Smoldering Questions

Multiple myeloma is always preceded by a precursor phase, and in a minority of patients the diagnosis may occur in the smoldering myeloma phase. The timing of treatment initiation in these patients “has become a very controversial area,” according to Dr. Callander. Several scoring systems have been designed to determine individual risk for progression to myeloma.

One of the most popular scoring systems is from the Mayo Clinic—the “20/2/20 scoring system.” It includes the following factors: monoclonal protein >2 g, serum free light-chain ratio (FLCr) >20 mg/L, and bone marrow plasma cells >20%. Patients with none of these factors are deemed at low risk, patients with 1 risk factor are at intermediate risk, and those having ≥2 factors are considered high risk. For these respective categories, the median time to disease progression has been shown to be 110 months, 68 months, and 29 months, with 2-year rates of disease progression of 10%, 26%, and 47%.¹ Some of the newer scoring systems offer a more dynamic assessment over time.

Management of patients with high-risk smoldering myeloma is also a subject of ongoing debate, with options ranging from “modest treatment to slow progression” to “aggressive myeloma treatment to completely stop myeloma from developing,” Dr. Callander said. ECOG 3A06 favored lenalidomide (without dexamethasone) in high-risk patients (hazard ratio [HR], 0.24; 95% CI, 7.3%–31.6%) at 3 years.² CENTAURUS evaluated daratumumab at various schedules and demonstrated long-lasting responses.³

A more intensive approach using carfilzomib/lenalidomide/dexamethasone followed by transplantation, consolidation, and maintenance achieved very high rates of response, complete response, and undetectable minimal residual disease (MRD) in GEM-CESAR; however, at 3 years approximately 7% of patients had experienced disease progression.⁴ Currently, the ASCENT trial is evaluating an intensive schedule of carfilzomib/lenalidomide/dexamethasone/daratumumab with maintenance; 97% of patients have achieved undetectable MRD, but still 10% experienced disease progression at 3 years.⁵

“All these studies essentially end up in the same place, so we are encouraging all patients with smoldering myeloma to enroll in EAA173 (DETER-SMM),” said Dr. Callander, the study’s principal investigator (ClinicalTrials.gov identifier: NCT03937635). This study is randomly assigning patients to receive lenalidomide alone or with daratumumab “to see if 2 years of limited therapy can alter the natural history.”

Dr. Kumar provided these summary comments: “It’s very important to correctly diagnose smoldering myeloma, to risk-stratify patients, and to consider enrolling high-risk patients in clinical trials. In the absence of a trial, treatment with lenalidomide should be considered. In the absence of therapy, these patients need to be watched very closely.”

Risk Stratification in Newly Diagnosed Patients

Risk stratification is prognostic, with different outcomes mostly defined by the underlying cytogenetic abnormalities. Over time, additional abnormalities appear, including amplifications, deletions, monosomies, and point mutations on different genes. Much of this heterogeneity can be captured by staging systems. The Second Revision of the International Staging System (R2-ISS) has incorporated genetic abnormalities, with scores ascribed to them, resulting in R2-ISS categories I to IV.⁶ With an increasing number of abnormalities, patient outcomes worsen. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Multiple Myeloma have extensively modified the disease staging and risk stratification system to incorporate R2-ISS.

Dr. Kumar and colleagues at Mayo developed a similar, and possibly simpler, scoring system based on abnormalities that highly correlate with outcomes. He reminded listeners these systems capture <80% of disease heterogeneity, with the remaining patients “undefined at diagnosis.”

Treatment of Newly Diagnosed Patients

“One can argue that the most important part of myeloma therapy is the treatment of newly diagnosed disease. That’s where we often employ our best tools, which give many patients greater disease control,” Dr. Kumar said.

The induction regimens of bortezomib/lenalidomide/dexamethasone (VRd)—and more recently VRd + daratumumab (D-VRd)—are well established. Recently, the landmark PERSEUS trial of newly diagnosed patients eligible for autologous stem cell transplantation (ASCT) were randomly assigned to VRd or D-VRd, followed by transplant, consolidation with the same regimens, and maintenance with lenalidomide or lenalidomide/daratumumab.⁷ The addition of daratumumab significantly increased the rate of deep responses and undetectable MRD across patient subgroups (except patients aged ≥65 years) and significantly improved progression-free survival (PFS) by an absolute 17% (HR, 0.42; 95% CI, 0.30–0.59; P<.001).

