Is It Time to Intervene in Smoldering Myeloma?

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Early intervention in smoldering multiple myeloma prevents progression to symptomatic disease and should be strongly considered for patients meeting new criteria for high risk, according to Sagar Lonial, MD, Professor and Chair of Hematology and Medical Oncology and the Anne and Bernard Gray Professor in Cancer at Emory University School of Medicine and Winship Cancer Institute, Atlanta.1

Sagar Lonial, MD

Sagar Lonial, MD

“With lenalidomide as a preventive strategy, in a data set that I think looks good, we demonstrated a 78% risk reduction across the board and a 90% risk reduction purely in the high-risk category,” Dr. Lonial said at the 2019 Debates and Didactics in Hematology and Oncology Conference at Sea Island, Georgia. At the conference, sponsored annually by Winship Cancer Institute, Dr. Lonial described support for this approach and urged attendees to adopt the new “20/2/20” criteria for establishing risk. (It is based on the presence of bone marrow plasma cells > 20%, M protein spike > 2 g/dL, and a free light chain ratio > 20.)

New Ways of Stratifying Risk of Disease Progression

Smoldering myeloma is not one entity but represents a heterogeneous group of patients with varying risks of disease progression. “Identifying and teasing these subsets out has become a challenge that many of us have tried to take on in the past few years,” Dr. Lonial said.

According to criteria proposed by Rajkumar et al in 2015, any one of a dozen features can identify patients with smoldering myeloma with at least a 50% risk of disease progression.2 That list, however, includes genetic factors [specifically t4(4;14), del(17p), or 1q gain], “which, it turns out, do influence long-term outcomes but do not, in isolation, predict for disease progression,” according to Dr. Lonial. “Although the system gives you lots of choices, it actually doesn’t provide you with additional insight going forward.”

More recently, attempts have been made to develop a better risk stratification approach. In 2018, Mayo Clinic researchers published what they call the “20/20/20 criteria” (more aptly called “20/2/20,” according to Dr. Lonial). As previously mentioned, it is based on the presence of bone marrow plasma cells > 20%, M protein spike > 2 g/dL, and a free light chain ratio > 20.

In a study of 182 patients with smoldering disease,3 each of these three factors independently predicted for a shorter median time to disease progression: 110 months for patients at low risk (no risk factors), 68 months for those at intermediate risk (one risk factor), and 29 months for those at high risk (at least two of the three risk factors).

At the 2019 ASCO Annual Meeting, the International Myeloma Working Group reported data from a somewhat more complex multipoint scoring system.4 Within this model, the 20/2/20 criteria robustly predicted risk, with the low-risk group demonstrating a 5% risk of disease progression at 2 years; the intermediate-risk group, a 17% risk; and the high-risk group, a 46% risk. The 20/2/20 criteria are “tighter” than those used previously and represent a simple test that may identify patients at very high risk, concluded Dr. Lonial.

Spanish Trial Shows Benefit of Intervention yet Has Design Limitations

In 2013, Spanish researchers reported the results of intervention in patients with smoldering myeloma they defined as high risk in the phase III QuiRedex trial.4 Those patients randomly assigned to receive lenalidomide/dexamethasone (induction plus 2 years of maintenance) had a substantial improvement in both progression-free and overall survival vs placebo.

After long-term follow-up (median of 75 months), the median time to disease progression was not reached in the intervention arm but was 23 months in the placebo arm (hazard ratio [HR] = 0.24; P < .001).5 Progression to myeloma was observed in 86% vs 39%, whereas 82% and 64%, respectively, were alive (HR = 0.43). Adverse events were mainly grade 2 or lower.

“Despite these magnificent differences, early intervention was not adopted as a standard approach around the world,” explained Dr. Lonial, mostly because of concerns over the study design. The fact that patients could be enrolled based on radiographic findings, rather than advanced imaging techniques, meant that some patients already had myeloma and were not receiving optimal treatment.

“We’ve been waiting on additional confirmatory data to try to understand whether or not early intervention really makes a difference,” he said.

