studies have shown no difference in overall survival between up-front and delayed HDT (Fermand, Ravaud et al. 1998; Kumar, Lacy et al. 2012).

Tandem autologous transplant as 1st line therapy

Evidence for a tandem auto up-front was reviewed by Cavo et al (Cavo, Rajkumar et al. 2011). Two of five RCT showed OS benefit. A meta-analysis of data (including one trial which was subsequently withdrawn) did not show an OS benefit. In two studies post hoc analyses showed benefit in patients who failed to achieve high quality responses after the first transplant. The BMT CTN is currently compared single with double ASCT in the era of novel agents. In the meantime, the IMWG recommends consideration of up-front 2nd ASCT in those patients who fail to achieve a VGPR or CR after 1st ASCT.

Up-front or delayed autologous transplant?

One randomised study (Fermand, Ravaud et al. 1998) and two non-randomised studies (Dunavin, Wei et al. 2012; Kumar, Lacy et al. 2012) have reported no difference in overall survival between early and delayed ASCT. At an educational session at Lugano in 2013 Rajkumar commented that “The Mayo [Clinic] believes that transplant is good if patient is eligible, but timing of transplant is not critical, half of patients choose late transplant, half early. The late ones are “patients like you and me, eg surgeons who want to carry on and don’t want to be considered patients”. If delayed transplantation is considered it is recommended that haematopoietic cells must be collected and stored in first remission.

2nd autologous transplant in relapsed myeloma following ASCT1

Response rates after non-transplant salvage therapy is typically around 50% with progression-free survival of less than 12 months. Few studies have directly compared the efficacy and safety of second ASCT after relapse with non-transplant therapy and most patients were treated in the era before novel agents, i.e. thalidomide, lenalidomide and bortezomib. In the US the availability of ASCT2 is limited by insurance cover.

Two matched-pair analyses supported the case for ASCT2 being superior to conventional treatment (Cook, Liakopoulou et al. 2011, Yhim, Kim et al. 2013). A CIBMTR registry study reported 1-year non-relapse mortality (NRM) of 2%. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46% (Michaelis, Saad et al. 2013). Single centre studies report around 2-8% transplant-related mortality (TRM) (Elice, Raimondi et al. 2006, Qazilbash, Saliba et al. 2006, Burzynski, Toro et al. 2009, Mikhael, Zadeh et al. 2009, Saad, Vesole et al. 2011, Shah, Ahmed et al. 2011, Jimenez-Zepeda, Mikhael et al. 2012).

A randomised, open-label phase III study confirms the benefit of 2nd autologous transplant although the comparator arm of single agent cyclophosphamide is no longer used and results with novel agents may be better.

Factors predicting a favorable outcome are

Patients who relapse within 18 months after ASCT1 probably should not receive a 2nd ASCT if there are alternative treatments available.

Further reading

Holstein, S. A. and P. L. McCarthy (2016). "Improved survival with salvage autologous stem-cell transplantation in myeloma." Lancet Haematol 3(7): e306-307.

Cook, G., et al. (2014). "High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial." Lancet Oncol 15(8): 874-885.

Allogeneic transplant following ASCT for myeloma in 1st remission

Armeson et al utilized meta-analysis to compare tandem ASCT with ASCT followed by RIC allo as 1st line therapy in trials with biological randomisation (Armeson, Hill et al. 2012). Six trials including 1192 tandem ASCT and 630 ASCT-RIC patients were included. OS was n.d. in the first 36 months. It is possible that with longer follow-up a survival advantage may be seen in the allogeneic transplant arm but currently this is not standard of care.

Allogeneic transplant for relapsed myeloma

The role of allogeneic transplantation in myeloma remains the subject of debate and there is no consensus. A minority of patients are young enough to consider conventional myelo-ablative conditioning and reduced-intensity transplantation has not produced durable remissions.

About this Canterbury DHB document (8154):

Document Owner:

Andrew Butler (see Who's Who)

Issue Date:

December 2016

Next Review:

December 2018

Keywords:

Note: Only the electronic version is controlled. Once printed, this is no longer a controlled document. Disclaimer

Topic Code: 8154