Patients eligible for transplant

Monthly Educational Theme | Transplant in Myeloma

Each month, the Multiple Myeloma (MM) Hub is focusing on a different educational theme which, for the month of November, will be transplantation. Autologous stem cell transplantation (ASCT) and allogeneic stem cell transplantation (allo-SCT) have long been part of the treatment pathway for patients with MM, with ASCT more commonly used than allo-SCT.1

Following diagnosis, clinical treatment decisions are often made based on transplant eligibility with patients categorized as either transplant eligible or ineligible. Transplant eligible patients proceed to receive induction therapy, followed by stem-cell mobilization, conditioning and transplant. Post-transplant consolidation and maintenance are then provided.1

Despite its steadfast presence in the treatment pathway, there are still many debated topics surrounding the use of transplant in MM. These questions include; what are the optimal regimens? When should allo-SCT be used? Does single or tandem transplant provide the best outcomes? The answers to these questions are usually based on clinical presentation, with specific patient populations responding better to transplant than others.1

This article summarizes the current information available on the MM Hub on this topic, including links to articles and expert interviews.  

ASCT | Induction Regimens

During the annual meeting European Society for Blood and Marrow Transplantation (EBMT) 2019, Professor (Prof.) Mohamad Mohty discussed the evolution of induction regimens in MM. He highlighted the pivotal IFM 2005-01 trial that showed bortezomib (V) + dexamethasone (d, Vd), was superior to the historically utilized triplet of vincristine + doxorubicin + d (VAd). Prof. Mohty proceeded to present trials involving newer regimens, such as V + lenalidomide (R) + d (VRd), as well as trials involving the addition of monoclonal antibodies (mAbs), such as daratumumab (dara), to traditional doublet and triplet regimens. The MM Hub were pleased to speak to Prof. Mohty about this topic during the EBMT meeting (video below):

Mohamad Mohty | EBMT 2019 | Optimal induction regimen for autologous stem cell transplant in MM

The MM Hub were also pleased to speak to Enrique Ocio during the American Society for Clinical Oncology (ASCO) meeting, 2019, about his clinical experience in selecting induction regimens for patients with newly diagnosed MM (NDMM).

Enrique Ocio | ASCO 2019 | Induction regimens in NDMM: my clinical experience

Induction therapies were also a hot topic during the Society of Hematologic Oncology (SOHO) meeting, 2019, where Ajay Nooka presented a summary of induction therapies for both transplant eligible, and ineligible patients.

Additionally, the MM Hub spoke to Prof. Joan Bladé at the 2018 EBMT meeting where Prof. Bladé presented his expert opinion on optimal induction regimens in the transplant setting.

Joan Bladé | EBMT 2018 | Optimal induction in the transplant setting

ASCT in real-world clinical practice

A subgroup analysis from the EMMOS study of the real-world clinical experience of induction regimens, was presented by Prof. Mohty at the 2019 EBMT meeting. VTd was shown to be the most commonly used induction regimen, and real-world response rates were comparable to phase III trials. Current restrictions to the use of novel immunotherapies and agents, such as lack of efficacy data, health authority approval and expense, mean VTd is likely to remain standard of care (SOC).

ASCT | Optimal regimens

Following induction there is a process of stem cell mobilization and conditioning, followed by transplant, consolidation and maintenance. In April 2019, two review articles on the topic of transplantation were published, which the MM Hub were pleased to summarize. The authors conclusions on optimal regimens are summarized in Table 1 below.

Table 1. Summary of conclusions of optimal regimens in transplant in MM

What is the optimal induction regimen for ASCT?

V + thalidomide (T) + d (VTd) and VRd will likely remain the SOC, though the addition of dara is likely to show improved results and may, in future, be used in induction regimens

What is the best strategy for stem cell mobilization?

Chemomobilization with high-dose cyclophosphamide plus granulocyte colony stimulating factor (G-CSF) or steady-state mobilization, with the addition of pre-emptive plerixafor, if necessary, are currently the most frequently used regimens

What is the ideal conditioning regimen?

High-dose melphalan (HDM) remains the conditioning regimen of choice prior to ASCT

What is the optimal consolidation therapy?

