Smoldering Multiple Myeloma Management Hinges on the Debate Between Treatment and Observation

Angela Dispenzieri, MD

The smoldering multiple myeloma (MM) treatment paradigm harbors fractures in the consensus regarding the optimal management of this disease, with some experts favoring a watch-and-wait approach and others advocating for early treatment.

At the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023), a debate was held between Angela Dispenzieri, MD, and Sagar Lonial, MD, FACP, about this topic.

Dispenzieri, consultant, Division of Hematology, Department of Internal Medicine; consultant, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology; and consultant, Department of Molecular Medicine, of Mayo Clinic in Rochester, Minnesota, said that a watch-and-wait approach was best for patients with smoldering MM. Lonial, consultant, Division of Hematology, Department of Internal Medicine; consultant, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology; and consultant, Department of Molecular Medicine, Mayo Clinic, suggested that treatment should be conducted for select patients.

Watch and Wait

According to research by Rajkumar et al,1 most patients with smoldering MM have monoclonal gammopathy of undetermined significance (MGUS) disease, which is precancerous, but about one-third of patients have the biologic malignancy. Currently, there is no way to determine which patients are which by evaluating patients’ pathologic and molecular characteristics. Instead, hematologists/oncologists use risk factors to decide whether to treat or hold off on treating these patients.

Dispenzieri focused her presentation on the low-risk to intermediate-risk population of patients with smoldering MM.

“Smoldering myeloma is a disease that we’re learning more and more about. The important thing to know about smoldering is that it’s a very heterogeneous process, and smoldering MM is a very heterogeneous condition. There are high-risk patients—that is a group that does warrant therapy—but that’s a small subset of the smoldering population. The others, probably close to two-thirds of the group at this juncture, are clear watch-and-wait candidates,” said Dispenzieri, in an interview with The SOHO Daily News. “I think that we’re learning about what the best strategy should be among the high-risk patients. That is probably the area of most intense study at this juncture.”

In support of her argument for the watch-and-wait approach in the lower-risk smoldering MM population, Dispenzieri cited the International Myeloma Working Group (IMWG) risk stratification model for smoldering MM. In accordance with this model, a patient has high-risk disease if they have M-protein over 2 g/dL, bone marrow plasma cell (BMPC) infiltration over 20%, or a ratio of involved vs uninvolved serum free light chain (sFLCr) greater than 20.2 Other patients are low to intermediate risk and can go untreated. Dispenzieri does note, however, that ongoing research may change risk stratification for smoldering MM.

The foundation of this stratification model is a study of 421 patients with smoldering MM who were diagnosed between 2003 and 2015. Time to progression (TTP) varied among patients, and this is how risk groups were generated. The median TTP was 57 months (95% CI, 45-72). BMPC greater than 20% (HR, 2.28; CI, 1.63-3.20; P< .0001), M-protein greater than 2 g/dL (HR, 1.56; CI, 1.11-2.20; P=.01), and FLCr greater than 20 (HR, 2.13; CI, 1.55-2.93; P<.0001) are predictive of TTP. Therefore, low-risk patients are those with none of these risk factors, intermediate-risk patients are those with 1 to 3 of these risk factors, and high-risk patients are those with 2 or more of these risk factors.³

“There are a number of different studies looking at the sort of the biology of the plasma cells and the microenvironment, as opposed to just the cut points. We’ve been using arbitrary thresholds, and they’ve served us reasonably well. We’ve used the number of plasma cells, size of the M protein, the free light chain ratio as surrogates for risk. But I think that there’s going to be evolving consensus down the road that there are going to be biologic markers that are more sophisticated and more informative than just these cut points that really are looking at the true molecular biology of the plasma cells and the biology of the microenvironment within the bone marrow,” explained Dispenzieri.

Dispenzieri’s stance aligns with that of the IMWG, which concluded in the paper about its risk stratification model that the presence of mutation, alteration, and the microenvironment of the tumors should also be a factor when determining a patient’s risk.²

Lonial’s presentation had a similar theme. In response, Dispenzieri said, “It’s clear that, yes, high-risk, smoldering patients do progress, and that it is warranted to contemplate treating these patients. But the lower-risk patients really don’t require therapy.”

Time to Treat

When it comes to Dispenzieri’s statement of watching and waiting when caring for patients with low- to intermediate-risk MM, Lonial agrees. But, in the high-risk population, research shows that patients do require treatment.
“From my perspective, we do have good treatment options that have a significant benefit, with minimal [adverse events] that can delay the time to developing myeloma, and in many cases, patients may not develop myeloma down the road at all. I think that’s sort of the crux of my argument,” said Lonial, in an interview with The SOHO Daily News.

