Dr Kaufman Discusses the Role of Maintenance Therapy in MM

Jonathan L. Kaufman, MD, Professor of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, discusses the role of maintenance therapy in multiple myeloma (MM); the data of which were presented at the 2021 virtual Lymphoma, Leukemia & Myeloma (LL&M) Congress.

Dr Kaufman said the most common type of patient that utilizes maintenance therapy are transplant-eligible patients after transplant. He then referred to data from the phase 3, double-blind, randomized, placebo-controlled Tourmaline-MM3 study on oral ixazomib maintenance followed by autologous stem cell transplant (ASCT). The study met its primary end point and showed an improvement in progression free survival (PFS). Of note, Dr Kaufman said, the overall improvement in PFS was short—just over 5 months—and recent data demonstrated no difference in overall survival (OS).

Lenalidomide, he said, is the most commonly used maintenance therapy in MM today. Dr Kaufman said this is due to 4 major studies, 3 of which were analyzed in a meta-analysis that showed a clear improvement in PFS in patients with MM who received lenalidomide maintenance after ASCT. Of note, the median PFS for observation post-transplant was about 2 years, and it more than doubled with the use of lenalidomide.

“That dramatic improvement in PFS then subsequently translated into a clinically significant, and statistically significant improvement and OS. If you look at 7-year OS, there’s an absolute difference of 12 percent,” Dr Kaufman said.

The importance of this meta-analysis is twofold, Dr Kaufman said. First, it establishes lenalidomide as a maintenance therapy of choice associated with improvement in survival. Second, the median time that patients were on lenalidomide maintenance was approximately 2 years.

“I’m not suggesting 2 years is the right amount, but with just a median of 2 years of lenalidomide, we’re able to get this survival advantage,” Dr Kaufman said.

The fourth study, the phase 3 Myeloma XI Trial, focused on the risk status of ASCT-eligible patients who received lenalidomide maintenance. Dr Kaufman said the data clearly shows that lenalidomide maintenance is effective for high- and standard-risk, however it does not overcome the risk status. High risk patients are classified as having the presence of t(4;14), t(14;16), t(14;20), del 17p, or gain 1q lesions. Ultrahigh risk includes the presence of more than 1 lesion, and standard risk is the absence of these lesions.

“There’s clear evidence that there’s improvement in lenalidomide for high risk patients and ultrahigh risk with the use of single-agent lenalidomide for maintenance therapy,” Dr Kaufman said.

Dr Kaufman said Emory University utilizes a risk-adapted model for patients undergoing maintenance therapy. For standard risk patients, single-agent lenalidomide is used until progression, and for high-risk patients, the combination of lenalidomide, bortezomib, and dexamethasone (RVd) is given for 3 years, then lenalidomide as a single-agent until progression. Out of 1,000 consecutive patients treated uniformly with RVd induction auto-transplant and risk-adaptive maintenance, Dr Kaufman said there was impressive PFS for standard-risk (76.52 months, 95% CI, 66.87-86.17) as well as high risk (40.25 months, 95% CI, 33.53-46.96). The OS for this approach was greater than 6 years, Dr Kaufman said.

“Even 3-drug therapy does not completely overcome high-risk, but a median PFS of 3 and a half years is far superior to what we would expect with lenalidomide alone,” Dr Kaufman said.

Dr Kaufman then covered the IFM 2009 Study, which focused on the role of 1 year of lenalidomide maintenance on 700 MRD-negative or -positive patients randomized to receive RVd alone or transplant. Of note, with only 1 year of lenalidomide maintenance, Dr Kaufman said, there was significant improvement in PFS with transplant compared to RVd alone, even in patients who achieved undetectable MRD at 10^-6. Patients who were MRD negative and had a transplant with only 1 year of lenalidomide maintenance had a continuous drop of PFS.

“This would argue that 1 year of maintenance is not enough post-transplant,” Dr Kaufman said.

Focusing on the role of transplant, Dr Kaufman overviewed the second randomization of the FORTE study, which focused on the efficacy of lenalidomide (R) versus carfilzomib plus lenalidomide (KR) maintenance in patients with MM with or without ASCT. The carfilzomib dosing was a single dose given every 2 weeks for 2 years, and a lenalidomide dose at standard 3 out of 4 weeks. From a PFS perspective, Dr Kaufman said, the combination arm was superior to single agent lenalidomide.