“GRIFFIN⁸ and PERSEUS⁷ tell us that maybe a 4-drug regimen is better than a 3-drug regimen in a patient going for transplantation. The question now becomes, do we need a stem cell transplantation? We don’t have an answer in the context of quadruplet induction, but the data for triplet induction are very compelling,” Dr. Kumar said, based on IFM 2009, which showed a 30% reduction in disease progression with immediate transplant.⁹ “It was clear that integrating ASCT as part of up-front therapy led to significant improvements in PFS. We have similar data from other studies…. The question is not whether you need to transplant, but whether it is better as part of up-front treatment or at the time of relapse.”

Other questions regarding the optimal strategy were addressed by the FORTE trial. In this study, among several approaches, outcomes were best in patients receiving carfilzomib/lenalidomide/dexamethasone triplet induction followed by ASCT.¹⁰

For patients not eligible for ASCT, common treatment approaches include the less-intensive, more-tolerable “RVD lite” regimen for frail patients and lenalidomide/dexamethasone + daratumumab until disease progression, which in the MAIA trial significantly improved PFS (HR, 0.53; 95% CI, 0.43–0.66; P<.0001) and overall survival (HR, 0.68; 95% CI, 0.53–0.86; P=.0013) over Rd alone.¹¹ “This study met the mark, and this regimen has become a standard,” Dr. Callander commented.

Management After Transplant

Following ASCT, should patients start maintenance, undergo additional consolidation, or even receive a second transplant? The BMT CTN 0702 trial showed, in the context of an effective induction regimen, no difference in PFS or overall survival with either consolidation or a second transplant.¹² Maintenance therapy, on the other hand, has become a common practice, and although lenalidomide is the standard, new agents are being evaluated in this setting.

CASSIOPEIA found that daratumumab maintenance after quadruplet induction (D-VRd) significantly reduced the risk of disease progression or death compared with observation alone. However, when the induction regimen included daratumumab, there appeared to be no additional benefit from daratumumab maintenance.¹³ “The role of daratumumab maintenance remains unclear,” Dr. Kumar said, noting this question is being addressed by the SWOG S1803 DRAMMATIC study (NCT04071457).

Approaches in High-Risk Patients

As Dr. Kumar noted, the treatment of high-risk patients, who accumulate more genetic abnormalities over time, is more challenging, warranting intensification of therapy with longer durations of treatment. The OPTIMUM trial evaluated induction with daratumumab/cyclophosphamide/bortezomib/lenalidomide/dexamethasone (Dara-CVRd) followed by intensive chemotherapy and ASCT, with 6 cycles of Dara-VRd as the first consolidation and 12 cycles of Dara-VR as the second; daratumumab/lenalidomide was used for maintenance until disease progression.¹⁴ Initial analysis showed outcomes to be superior to historical controls, he reported.

Dr. Kumar emphasized that ASCT is an important aspect of treatment for high-risk patients, as shown in the DETERMINATION trial.¹⁵ Treatment with RVd followed by ASCT and maintenance yielded a median PFS of 55.5 months compared with 17.1 months with RVd alone. “These findings highlight the need to achieve a deep response early on and then to maintain that deep response by using intense maintenance therapy subsequently,” he commented.

Treatment of Relapse

At the suggestion of relapse, a thorough reassessment of the patient’s condition is critical, Dr. Callander emphasized. Today, that includes advanced imaging and perhaps a bone marrow biopsy. For patients with low-risk relapse, such as those with no serious new problems, one approach is to “hold off and determine the tempo of the relapse,” she said. “It may be helpful to consider therapy that has been tested in lenalidomide-refractory disease…. There is no evidence that changing from one anti-CD38 agent to another will provide benefit.”

