The 2019 American Society of Hematology (ASCO) Annual Meeting in Chicago is fast approaching (May 31-June 4). Out of a total of 4,950 abstracts released Wednesday, May 15, 210 are myeloma related. As usual, there is one oral session on Sunday, June 1 from 9:45 am -12:45 pm, which includes the top eight oral abstracts (numbers 8000 through 8007). I will review these, plus a couple of poster presentations that are worthy of mention (#8015 and #8023) to give my initial Top 10 Abstracts for ASCO 2019.
Oral presentations
The first two abstracts (8000 and 8001) deal with high-risk smoldering multiple myeloma (HR SMM). Dr. Jesús San Miguel is the lead author of abstract 8000, the first IMWG analysis of new criteria for HR SMM since the incorporation of “myeloma defining events” (MDE) into the revised IMWG diagnostic criteria in 2014. The key observation made by Dr. San Miguel and his team is that three parameters—(serum spike level [cutoff 2 Gms/dl]; bone marrow plasma cell percentage (BMPC%: cutoff 20%); and Freelite ratio (involved over uninvolved, with a cutoff of 20)—are the best to delineate HR SMM in terms of likelihood of progression at two years. This “2/20/20” criterion identifies an important group to be considered for early treatment intervention. Additional analyses are underway to allow definitive exclusion of low-risk SMM patients, and these data will be part of future presentations.
Abstract 8001, with Dr. Sagar Lonial as the lead author, is the report of the important E3A06 trial, which enrolled patients with intermediate or high-risk SMM into a randomized treatment trial using lenalidomide in two phases. In phase II, 44 patients received lenalidomide to assess both safety and efficacy. Then, 182 patients were randomly assigned in the phase III portion to receive lenalidomide (25 mg for 21 days each month) versus observation.
In both phase II and phase III portions, lenalidomide led to improved outcomes. In the randomized portion, the progression-free survival (PFS) was 98%, 93%, and 91% at 1, 2, and 3 years for those receiving lenalidomide versus 89%, 76%, and 66% with observation. These results are very encouraging and support other data indicating benefit with early intervention. Perhaps even more importantly, this randomized trial strongly validates the risk of progression without intervention, which is 24% and 34% at 2 and 3 years of follow-up.
Of concern, there was significant toxicity with the lenalidomide: 80% of patients in phase II and 51% of patients in phase III had to discontinue treatment. Further studies will reveal the magnitude of benefit, even in patients who discontinued treatment early. I am sure these data, combined with the proposed new criteria for HR SMM abstract, will generate considerable discussion at the time of ASCO.
Abstract 8002, from the Italian study group based in Milan, reports the results of the FORTE trial, which assess outcomes in newly diagnosed myeloma patients treated with KRd with or without ASCT. They key conclusion is that 12 cycles of KRd versus KRd + ASCT were equally effective in producing high-quality responses. Impressively, in patients with R-ISS stage I disease, MRD negative rates of 69% and 62% were achieved. These findings will certainly add to the current ongoing debate about the role of ASCT in the frontline setting.
Abstract 8003, from the French study group (IFM), reports the results of the CASSIOPEIA trial, which compares VTd with and without daratumumab in the treatment of newly diagnosed myeloma for transplant-eligible patients. The conclusion is rather straightforward. The addition of daratumumab improved both the depth of response (including MRD negativity) and duration of response (PFS). Of note, the rate of MRD negativity (at 10-5 level) in this trial in patients achieving ≥ CR was 33.7% for dara-VRD versus 19.9% with VTd alone. This study adds to the significant data demonstrating the efficacy and safety of added daratumumab in the frontline setting.
Abstract 8004 presents the results of a study led by Dr. Paul Richardson and the Dana-Farber team comparing isatuximab + pomalidomide/dexamethasone (IsaPd) versus Pd alone. In this study involving 307 patients with relapsed/refractory myeloma, as one might expect, outcomes were improved with the 3-drug combination, in terms of both ORR and PFS. The PFS was 11.5 months for IsaPd versus 6.5 months for Pd alone. The ≥ VGPR rate was 31.8% versus 8.5% with MRD negative rates of 5.2% and 0% respectively. The safety and added efficacy of isatuximab in this setting is thus demonstrated, although the magnitude of added benefit is not as impressive as one might have expected.
Abstract 8005 is a simple, but very important report indicating the safety and efficacy of daratumumab administered by the subcutaneous (SQ) route. The SQ dara was “non-inferior” to the IV administration, which was excellent, and even more importantly, the number of reactions were lower, safely comparable, and the administration time substantially reduced. In this study, the SQ dara was administered over 3 to 5 minutes using alternating left/right abdominal sites, and remarkably well-tolerated. This is very good news for patients, as daratumumab is being integrated into more and more regimens throughout the course of the disease.
Abstract 8006, presented by Dr. Sagar Lonial, summarizes early data with a new IMiD-type agent (called CELMoD) evaluated in relapsed/refractory myeloma. As of the time of the abstract, 58 patients had been treated, with an ORR of 31%. Although the patients had prior exposure to lenalidomide and/or pomalidomide, it is not clear if patients were IMiD refractory. Nonetheless, these are encouraging early data with no apparent negative safety signals.
Abstract 8007, presented by Dr. Max S. Topp on behalf of a multicenter team, summarized data using the BCMA-targeted BiTE AMG 420, results of which were also presented at ASH 2018. In this update, 42 patients were treated. A key goal was to identify a safe and effective dose. The 800 µg/day dose was deemed too high and the 400 µg/day dose selected for ongoing studies. At the 400 µg/day dose, there were 7/10 responders with 5 of the 7 achieving stringent CR. In other words, promising efficacy at the more tolerable 400-µg dose.
Posters
The two posters I have selected deal with the outcomes of patients linked to FiSH abnormalities: abstract #8015 assesses the impact of t(11;14) and abstract #8023 evaluates the role of 1q21 amplification/gain.
The t(11;14) study is another IMWG multicenter study, and I am (full disclosure) the lead author. This analysis included 848 patients out a full, planned cohort of 1,500 patients. Key initial observations are: combinations of an IMiD plus a proteasome inhibitor agent have the best survival outcomes, and the early use of ASCT results in a median overall survival approaching 10 years. So, very good outcomes for such patients. More detailed analyses are to follow.
The 1q21 analysis assesses the outcomes linked to the use of the so-called total therapy regimen utilized at the University of Arkansas for Medical Sciences (UAMS), Little Rock. There were 607 patients included in the analysis. This retrospective analysis showed that the presence of the 1q21 abnormality in the various subgroup protocols was associated with reduced PFS and OS. This is consistent with several other analyses reflecting the importance of the 1q21 abnormality and the need to incorporate this testing into treatment protocols.
The bottom line
Although no dramatic breakthroughs are being reported at the 2019 ASCO Annual Meeting, several very important observations can inform patient and physician decision-making moving forward.
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Dr. Brian G.M. Durie founded and now serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.
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