There is more than 1 study that supports Lonial’s argument, he explained during his presentation.

“I think the question of early intervention for high-risk smoldering is an area where we’ve now seen 2 randomized phase 3 trials comparing early intervention vs observation, both of which showed a significant time in delaying time to developing symptomatic myeloma. Those 2 trials have now led to many other trials evaluating whether more intensive therapy or different types of therapy can offer similar benefits.”

In a prospective, randomized study led by Lonial, early intervention with lenalidomide (Revlimid) in patients with smoldering MM led to significant deferment in patients’ progression to symptomatic MM and end-organ damage.⁴

The study included 182 patients with smoldering MM who were randomized to receive lenalidomide (n = 92) or were observed using the watch-and-wait approach (n = 90). After being followed for a median duration of 35 months, response to therapy in the lenalidomide arm was observed in 50% (95% CI, 39%-61%), while no responses were shown in the observation arm. In addition, the progression-free survival (PFS) rate observed with lenalidomide was significantly prolonged compared with the watch-and-wait arm (HR, 0.28; 95% CI, 0.12-0.62; P=.002). At the 1-year mark, the PFS rates in the lenalidomide arm vs the watch-and-wait arm were 98% vs 89%, respectively. At 2 years, the lenalidomide arm had a PFS rate of 93% vs 76% in the watch-and-wait arm. Finally, at 3 years, the PFS rates were 91% vs 66%, respectively. Six patients in the lenalidomide arm died compared with 4 patients in the watch-and-wait arm (HR, 0.46; 95% CI, 0.08-2.53).

Twenty-eight percent of patients in the lenalidomide arm experienced grade 3 or 4 nonhematologic adverse events vs none of the patients who did not receive any treatment.

The research concluded that although observation is the standard of care approach, the treatment approach may prevent some patients from developing biologic MM.

In other studies, including QUIREDEX (NCT00480363), conducted in Spain, and the E3A06 trial (NCT01169337) led by Lonial, overall survival was improved with early treatment consisting of lenalidomide and dexamethasone or lenalidomide alone. These data supported a change to clinical practice, according to Lonial et al.^4,6

“In those trials at 3 years, the chance of not progressing to myeloma is identical to what I said about the lenalidomide-alone study, suggesting that there isn’t an early improvement in those more intensive treatments,” explained Lonial. “In fact, what they may be doing in those approaches is moving all the treatment earlier by 2 or 3 years, but not necessarily impacting the natural history.”

Future Treatment Approaches

There was a consensus between the 2 physicians on the current standard of care and the changing opinions among experts who study smoldering MM. In the future, both Dispenzieri and Lonial have hopes for how research will investigate approaches to care for patients with smoldering MM, regardless of risk.

“I think that maybe through molecular or immune mechanisms, we can truly put low-risk patients in more of the category of a [MGUS] to say, these are people who almost don’t have to worry. Peeling off that sort of intermediate group, and sort of saying that these intermediate patients are true high risk, and we need to come up with a therapy, and looking at the low risk, saying that these are patients who we are going to watch and wait because the likelihood of them getting into trouble, so to speak, is going to be very low,” Dispenzieri said. “The important things will be to understand the underpinnings of disease, further improve upon classification based on biology, and know whether we should treat high-risk smoldering multiple myeloma as multiple myeloma,” Dispenzieri added.

Lonial said, “[H]istorically, we’ve been focused on either clinical criteria or genetic criteria to identify the high-risk patient population, but I don’t think genetics alone are sufficient. The reason I say that is that the genetic spectrum is exactly the same in smoldering myeloma as it is in MGUS or symptomatic myeloma. I don’t think that genetics alone tell the story of why some patients progress and others don’t. I think [we must] focus on the immune microenvironment and understanding what is different. Also, what is different or what changes about the immune system are there when a patient progresses, and can we use that to try to prevent progression without necessarily eliminating the clone? What if you can just control the clone with the immune system, but not necessarily make it go away? Particularly in an older patient population, less intensive therapy may be more effective than more intensive therapy.”

References

1. Rajkumar SV, Kumar S, Lonial S, Mateos MV. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12(9):129. doi:10.1038/s41408-022-00719-0
2. Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;16;10(10):102. doi:10.1038/s41408-020-00366-3
3. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;12;8(6):59. doi:10.1038/s41408-018-0077-4
4. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020; 38(11):1126-1137. doi:10.1200/JCO.19.01740
5. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013; 369(5):438-447.
   doi:10.1056/NEJMoa1300439
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. J Clin Oncol. 37(suppl 15):8001. doi:10.1200/JCO.2019.37.15_suppl.8001