VRd consolidation + R maintenance may be effective in young, fit patients with low-risk NDMM, but this is still debated

What is the optimal maintenance therapy?

R is proposed as the SOC in this transplant eligible setting, though trials involving newer agents, such as ixazomib, are ongoing and show promising results

A recent meta-analysis and systematic review of plerixafor for stem cell mobilization for ASCT found that the use of plerixafor led to increased hematopoietic stem cell (HSC) collection, in less time and with no associated increase in adverse events (AEs).

ASCT | Big questions

There are several questions remaining regarding the role of ASCT in the treatment of MM. Some of these are addressed in an article on the big questions in MM, as summarized in Table 2.

Table 2. A summary of the big questions in ASCT

Is single or tandem ASCT more beneficial?

Tandem ASCT is feasible and likely beneficial in a small subgroup of patients with high-risk cytogenetics and revised International Staging System (R-ISS) category three disease, and in those achieving less than a very good partial response (VGPR) to first transplant. However, the latter group may likely benefit from the newest consolidation methods, so this decision should be carefully considered.

Is tandem ASCT beneficial in the high-risk subgroup?

It is unclear whether tandem ASCT is beneficial in high-risk MM, though the International Myeloma Working Group (IMWG) recommend tandem ASCT for patients with high-risk NDMM.

Which gives better responses; triplet combinations containing novel agents or ASCT?

Trials of ASCT versus novel agent-based treatments in patients with NDMM show an advantage of ASCT over non-transplant approaches. ASCT therefore remains SOC despite increased availability of novel agents. Future studies comparing triplets + daratumumab + HDM + ASCT to triplet regimens + HDM + ASCT alone may change this dynamic

Should ASCT be conducted early or late in the treatment pathway?

Early ASCT is the SOC, improving outcomes regardless of whether it is performed in the frontline setting or as salvage therapy. However, delaying ASCT is feasible, though it is currently unclear which subgroup of patients would see the most benefit. Delayed ASCT may be considered based on patient preferences, lack of high-risk cytogenetics and a sufficient stem cell harvest.

Is there a role for salvage ASCT?

Salvage ASCT is an option in fit patients for whom the time between ASCT and relapse is over 18 months and is recommended by both the US and European guidelines, subject to a prior adequate stem cell collection. Trials looking at salvage ASCT versus novel agents are ongoing, with it being a potentially difficult decision of who the optimal patient is for salvage ASCT, in light of the novel agents that are now available

During the recent XVII International Myeloma Workshop (IMW) meeting, a session on “Great debates in myeloma” was held. In this session, two debates surrounding transplant were held.

  • Should duration of maintenance therapy post-ASCT be fixed or indefinite?
    • Cyrille Touzeau, definitive duration. Conclusion: indefinite R-maintenance is inducing R-refractory disease, which is challenging to treat, provides patients with a sub-optimal quality of life (QoL) and has a high cost impact
    • Philip McCarthy, indefinite duration. Conclusion: maintenance has been shown to provide a continued effect, improved PFS in the Myeloma XI study, and prevented earlier progression and the need for salvage therapies
  • Will ASCT remain SOC in five-years?
    • Pieter Sonneveld, yes. Conclusion: ASCT is a proven and effective treatment, we should use it, and incorporate novel agents where appropriate, but not replace it entirely
    • Ola Landgren, no. Conclusion: HDM is cytotoxic, new and effective treatments can induce high minimal residual disease (MRD)-negativity rates and medicine should advance forwards

With new novel therapies under development, there is also a potential that ASCT may be replaced by immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy. The MM Hub were pleased to speak to our co-chair, Prof. Sagar Lonial, at the European School of Heamatology (ESH) meeting about this potential (video below).

Sagar Lonial | ESH MM 2019 | The potential of CAR T therapy to replace autologous stem cell transplantation

ASCT | Comorbidities and risk factors  

At this year’s EBMT meeting, Christoph Scheid presented an analysis of the role of renal impairment in patients undergoing ASCT, on behalf of the Chronic Malignancies Working Party (CMWP) of the EBMT. This study confirmed renal impairment at diagnosis is a negative prognostic factor, but interestingly that the impairment status at transplant did not significantly increase non-relapse mortality (NRM). Since PFS and OS were not negatively impacted by a failure to achieve a renal response between diagnosis and treatment, the authors recommended these patients remain candidates for transplant.

