ASCO Educational Session: Consolidation and Maintenance: Moving Beyond Autotransplant

The learning objectives for this session included:
1. Describing optimal approaches and evidence-based data outlining the role of consolidation therapy after autologous transplant.
2. Discussing when and how to choose maintenance approaches, including the duration of therapy.
3. Identifying which patients are best suited for an allogeneic transplant approach, and current clinical trials that are making successful headway.

The three talks are summarized below.

Maintenance Therapy for Myeloma: Present and Future:
Dr. Amrita Krishnan, City of Hope

Dr, Krishnan spoke about the pros and cons of maintenance therapy after transplant. In the US. almost all patients who receive a transplant receive subsequent maintenance therapy; this includes roughly 6000 transplant patients per year. Important variables to consider when contemplating maintenance therapy include duration of therapy, cost, and side effects. Current maintenance options stem from the CALGB Meta Analysis of 1200 patients who achieved a 2.5 year increase in overall survival after transplant with Len maintenance. Velcade had also been used for maintenance, for example in the HOVON trial, where it was shown to increase both progression free survival and overall survival in the post-transplant maintenance arena.

Dr. Krishnan then went on to highlight new maintenance options for the future, starting with KRD (Kyprolis/Rev/dex) which markedly improved the ability of patient to attain Minimal Residual Disease (MRD) negative status after a transplant; the addition of Daratumumab as a maintenance drug in the HOVON/IFM study; and also Ixazomib in a MD Anderson trial with Len, and anti-cancer vaccines in the BMT CTN Protocol 1401 trial. One caveat with vaccines as maintenance is that they are usually given in the trial along with Len, so the vaccine effect on its own may be hard to distinguish.

With maintenance therapy there are toxicities to take into consideration, such as those seen with thalidomide in BMT CTN0102, Len in CALGB 100104 and include peripheral neuropathy grade 2/3, and the occurrence of secondary primary malignancies (SPM).

Dr. Krishnan went on to discuss whether maintenance therapy may only be advisable for high risk MM patients (as defined by those with 17p deletion); here any toxicity would be less of an issue due to the high risk nature of the disease, or whether maintenance would only be appropriate for those patients who do not achieve MRD – status and remain MRD +.

In conclusion, Dr. Krishnan stated that maintenance therapy remains a pillar of MM therapy, and that maintenance should be optimized for patients. New immune approaches such as vaccines, T cells, and checkpoint inhibitors, and new drugs including antibodies and oral proteasome inhibitors, should all be considered. Overall, maintenance therapy should be carefully selected for each patient, with an eye to minimize duration of maintenance therapy to minimize toxicity to the patient and to minimize costs.

What Is Optimal Consolidation After Autologous Transplant?:
Dr. Ravi Vij, Washington University School of Medicine

Consolidation therapy following ASCT implies a short period of intensive treatment with a single agent or combination therapy. This strategy aims to further reduce disease burden following high dose chemotherapy and stem cell rescue, with the assumption that depth of response can predict overall outcome in MM.

Traditional consolidation approaches are used after single or tandem transplants with and without cytotoxic chemotherapy. Now that there are a number of well tolerated newer therapies available, some of these new agents have been evaluated for their use in consolidation. Immunomodulatory agents such as Revlimid, proteasome inhibitors such as Velcade, and combination therapies such as Revlimid/Velcade and Revlimid/Kyprolis have all been studied as consolidation therapy. These studies offer many of the same treatment benefits of the older cytotoxic therapies with fewer side effects.

Unfortunately there have not been many studies that have been able to directly measure the impact of different consolidation therapies on treatment efficacy and long term survival, because the studies are too different to compare. Therefore, the value of having consolidation therapy is usually inferred using other information, such as rates of complete response after consolidation. There is however significant data showing that consolidation therapy can improve depth of response in MM, and depth of response has been associated with improvements in outcome.

In conclusion, Dr. Vij mentioned that while many physicians now utilize lower dose long term maintenance therapy instead of consolidation after transplant, the jury is still out as to which of these treatment modalities will provide patients with the best outcomes. A new trial, the CTN 0702 STAMINA trial, will directly compare the three most common post-transplant approaches, tandem ASCT, consolidation therapy, and immediate maintenance therapy, and will offer much guidance in this area, so stay tuned for these results.

Is There a Role for Allogeneic Transplant in Multiple Myeloma?:
Dr. Parameswaran Hari, Medical College of Wisconsin

In allogeneic transplant, MM patients receive new bone marrow stem cells from a donor, rather than stem cells which have been harvested from their own bone marrow. Allogenic transplant, or Allo, has been called “the crudest and oldest immunotherapy for MM” and has been in use since 1991. Allo can cure some MM patients through the Graft vs Tumor Effect, or “Allo Effect”, where infusion of the donor lymphocytes can induce remission in the MM patient and the chronic graft vs. host disease, which will occur because the donor lymphocytes are not a perfect match for the patient, can lower the rate of relapse. New technologies have made successful allo transplants safer and more feasible, since cells from unrelated donors can now be used, and there is much lower risk of treatment related mortality (TRM). Some physicians now couple a first auto transplant (cells harvested from the patient) with a second allo transplant (cells from an unrelated donor) to take advantage of the immunotherapy-like effect of an allo transplant. Allo transplant is much more common in Europe, where almost every MM patient will receive an allo transplant either up front (12%), in a tandem auto-allo setting (19%), or later in therapy (69%).

Use of an allo transplant should be examined in a scenario of probability of benefit vs. the risks involved. Allo transplant may be indicated for younger, high risk MM patients who have early relapse after their first treatment, rather than older standard risk patients with a predicted low risk of relapse who for example achieve MRD negative status after induction.
Use of immunotherapy after allo or auto transplant offers the best chance for these types of therapy to provide benefit. After transplant, patients are in a minimal residual disease state, which provides for a favorable bone microenvironment ideal for immune therapy.

With newer therapies, there are more options available for safe immunotherapy after an auto transplant, if an allo transplant is not advised. These new therapies include vaccines, T cell based including CAR-T, antibody therapy, immune checkpoint inhibitors, and NK cell based therapies. Each of these are in their early stages of use in this setting and offer advantages and disadvantages; ask your doctor if any might be the right therapy for you based on your disease and treatment history.

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