18th International Myeloma Workshop

Should every transplant eligible NDMM patient receive a transplant?

Prof Morie Gertz - Mayo Clinic, Rochester, USA

Today I’m going to be talking about a debate I’ll be doing with my associates regarding the validity of stem cell transplant in the era of novel agent therapy. As far back as 1990, before novel agents, there was evidence that high dose therapy and stem cell transplant did not improve overall survival in patients with multiple myeloma. It has been demonstrated that patients who have an early stem cell harvest and late stem cell transplantation after progression have similar survivals compared with those patients that actually undergo stem cell transplantation early in the course of the disease.

In 2000 overall survival after stem cell transplantation based on disease status did demonstrate a change from the time of transplant whether they were refractory to the disease or relapsed off of therapy or on therapy. But overall survival was no different than those patients who had transplant after four months of induction therapy.

It was demonstrated that following IMiD based induction therapy, usually thalidomide or lenalidomide in patients with newly diagnosed multiple myeloma, overall survival from the initiation of the first therapy was really no different between those patients who had a delayed stem cell transplant and early stem cell transplant and that data was first published in 2012.

Subsequent studies followed looking at patients receiving either thalidomide based, bortezomib based or lenalidomide based, comparing those patients who were transplanted within one year of diagnosis compared to those who were transplanted greater than one year after diagnosis and no survival advantage has been demonstrated.

One of the most important trials was the IFM 2009 trial; this has a follow-up of eight years. Although progression free survival was better in the early transplant group, the median overall survival not reached in both groups showed no difference in the strategy of early versus late stem cell transplantation.

In the EMN02 study that looked at bortezomib melphalan prednisone followed by melphalan prednisone compared to high dose therapy and a single or double transplant with a randomisation to consolidation and maintenance therapy in all patients, once again overall survival was not different between the two groups. When we look at the New England Journal article that looked at high dose melphalan plus lenalidomide maintenance compared to melphalan prednisone lenalidomide plus lenalidomide maintenance once again the three year overall survival was not significantly prolonged in the transplant group once the introduction of novel agents. The lack of overall survival benefit suggests that the third stem cell transplantation until relapse is feasible and does not compromise overall outcomes.

The goal of therapy is MRD negativity, we know that. That’s our goal currently for patients with multiple myeloma. No matter how we get to MRD negativity outcomes are excellent. As combinations of non-cross resistant agents are used in induction, consolidation and maintenance the role for stem cell transplant will continue to decline. When we look at some of the daratumumab containing regimens – CASTOR, POLLUX, ALCYONE and MAIA – which are daratumumab for non-transplant eligible patients, MRD negativity rates are now 28%. With non-transplant regimens carfilzomib with lenalidomide and dexamethasone followed by lenalidomide maintenance in 45 newly diagnosed multiple myeloma patients had minimal residual disease negativity of 100% by multiparametric flow cytometry, 67% by next generation sequencing, suggesting that with multiple novel agents high MRD negativity can be achieved without resorting to stem cell transplantation. In the non-randomised MANHATTAN clinical trial carfilzomib lenalidomide dexamethasone daratumumab resulted in an MRD negativity at a 10-5 sensitivity in 71% with a progression free survival at one year of 98%.

In a meta-analysis of 3,171 patients autologous transplantation in the univariate analysis produced statistical significance but in the multivariate summary the p-value was 0.36 and did not favour high dose therapy in the era of novel agents. The role of high dose melphalan, really there’s now an issue of a paradigm shift because when you look at SEER data and CIBMTR data the relative risk of benefit for patients developing secondary malignancies, AML and MDS, is much higher in the transplant population. So we have to consider the issue of second primary malignancies.

So, to summarise, we need to stop thinking of stem cell transplantation as the platform on which all myeloma therapy is built. The first question we ask should no longer be ‘Is the patient transplant eligible?’ We need to consider stem cell transplant as a regimen rather than the platform and the basis of therapy. We need to consider the selection of stem cell transplant and its sequencing in the therapy of patients with myeloma depending on what are the available other regimens, what are the reimbursement issues, what are the access to clinical trials and what is the availability of novel agents. So although stem cell transplantation potentially has a role, it’s certainly not mandatory to consider as part of induction therapy in our patients with newly diagnosed multiple myeloma.

Thank you very much for your attention.