ASH 2022: Multiple Myeloma

CME

Key Studies in Multiple Myeloma: Independent Conference Coverage of ASH 2022

Physicians: Maximum of 1.50 AMA PRA Category 1 Credits

Released: March 21, 2023

Expiration: March 20, 2025

Shaji K. Kumar
Shaji K. Kumar, MD
Sagar Lonial
Sagar Lonial, MD, FACP

Activity

Progress
1 2
Course Completed
ASCENT: Background

Shaji K. Kumar, MD:
The ASCENT trial is an open-label phase II study assessing limited-duration therapy in patients with high-risk SMM.1 Currently, patients with high-risk SMM should be considered for treatment, as approximately one half of these patients will progress to active MM within 2 years. Two previous phase III trials have demonstrated improved outcomes when evaluating lenalidomide or lenalidomide and dexamethasone compared with observation in patients with high-risk SMM. The QuiRedex trial reported improved PFS and OS with Rd vs observation.2 The E3A06 trial also demonstrated improved PFS with lenalidomide vs observation.3 This is an area that has been of great interest because it potentially provides us with an option to change the natural history of the disease and possibly cure some of these patients.

From the concept of a cure, at least 2 large studies have evaluated the outcomes of high-intensity therapy for patients with high-risk SMM. One is the ASCENT trial that evaluated the combination of fixed duration daratumumab, carfilzomib, lenalidomide, and dexamethasone (dara-KRd) in patients with high-risk SMM.1 The other is the phase II GEM-CESAR trial assessing 6 cycles of KRd followed by ASCT, 2 cycles of KRd consolidation, and then Rd maintenance for 24 cycles in patients with high-risk SMM.

ASCENT: Study Design

Shaji K. Kumar, MD:
In the phase II ASCENT trial, patients with high-risk SMM, as defined by the IMWG 20/2/20 criteria,4 were treated with dara-KRd for 6 cycles of induction, followed by 6 cycles of dara-KRd consolidation. Patients then received maintenance with lenalidomide and daratumumab for an additional twelve 4-week cycles, for 2 years of therapy. The primary endpoint of the study was the rate of confirmed stringent complete response (CR). Numerous secondary endpoints were also explored.

ASCENT: Baseline Characteristics and Patient Disposition

Shaji K. Kumar, MD:
In total, 87 patients with ages ranging between 41 and 76 years were enrolled. Most patients were enrolled based on the IMWG 20/2/20 criteria, and the remaining patients had an IMWG scoring system score of 9 or more. After median follow-up of 26.2 months, 31% remained on therapy, and 55% completed 24 cycles; 14% of the patients discontinued therapy before completion because of AEs, physician decision, or patient decision (n = 3 each), and 2 patients experienced disease progression.

ASCENT: Response

Shaji K. Kumar, MD:
The ORR with dara-KRd was 97%, with the majority (92%) having a very good partial response (VGPR) or better. When assessing bone marrow minimal residual disease (MRD) negativity using EuroFlow methodology, 84% (73 patients) were MRD negative. Of these, 53 patients were also in a CR. Patients responded quickly to therapy, including the time to MRD negativity, which was a median of 6 months. More than 50% of the patients were MRD negative at the end of induction therapy.

ASCENT: Survival

Shaji K. Kumar, MD:
The 3-year PFS rate with dara-KRd was 89.9%. Four patients progressed, 3 had biochemical progression, and 1 developed plasma cell leukemia 6 months after completing therapy. The median PFS was not yet reached.

ASCENT: Adverse Events

Shaji K. Kumar, MD:
The AE profile was consistent with previous experience for patients receiving this kind of combination regimen. Overall, most patients had at least 1 toxicity related to therapy. Hematologic AEs of grade ≥3 were observed in 18% of patients. Approximately 51% of patients experienced nonhematologic AEs of grade ≥3.

Most AEs were managed with dose modifications as most people continued to complete the 24 cycles of therapy. The types of AEs, including the nonhematologic AEs (ie, infections and hypertension), were similar to those observed with this combination in active MM. 

ASCENT: Investigators’ Conclusions

Shaji K. Kumar, MD:
Overall, the ASCENT trial demonstrates that the combination of dara-KRd is effective in patients with newly diagnosed high-risk SMM. Outcomes were similar to those in the setting of newly diagnosed active MM in terms of AE profile and response rates. Most patients remain in deep response after 2 years, but longer follow-up is needed.

