Preventing Progression and Chasing Cure in Smoldering Myeloma

Maria-Victoria Mateos, MD

Data from several clinical trials support treatment with lenalidomide (Revlimid) plus low-dose dexamethasone in select patients with high-risk smoldering multiple myeloma to prevent disease progression, said Maria-Victoria Mateos, MD, adding that other promising combinations under investigation are showing curative potential.

“Important questions to consider are ‘Who to treat, when to treat, and how to treat,’” said Mateos, hematologist and director of the Myeloma unit at the University Hospital of Salamanca in Spain, in a presentation during the Charlotte Plasma Disorder Congress. “But before moving forward with these questions, should we treat patients with smoldering myeloma?”

In terms of deciding which patients are candidates for treatment, it is important to understand that management should be risk-adapted, explained Mateos. Patients with smoldering myeloma who have a progression risk of 50% at 2 years should receive treatment, based on the 2/20/20 criteria. The Spanish Myeloma Group model has also been validated in a clinical trial, and as such, patients with high-risk smoldering myeloma can be treated according to this criteria as well.

The most appropriate time to treat is at the moment of diagnosis, she added. “However, you need be sure, and the patient has to also be confident with you,” said Mateos. “In the case of doubt, it’s much better to watch and wait and to evaluate the potential pattern of evolution using dynamic models.”

There are currently 50 clinical trials evaluating early treatment in patients with high-risk smoldering myeloma, according to Mateos. If the decision is made to treat a patient, there are two potential approaches to take: to prevent the development of multiple myeloma or to plan a curative approach to eradicate the disease entirely.

Preventive Approaches Show Promise

In the multicenter, randomized phase III QuiRedex trial, investigators compared lenalidomide plus dexamethasone induction therapy followed by lenalidomide maintenance with observation in a series of 120 patients with high-risk smoldering myeloma. The primary endpoint of the trial was time to progression to multiple myeloma.

Results showed that early treatment with lenalidomide plus dexamethasone resulted in a significant benefit in terms of delaying progression at a median follow-up of 40 months (HR, 0.18; P <.001)¹ and longer-term follow-up of 75 months (HR, 0.24; P <.001)². There was also a significant overall survival (OS) benefit observed with the combination, with a hazard ratio of 0.31 (P = .03) at a median follow-up of 40 months and 0.43 (P = .024) at 75 months.

In another intervention, when biochemical progression was observed in patients who had received low-dose lenalidomide as maintenance therapy, investigators added a low dose of dexamethasone (20 mg for 4 days). This approach resulted in stable disease in a significant number of patients (n = 12/15). “In fact, this early therapeutic approach was of benefit in terms of OS as well,” said Mateos. The hazard ratio for OS in patients who did not progress or in patients who biochemically progressed and were early treated with lenalidomide plus very low-dose dexamethasone, was significant, at 0.14.”

In the phase III E3A06 study, investigators looked at treatment with lenalidomide alone versus observation in asymptomatic patients with smoldering myeloma (n = 182). Results presented at the 2019 ASCO Annual Meeting showed that early treatment with lenalidomide significantly prevented progression to multiple myeloma—especially in the subgroup of patients considered to be high-risk.³ Lenalidomide also led to a 72% reduction in the risk of disease progression (HR, 0.28).

“Lenalidomide or lenalidomide and dexamethasone (Rd) has been considered a backbone to which other novel agents can be added,” said Mateos. “These 3-drug based combinations have been evaluated in some phase I/II clinical trials conducted in patients with intermediate to high-risk smoldering myeloma.”

One such combination, composed of the monoclonal antibody elotuzumab plus Rd, was evaluated in a phase II trial of patients with intermediate- and high-risk smoldering myeloma (n = 49). Data presented at the 2018 ASH Annual Meeting showed an overall response rate (ORR) of 84%.⁴

“Most important to mention is that the PFS is quite good. With a median follow-up of approximately 30 months, there is no patient who has already progressed to symptomatic disease,” said Mateos.

Another small phase II trial is evaluating the use of ixazomib (Ninlaro) in combination with Rd in the same high-risk patient population (n = 29). The combination showed an ORR of 93.1%, with 56% of patients achieving a complete response (CR) or a very good partial response.⁵ Longer follow-up is needed, but the combination appears to be promising, said Mateos.

The combination of carfilzomib (Kyprolis) with Rd is also being evaluated in patients with high-risk smoldering myeloma, she added.

Chasing Cure

There are also approaches that are being investigated with the intention of curing smoldering myeloma before myeloma is developed, said Mateos.

The ongoing randomized phase II CENTAURUS trial (NCT02316106) is comparing the use of the monoclonal antibody daratumumab (Darzalex) with observation in patients with intermediate- or high-risk smoldering myeloma. Furthermore, the phase II GEM-CESAR trial is evaluating the use of carfilzomib plus RD (KRd) in 6 induction cycles, followed by autologous stem cell transplant, consolidation with KRd for 2 cycles, and maintenance lenalidomide with very low-dose dexamethasone for up to 2 years in patients with high-risk smoldering myeloma (n = 90).

Eighty-three of the 90 patients are receiving maintenance with Rd.

Preliminary efficacy data showed that after induction, transplant, and consolidation, responses improved over time and the CR rate was 41% after induction, 64% after transplant, and 76% after consolidation.⁶ The MRD-negative rate was also increasing with 61% of patients having achieved MRD negativity after consolidation.

There are 40 patients who completed induction, transplant, consolidation, and 1 year of maintenance. The CR rate for those patients who had completed the 1 year of maintenance is 85% and 68% of those patients are MRD-negative. The median follow-up is about 2 years, but longer-term follow-up is needed, she concluded.

“How do you select a preventive versus curative strategy for patients with smoldering myeloma? I honestly don’t have the answer,” Mateos admitted. “We have to focus more on the bone marrow microenvironment.”

References

1. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Eng J Med. 2013;369(5)438-447. doi: 10.1056/NEJMoa1300439.
2. 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. 2016;17(8):1127-1136. doi: 10.1016/S1470-2045(16)30124-3.
3. 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. 2019;37(suppl 15; abstr 8001). doi: 10.1200/JCO.2019.37.15_suppl.8001.
4. Liu C-J, Ghobrial IM, Bustoros M, et al. Phase II trial of combination of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. Blood. 2018;132(suppl 1):154. doi: 10.1182/blood-2018-154.
5. 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. Blood. 2018;132(suppl 1): 804. doi: 10.1182/blood-2018-99-117871.
6. Mateos MV, Martínez-López J, Rodríguez-Otero P, et al. CURATIVE strategy (GEM-CESAR) for high-risk smoldering myeloma: carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd. Presented at: 2019 European Hematology Association Congress; June 14-17, 2019; Amsterdam, The Netherlands. Abstract S871.