The type of treatment and duration of prior response are important in selecting treatment; it is best to provide treatment with an agent that the patient was not previously exposed to. “Once we go through the first 3 major classes of drugs—proteasome inhibitors, immunomodulatory drugs (IMiDs), and anti-CD38 antibodies—it becomes more challenging,” Dr. Kumar added.

If the patient is refractory to lenalidomide—which is increasingly common—it is recommended to forgo additional IMiDs or perhaps use a second-generation agent, such as pomalidomide. A dozen or so regimens are being used in this setting; some of the newer ones include daratumumab/pomalidomide ± dexamethasone; isatuximab-irfc/carfilzomib/dexamethasone; and carfilzomib/daratumumab/dexamethasone. ASCT at first relapse is also a good option for some patients, according to Dr. Callander.

Patients with triple-class–refractory disease are often those with high-risk cytogenetics at baseline, and their outcomes are typically poor. Approved drugs include selinexor, CAR T-cell therapy targeting BCMA (eg, idecabtagene vicleucel and ciltacabtagene autoleucel) and T-cell engagers (eg, teclistamab-cqyv, elranatamab-bcmm, talquetamab-tgvs). Numerous other approaches are in clinical trials, including the BCMA-targeted antibody–drug conjugate belantamab mafodotin-blmf, other T-cell engagers, allogeneic CAR T-cell therapy, the BCL2 inhibitor venetoclax, and the oral CRBN E3 ligase modulatory drugs (CELMoDs).

Focus on Immunotherapy

“The advent of immunotherapy has changed the treatment paradigm, particularly CAR T-cell therapy and bispecific antibodies. Obviously, we want to leverage these agents, so early on we need to consider when we are going to use them,” Dr. Kumar said.

In the KarMMa trial, which examined disease in patients with highly refractory disease, idecabtagene vicleucel (delivered at the highest dose) achieved an 81% response rate and undetectable MRD in 79% of complete responders.¹⁶ Similarly, in CARTITUDE-1, ciltacabtagene autoleucel produced very good partial responses or better in 94.9% of patients, of whom 82.5% were stringent complete responses.¹⁷ Median PFS was approximately 9 months in KarMMa, and it was close to 3 years in CARTITUDE-1, but these populations were “fundamentally different,” he noted.

The interest is now in using CAR T-cell therapy earlier in the course of treatment, as was examined in patients with ≥1 prior lines of therapy in the CARTITUDE-4 trial.¹⁸ Median PFS was not reached with ciltacabtagene autoleucel, and it was 11.8 months with standard therapy (HR, 0.26; 95% CI, 0.18–0.38; P<.001). In a population relapsing on 2 to 4 lines, KarMMa-3 showed a median PFS of 13.3 months with idecabtagene vicleucel versus 4.4 months with standard therapy (HR, 0.49; 95% CI, 0.38–0.65; P<.001),¹⁹ triggering a change in labeling that allows this strategy in patients with ≥2 prior therapies.

Based on these findings, Dr. Callander predicted the treatment algorithm for relapse may change later this year. “There are even studies looking at CAR T now as initial therapy,” she said, suggesting it could someday rival ASCT as up-front therapy.

Other Immunotherapies

The bispecific antibodies teclistamab and elranatamab target BCMA, whereas talquetamab targets GPRC5D—all of which are now approved for patients with relapsed myeloma. “What made this class rapidly join our armamentarium,” Dr. Callander said, was the achievement of very deep responses in patients with ≥5 prior lines and impressive PFS, especially in patients with deep responses. However, she cautioned, these benefits come with a cost; side effects may include cytokine-release syndrome (mostly mild), immediate or delayed neurologic symptoms, and the serious but rare hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Prolonged cytopenias, T-cell suppression, B-cell aplasia, risk of infection, and mucocutaneous toxicity are also seen. “Giving bispecifics can be tricky,” she cautioned.

Furthermore, the optimal sequencing of cellular therapies is unclear. A recent study showed that treatment with a BCMA-targeted bispecific prior to CAR T-cell therapy may negatively affect outcomes with CAR T-cell therapy.²⁰ “Many experts advise giving CAR T-cell therapies first, followed by the bispecifics,” Dr. Callander stated.