The ASCENT and GEM-CESAR studies together provide a large cohort of patients with SMM who received intense therapy for a limited duration, which over time, can help answer the question of whether curing SMM is possible.1,5

Sagar Lonial, MD:
This is a very interesting and important study to see the curative potential of early intervention. However, the 3-year PFS of 90% in ASCENT with dara-KRd is consistent with the 3-year PFS of 91% observed in the E3A06 study, which just used single-agent lenalidomide.3 Additional analyses with longer follow-up will be important to understand the extent of the benefit with this more aggressive regimen and whether there will be a plateau with a fraction of patients who do not progress to active MM. The AEs were not out of proportion to what would be expected with traditional MM-like therapy.

Shaji K. Kumar, MD:
The concept of limited duration therapy is important here also when compared with some of the phase III trials, where often treatments were given until disease progression. The concept of limited therapy and possibly having a treatment-free interval for long periods of time, even without a cure, is still relevant. If patients do not need any additional MM therapy for years to come, that could also be a benefit.

Which of the following findings were reported in the phase II ASCENT trial evaluating intensive therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (dara-KRd) for 6 cycles of induction followed by 6 cycles of dara-KRd consolidation and maintenance therapy with lenalidomide and daratumumab for an additional twelve 4-week cycles for patients with high-risk smoldering MM (SMM)?

Phase II GEM-CESAR: Study Design

Sagar Lonial, MD:
As mentioned, the GEM-CESAR trial is another study evaluating the potential for curative therapy in high-risk SMM. GEM-CESAR was a phase II trial assessing 6 cycles of KRd followed by transplant, 2 cycles of KRd consolidation, and then maintenance with lenalidomide and dexamethasone for 24 cycles in 90 patients with high-risk SMM. After induction, ASCT, and consolidation, 76% achieved a CR or better, and 63% were MRD negative.5

This post hoc analysis of the GEM-CESAR study evaluated the subset of patients with sustained MRD negativity at 4 years following transplant.6 However, ultimately, the overall population data should be analyzed by ITT, not just the patients who achieved MRD negativity. This study included 90 patients who fit within the Mayo and/or Spanish definition of newly diagnosed high-risk SMM (pre-2014 diagnostic criteria) with ≥3 g/dL serum M-protein and ≥10% plasma cells in the bone marrow or either ≥3 g/dL serum M-protein or ≥10% plasma cells in the bone marrow and >95% of aberrant plasma cells within plasma cells in the bone marrow. The primary endpoint was MRD negativity at 3 years and 5 years after high dose therapy (HDT)-ASCT. The 3-year assessment was amended to 4-year assessment because of the COVID-19 pandemic.6

GEM-CESAR: Baseline Characteristics

Sagar Lonial, MD:
When looking at the baseline characteristics of patients enrolled on this trial, some patients (21%) were classified as high-risk SMM by the Mayo model, others were classified as high-risk SMM by the Spanish model (52%), and 27% were considered high-risk by both models. This demonstrates the dichotomy in the high-risk category and the staging of SMM. The categorizations based on various risk models may differ in what patients are included in the high-risk SMM subset because of differences in the criteria and characteristics included in each model, but the overall risk of progression in the population is the same.

GEM-CESAR: Response Over Time in ITT Population

Sagar Lonial, MD:
When looking at the response from the GEM-CESAR trial over time, the response rates were high and consistent with those observed in the ASCENT trial, with an ORR of 95% after maintenance therapy.

High rates of MRD negativity (10-5) were observed, ranging from 40% after induction to 63% after ASCT and consolidation. However, the rate of MRD negativity decreased in the maintenance phase to 52%. It raises a question about sustained MRD negativity with this approach. Like the data from the ASCENT trial, longer term follow-up will be important to assess this limited duration therapy for patients with high-risk SMM.

GEM-CESAR: Undetectable MRD 3 Mo and 4 Yr After ASCT (Primary Endpoint)

Sagar Lonial, MD:
The primary endpoint of this trial was MRD negativity (by flow cytometry) after ASCT and 4 years after ASCT. The rate of undetectable MRD (with a sensitivity of 10-5) 3 months after ASCT was 68%, and 43% of participants remained MRD negative after 4 years. The percentage of patients with MRD negativity at 10-6 remained steady at 48% after 3 months and at 4 years.

The idea that a large percentage of patients who have MRD negative disease can be sustained at 4 years is encouraging data. However, it is also important to point out that these MRD data included only patients who were at risk with MRD assessment performed or those who discontinued because of progressive disease (considered MRD positive) and did not include all patients from the ITT population.

GEM-CESAR: Biochemical Progression to MM

Sagar Lonial, MD:
Biochemical progression is an exploratory endpoint in SMM and predicts progression to active MM. In the GEM-CESAR trial, 38% of patients experienced biochemical progression, and the 70-month rate of biochemical progression was 62%.

It is important to remember that patients experiencing biochemical progression may not need treatment. However, these patients are at higher risk of progression to active MM, and these data suggest that the potential for cure with KRd and ASCT may not be as high as anticipated, and additional treatment for MM may be needed.

