Triplet Therapy, ASCT Frontline Standard for Multiple Myeloma

Silas Inman @silasinman
Published: Sunday, Oct 02, 2016

Dr. George Somlo

George Somlo, MD

The preferred primary therapy for patients with multiple myeloma is induction therapy with a triplet regimen containing a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and dexamethasone followed by autologous stem cell transplantation (ASCT), consolidation, and maintenance, according to George Somlo, MD, at the 2016 NCCN Annual Congress on Hematologic Malignancies.

"Stem cell transplant is still an option but the new paradigm is to include novel agents in the induction followed by autologous stem cell transplantation for appropriate patients," said Somlo, from the City of Hope Comprehensive Cancer Center. "The question of consolidation or maintenance could be semantics but there is a need for some sort of maintenance therapy. Essentially, we're trying to treat myeloma now closer to leukemia, we don't fool ourselves into thinking that induction will keep a patient in remission."

The ultimate goal of primary therapy is to induce a very good partial response (VGPR) or better. In the latest NCCN criteria, a VGPR is defined as serum and urine M-protein levels that are detectable only when using immunofixation and not by electrophoresis or represented by a 90% reduction in serum M protein and a urine level of <100 mg per 24 hour.

The probability of survival is significantly better in those who achieve a VGPR or complete remission (CR), when compared with those who achieve a PR (P = .0017). Moreover, patients achieving a stringent CR have a significantly better 5-year overall survival (OS) rate (80%) versus those who achieve a CR (53%) or a near CR (47%).

"Initiate the therapy that you think has the highest likelihood of inducing a patient to at least a very good partial response but ideally a complete remission," said Somlo. In many instances, this will involve the continued use of ASCT, he noted. "I think it is fair to say, at least for the time being, ASCT is here to stay."

A phase III study conducted by the IFM and Dana-Farber that was presented at the 2015 ASH Annual Meeting1 assessed upfront therapy with the IMiD lenalidomide (Revlimid), PI bortezomib (Velcade), and dexamethasone (RVd) with or without ASCT for younger patients with multiple myeloma. Maintenance lenalidomide was administered in both arms for 1 year. Overall, there was a 31% reduction in the risk of progression or death with the use of transplant.

In the study, the 4-year progression-free survival (PFS) rate with ASCT was 47% compared with 35% for RVd alone (HR, 0.69; 95% CI, 0.56-0.84; P ≤.001). The VGPR or better rate was 88% with ASCT and 78% with RVd alone (P = .001). The 4-year OS rate was 81% with ASCT and 83% with RVd alone (HR, 1.2; 95% CI, 0.7-1.8).

"This, as well as many other studies, are difficult to interpret when it comes to overall survival, because in this case those patients who progressed after just standard consolidation therapy were allowed to undergo ASCT," said Somlo. "We have so many new drugs now that to have a study where after progression these patients aren't getting treatment in salvage would probably now be considered unethical."

Another phase III study, reported at the 2016 ASCO Annual Meeting,2 compared upfront ASCT with triplet therapy for patients with myeloma. This study included 1266 patients with newly diagnosed multiple myeloma who received induction therapy with the triplet regimen of bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCD) and then were randomly assigned to receive bortezomib, melphalan, and prednisone (VMP) or high-dose melphalan followed by either a single or double ASCT.

The median PFS was 44 months in the VMP arm and was not reached in the ASCT group. The 3-year PFS rates were 57.5% and 66.1%, for the VMP versus ASCT group, respectively (HR, 0.73; 95% CI, 0.59-0.90; P = .003). This benefit remained consistent in those with high- and standard-risk cytogenetics. The VGPR or better rates were 73.8% versus 88.5%, for the VMP and ASCT arms, respectively.

"Like many other studies, VGPR is higher in those who underwent ASCT," said Somlo. Following triplet therapy and ASCT, there remains a consistent and important role for maintenance therapy, he added.

At this point, the maintenance regimen of choice is lenalidomide, following a 40% reduction in the risk of death with the agent compared with placebo in the CALGB100104 study (HR, 0.60; P = .001).3 Median time to progression was 53 months with lenalidomide versus 26 months for placebo (HR, 0.54; P <.001).

This was also seen for maintenance lenalidomide following high-dose melphalan and ASCT in a meta-analysis presented at the 2016 ASCO Annual Meeting.4 In this study, the 7-year OS rate was 62% with the lenalidomide versus 50% with placebo. Median OS was not yet estimable in the lenalidomide arm versus 86.0 months in the control group.

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