The role of transplant may also vary depending on cytogenetic risk. Nico Gagelmann discussed the outcomes of patients with high-risk cytogenetics with the MM Hub during the EBMT meeting, 2019 (video below).

Nico Gagelmann | EBMT 2019 | Outcomes of patients with high-risk cytogenetics undergoing SCT in MM

Additionally, in specific patient populations, it may be necessary to pick an induction regimen based on disease risk. The MM Hub spoke to Brea Lipe about this topic at the ASCO meeting (video below).

Brea Lipe | ASCO 2019 | How would you pick an induction regimen based on disease risk?

Allo-SCT

Allo-SCT is most commonly used in hematological malignancies such as acute myeloid leukemia (AML) and lymphoma with the role of allo-SCT in MM still debated. Whilst some consider it potentially curative due to a graft-versus­-myeloma effect, it comes with an increased risk of graft-versus-host disease (GvHD) and studies have failed to show allo-SCT is able to provide a benefit over ASCT. A summary of expert opinions based on two reviews on allo-SCT is shown in Table 3.

Table 3. Allo-SCT in different patient populations

NDMM

Allo-SCT is not recommended as a SOC for patients with NDMM. Young, fit patients with NDMM however may be considered for allo-SCT in the clinical trial setting.

Relapsed/ refractory MM (RRMM)

The advantage of allo-SCT over ASCT has not been proven so far and allo-SCT for RRMM is currently limited to trial settings.

High-risk MM

In a clinical trial setting, allo-SCT may be considered for young, fit patients with high risk NDMM, in-line with IMWG recommendations, but is not routinely recommended.

Another study presented at EBMT in 2019 on behalf of the CMWP evaluated the outcomes of patients who received a second allo-SCT following graft failure or relapse with the authors concluding that second allo-HSCT may have a role for this specific subpopulation of patients.

During the EBMT meeting in 2018, Firoozeh Sahebi presented patient outcomes following haploidentical transplant. The authors concluded that haploidentical transplant was feasible in high-risk patients or those who have relapsed multiple times.

Transplant combination therapies

At the EBMT meeting in 2019,  Xiaolan Shi presented results from a study investigating the combination of dual-targeting CAR T-cells, with ASCT for patients with high-risk NDMM. The CAR T cells were designed to target CD19 and B-cell maturation antigen (BCMA) and were infused following ASCT.  This study had an overall response rate (ORR) of 100% (10/10) with a mild toxicity profile. Watch Chengcheng Fu discuss this approach below.

Chengcheng Fu | EBMT 19 | CAR T-cell therapy in the front-line treatment of patients with high-risk multiple myeloma

Geographical disparities

During the ASH meeting in 2017, we were pleased to speak to Prof. Mohty about the different roles that ASCT plays in Europe and the US. Watch the interview below.

Mohamad Mohty | ASH 2017 | Role of ASCT in MM: differences between US and Europe

Future of transplant in MM

At the European Hematology Association (EHA) annual meeting this year, the MM hub spoke to Prof. Mohty about the role of ASCT in the future treatment of patients with MM. This video is available below.

Mohamad Mohty | EHA 2019 | The role of autologous transplant in the future treatment of MM

Conclusion

Transplant remains a core part of the treatment pathway in MM, however there are many unanswered questions to consider. It is unlikely that a consensus will be reached, and this will be further complicated by the number of novel agents and immunotherapies currently under development. Where these fit into the treatment pathway, and the subsequent impact on the role of transplant in MM remains to be seen.

The MM Hub will be focusing on transplantation throughout November, so keep checking back for more of the latest information!

References
  1. Mina R. and Lonial S. Is there still a role for stem cell transplantation in multiple myeloma? Cancer. 2019 Apr 15. DOI: 10.1002/cncr.32060
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!