Expert Point of View: Irene Ghobrial, MD, and Monica M. Bertagnolli, MD, FACS, FASCO

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Irene Ghobrial, MD

Irene Ghobrial, MD

Irene Ghobrial, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, who has conducted seminal trials in smoldering myeloma, commented on the phase III E3A06 study. Asked by The ASCO Post whether E3A06 settles the issue of treating smoldering disease, Dr. Ghobrial responded, “Yes, and no.”

“Yes, because this is the first well-randomized phase III trial in the United States proving, for the first time, that treatment is better than observation. But then, maybe no, because lenalidomide, as used in this phase III trial, may not be enough for high-risk patients,” she said.

“We became excited about treating smoldering myeloma after the Spanish Myeloma Group showed lenalidomide plus dexamethasone reduced the risk of progression to active disease. Rates with treatment were 77% vs 30% with observation (hazard ratio [HR] = 0.18; P < .001). Overall survival at 3 years was 94% vs 80%, respectively (P = .03),” Dr. Ghobrial continued.

“For the first time, we could do something in smoldering disease to improve survival,” she noted. “However, the Spanish study was criticized because it included some patients who already had myeloma [ie, lytic bone lesions]. The study did not, therefore, change the standard of care.”

The E3A06 study includes a population that is more in line with the current classification of smoldering disease, and is therefore more convincing, she maintained, though it still falls a bit short, in her eyes. According to Dr. Ghobrial, high-risk patients are likely to need more active agents to prevent clonal selection.

Other Trials

To this end, Dr. Ghobrial was a co-investigator in two phase II studies that built upon the lenalidomide/dexamethasone backbone with the addition of elotuzumab and ixazomib. In trials presented at the 2018 American Society of Hematology Annual Meeting & Exposition, response rates exceeded 90%, and evolution to active disease was not observed.

In one study, the response rate to elotuzumab, lenalidomide, and dexamethasone was 84%, and the progression-free survival rate at 3 years was 95%.1 In the other, the response rate to ixazomib, lenalidomide, and dexamethasone after 15 months’ median follow-up was 93%.2 The Spanish Myeloma Group has also reported, in the phase II GEM--CESAR trial, that with the addition of carfilzomib to the lenalidomide/dexamethasone backbone, 94% of patients were progression-free and 98% were alive at 28 months.3 Single-agent daratumumab delayed progressive disease in intermediate- and high-risk smoldering multiple myeloma, as well, in the phase II CENTAURUS trial disease.4

With these and other newer approaches (possibly immunotherapy), it may be possible to “reach the sweet spot where we can achieve, without toxicity, deep remission and not cause clonal selection,” she predicted. While Dr. Ghobrial views more active drugs as necessary in preventing disease progression in high-risk patients, she felt other patients at lower risk of disease progression might be sufficiently treated with lenalidomide/dexamethasone alone. The nuances are not yet clear.

Words of Caution

Since smoldering myeloma has become an active area of research, it has become tempting to compare outcomes among the agents, Dr. Ghobrial said, but she cautioned against this, noting that the inclusion criteria for the trials were different. “You can’t compare trials across smoldering myeloma, because each uses a different risk classification for smoldering disease, and that’s a problem.” Future re-analysis of these trials may provide some of these answers, she said.

Monica M. Bertagnolli, MD, FACS, FASCO

Monica M. Bertagnolli, MD, FACS, FASCO

Meanwhile, she said E3A06 offers strong evidence of treatment benefit. “It’s a wonderful study and the first time we have definitively shown that treatment is better than observation, but it’s only a first step in so many different steps that will be needed for us to make a difference in smoldering myeloma.” 

ASCO President Monica M. Bertagnolli, MD, FACS, FASCO, commented that the identification of strategies to treat premalignant lesions and prevent cancer is an ASCO priority, “and an area where we have had far too few successes.” She said the results suggest intervention has “clear advantages” that physicians should consider. 

DISCLOSURE: Dr. Ghobrial has consulted for Takeda, Janssen, Bristol-Myers Squibb, and Celgene. For Dr. Bertagnolli’s disclosure information, visit


1. Liu C-J, Ghobrial IM, Bustoros M, et al: Phase II trial of combination of elotuzumab, lenalidomide and dexamethasone for high-risk smoldering multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 154. Presented December 1, 2018.

2. Bustoros M, Liu C-J, Reyes K, et al: Phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 804. Presented December 3, 2018.

3. Mateos MV, Lopez JM, Rodriguez-Otero P, et al: Curative strategy for high-risk smoldering myeloma (GEM-CESAR): Carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd. 2017 ASH Annual Meeting & Exposition. Abstract 402. Presented December 10, 2017.

4. Hofmeister CC, Chari A, Cohen Y, et al: Daratumumab monotherapy for patients with intermediate or high-risk smoldering multiple myeloma: Centaurus, a randomized, open-label, multicenter phase 2 study. 2017 ASH Annual Meeting & Exposition. Abstract 510. Presented December 10, 2017.

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In patients with intermediate- to high-risk smoldering multiple myeloma, treatment with single-agent lenalidomide, vs observation, led to a 72% reduction in the risk of disease progression at 3 years.1 Results of the phase III E3A06 study were presented at a press briefing in advance of the 2019...