“This is now randomized data that supports the work that we and others have done looking at the combination of proteasome inhibitors and IMiDs, and you’ll note that the improvement held true overall, held true for standard risk, and held true for high risk, normal LDH, abnormal LDH, and independent of stage. So, one would argue that we could potentially use this for everybody,” Dr Kaufman said.

The caution for using combination maintenance therapy for standard risk patients is that there is added toxicity, with 3% of patients developing thrombotic microangiopathy, 4% of patients having cardiac toxicity, and 3% of patients having a grade 3-4 hypertension, Dr Kaufman said.

The study also identified which groups benefitted after a median follow up of 37 months. In standard risk, there was a benefit as well as good outcomes. In high risk and ultrahigh risk, there was improvement as well, with the greatest relative improvement in the highest risk group, Dr Kaufman said.

“This carried forward with del 17p, gain 1q, t(4;14). The 1 group that didn’t see the benefit that we really need to figure out something different are those patients who have amplification of 1q—that is more than 1 additional copy of 1q or a minimum of 4 copies of 1q—but this tells us that very supportive of the combination of proteasome inhibitors and IMiDs in patients with high-risk post-induction transplant,” Dr Kaufman said.

Dr Kaufman then mentioned the GRIFFIN study, a randomized phase 2 study on the addition of daratumumab to standard therapy (RVd) versus RVd alone in transplant eligible patients with newly diagnosed MM. The standard approach was RVd transplant consolidation with RVd and then lenalidomide maintenance, Dr Kaufman said. The investigational approach was the same RVd with daratumumab added to each component. Meaning, patients that were randomized to the daratumumab arm received daratumumab throughout the entire treatment. The study met its primary end point of an improvement in stringent complete response (sCR) rate by the end of consolidation, Dr Kaufman said. At last year’s American Society of Hematology meeting, the maintenance data was updated to show that in the context of 12 months of maintenance, there was a significant improvement in the sCR and complete response (CR) rates compared to RVd alone as well as no statistical difference in PFS or OS.

For patients with newly diagnosed MM ineligible for transplant, most of the studies that have been done have not specifically focused on maintenance, but more considered ongoing therapy, Dr Kaufman said.

Thus, Dr Kaufman mentioned the phase 3 FIRST trial focusing on continuous lenalidomide and dexamethasone versus lenalidomide and dexamethasone for a fixed period of 18 months versus melphalan, prednisone and thalidomide. The study found an improvement in PFS for patients who continued lenalidomide maintenance therapy. The OS was superior in both lenalidomide arms compared to the melphalan, prednisone, and thalidomide arm.

Dr Kaufman said this led to what he considers one of the most important studies using lenalidomide, or lenalidomide and dexamethasone, over a long period of time. The randomized study included 100 patients in each arm to receive 9 months of lenalidomide and dexamethasone until progression and switch to single agent lenalidomide maintenance. Moving away from dexamethasone at the 9 months was not associated with decreased outcomes. Dr Kaufman said there’s evidence of improved outcomes when switching to lenalidomide maintenance.

“This study showed you can stop the dexamethasone and have no decrease in outcomes,” Dr Kaufman said.

The phase 3 MAIA study, which focused on induction and survival in patients with newly-diagnoised MM, compared daratumumab plus lenalidomide and dexamethasone, to lenalidomide and dexamethasone. Dr Kaufman said there was clear improvement in both PFS and OS. MRD negativity increased with the addition of daratumumab. There was also a reduced risk of progression or death with MRD negativity in both arms.

“How long do we need to continue the 3-drug regimen? I would argue with the data I just showed you, that you could confidently dose reduce or eliminate the dexamethasone after 9 months. And we know that we can safely give daratumumab after 2 or 3 doses without any steroids,” Dr Kaufman said.

In conclusion, Dr Kaufman said, lenalidomide remains the standard of care maintenance therapy in the post-auto transplant setting. Also, the combination of lenalidomide plus proteasome inhibitor maintenance should be used post-auto for high risk.—Emily Bader