GEM-CESAR: Factors Predicting Biochemical Progression to MM

Sagar Lonial, MD:
The main factor that predicted biochemical progression was MRD negativity. Patients who were MRD negative at the end of maintenance had a higher likelihood of biochemical PFS and remained in remission longer than those who were MRD positive (HR: 0.22; 95% CI: 0.09-0.50; P = .001). Similarly, patients with MRD negativity 4 years after treatment had a longer time to biochemical progression vs those who were MRD positive at this timepoint (HR: 0.11; 95% CI: 0.02-0.50; P = .001).

GEM-CESAR: Time to Progression to Active MM and OS

Sagar Lonial, MD:
The proportion of patients with progression to active MM in the GEM-CESAR trial appears to be consistent with the data from the ASCENT trial.1 When looking at the time to progression (TTP) to active MM, only 5 patients developed active or symptomatic MM, with a 70-month TTP rate of 94%.

The data on biochemical progression suggested that although 38% of patients had recrudescence of serum M-protein or free light chain ratio, the long term PFS looks good. It is unknown whether this would be any different with less intensive therapy.

GEM-CESAR: Factors Predicting Progression to Active MM

Sagar Lonial, MD:
Similar to the data with biochemical progression, MRD negativity is also a predictor of progression to active MM (P = .01).

Patients with ultra-high-risk SMM had a higher likelihood of progression to active MM than those with high-risk SMM (P = .03). There are subtleties in the definition of risk, and these definitions have changed since the design of this trial. In the GEM-CESAR trial, ultra-high-risk risk included patients with 1 or more of the following: serum free light chain ratio >100, >1 focal lesion on MRI, and ≥60% plasma cells in bone marrow. In current clinical practice, these patients are considered to have active MM based on the modified SLiM-CRAB criteria.

GEM-CESAR: OS

Sagar Lonial, MD:
When assessing OS, 7 patients died, and the OS rate was 92% at 70 months. Three deaths were related to progression of disease, whereas other deaths included cardiac arrest not related to treatment (n = 1), ischemic stroke during induction (n = 1), lung cancer (n = 1), and MDS (n = 1).

The OS data thus far suggest that patients are not being harmed while receiving more aggressive KRd and ASCT for high-risk SMM, but the question remains on whether the patients are being helped by treating them earlier. And that, to me at least, is a little bit harder to discern.

GEM-CESAR: Implications

Sagar Lonial, MD:
The investigators concluded that patients with high-risk SMM who received curative therapy with KRd followed by ASCT, KRd consolidation, and lenalidomide maintenance and were MRD negative at 4 years did remarkably well. Of all evaluable patients, 68% were MRD negative (10-5) at 3 months after ASCT, and 43% remained negative at 4 years after ASCT. This included 28 of 58 patients (48%) with MRD negativity at 10-6 at 4 years, which is higher than what would be expected in a patient population with active MM.

Now, the question is how to identify these patients who were able to achieve MRD negativity to potentially individualize treatment because many other patients had evidence of biochemical or overt relapse and may not benefit from this aggressive therapy. Although this long follow-up provides good information, there are not yet enough data to definitely state that high risk SMM should be treated with an intensive regimen usually reserved for active MM.

Shaji K. Kumar, MD:
Determining the ideal approach for these patients with high-risk SMM is very important. The ongoing phase III DETER SMM trial will provide additional information on the use of another regimen currently used in active MM, comparing daratumumab/lenalidomide/dexamethasone with Rd (NCT03937635).

The fraction of patients who achieve a cure in the GEM-CESAR trial is going to be less than the number of people who experienced biochemical progression, which suggests that the MM clone is growing back. It will be important to understand, over time, which patients need continued therapy to maintain a response and keep MM clones under control vs the ones where a limited duration, high intensity therapy is effective and hopefully never progress to active MM.

The GEM-CESAR and the ASCENT studies are complementary in that they both employ more aggressive approaches for SMM, one using a triplet plus transplantation and the other using aggressive therapy without ASCT, which are the 2 main approaches used in the setting of newly diagnosed MM. However, neither the GEM CESAR nor the ASCENT trial data can be used for directing therapy today. They should be considered clinical trials trying to answer the question of curability for this early stage disease.

For today, data from the previously published phase III trials demonstrating OS or PFS improvement with either lenalidomide or Rd can be referenced.2,3 At the minimum, patients with high-risk SMM should be treated with lenalidomide or Rd, but preference for these patients should be clinical trials. For patients with high-risk SMM who may quickly progress to active MM, a multidrug combination could be considered, but the question remains about whether there is additional benefit. Regardless of the approach, patients with SMM should be very closely monitored.