ECOG 3A06: Lenalidomide vs Observation

Dr. Lonial believes the more recent ECOG 3A06 trial, which he presented at the 2019 ASCO Annual Meeting, provides that confirmation.6 The study addressed most of the caveats of the Spanish trial, he said, by using modern imaging and allowing intermediate-risk patients to enroll (not just high-risk patients).

“With lenalidomide as a preventive strategy, we demonstrated a 78% risk reduction across the board and a 90% risk reduction purely in the high-risk category.”
— Sagar Lonial, MD

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“We demonstrated that prevention can actually make a difference. This is rare among hematologic malignancies, and, in that sense, it is very interesting,” he commented.

ECOG 3A06, which evaluated single-agent lenalidomide vs observation, is the largest randomized trial ever performed in smoldering myeloma. In the phase II portion, 44 patients received lenalidomide at 25 mg on days 1 to 21 every 28 days until disease progression or toxicity. In the phase III portion, 182 patients were randomly assigned to receive the intervention or observation. Patients in both arms were followed monthly to avoid observation bias.

Although the response rate to lenalidomide was relatively low (48% vs 0%) in the phase III trial (“and may be irrelevant in prevention”), the intervention resulted in a 72% reduction (P = .0005) in the risk of disease progression, after a median follow-up of 35 months. Also, of note, disease progression in this study was not defined as a 25% increase in M protein but also required the development of symptomatic CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions). The intervention did prevent the development of CRAB criteria and its hallmark organ damage. This was seen despite increasing M protein, ­added Dr. Lonial.

Adverse events were as expected with lenalidomide; health-related quality of life showed no detriment with the intervention. Secondary malignancies were more common with lenalidomide (11.4% vs 3.4%) but were mostly superficial skin cancers. Solid tumors occurred in just three patients treated with lenalidomide and two patients on the control arm.

In the phase II portion of the study, the median follow-up was 82 months, and 5-year progression-free survival was 78%. The data from the phase III trial appear to be mirroring the outcomes in the phase II trial, Dr. Lonial noted.

The greatest benefit appears to be observed in patients deemed at high risk by the 20/2/20 criteria, whose risk of disease progression (and risk of CRAB features) was reduced by 90%. Dr. Lonial sees this as further validation of the 20/2/20 criteria.

“I think 20/2/20 is probably the easiest mechanism to use right now to identify patients with smoldering disease at highest risk. And in that group, early therapy with either single-agent lenalidomide or lenalidomide/dexamethasone is reasonable, if you don’t have access to a clinical trial,” commented Dr. Lonial.

Dr. Lonial acknowledged that some clinicians will still hesitate to intervene in patients with smoldering disease. Since there is no urgency in starting these patients on therapy, he suggested keeping a close eye on them. With these data as support, he said, “If their disease is evolving, you should feel better about ­intervening.”

He urged attendees to considering enrolling patients on the phase III ECOG EAA173 trial of daratumumab plus lenalidomide/dexamethasone, vs lenalidomide/dexamethasone ( identifier NCT03937635). ■


DISCLOSURE: Dr. Lonial has served as a consultant for Celgene, Takeda, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Amgen, and Janssen and has received research support from Janssen, Takeda, and Celgene.


1. Lonial S: Smoldering multiple myeloma: How to approach workup and management? 2019 Debates and Didactics in Hematology and Oncology. Invited Lecture. Presented July 26, 2019.

2. Rajkumar SV, Landgren O, Mateos MV: Smoldering multiple myeloma. Blood 125:3069-3075, 2015.

3. Lakshman A, Rajkumar SV, Buadi FK, et al: Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 8:59, 2018.

4. San Miguel J, Mateos MV, Gonzalez V, et al: Updated risk stratification model for smoldering multiple myeloma incorporating the revised IMWG diagnostic criteria. 2019 ASCO Annual Meeting. Abstract 8000. Presented June 2, 2019.

5. Mateos MV, Hernández MT, Giraldo P, et al: Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): Long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 17:1127-1136, 2016.

6. Lonial S, Jacobus SJ, Weiss M, et al: E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8001. Presented June 2, 2019.