Strategies for Risk Stratification Inform Treatment Decisions in Multiple Myeloma

Natalie S. Callander, MD

The role of risk stratification in treatment decisions for patients with newly diagnosed, transplant eligible multiple myeloma vs newly diagnosed, transplant ineligible multiple myeloma was explored by Natalie S. Callander, MD, in a presentation at the National Comprehensive Cancer Center (NCCN) 2023 Annual Congress: Hematologic Malignancies held in San Francisco, California and virtually, September 22 to 23, 2023.¹

Overall, for patients at standard risk, Callander, a professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, suggested the triplet regimen VRd, consisting of the proteasome inhibitor bortezomib (Velcade), the immunomodulatory agent lenalidomide (Revlimid), and the corticosteroid dexamethasone. This is followed by autologous stem cell transplant (ASCT) and maintenance with lenalidomide until progression, followed by treatment with daratumumab (Darzalex).²

In general, for patients at high risk, defined as 2 or more high-risk cytogenetic abnormalities (HRCAs), extramedullary disease, and a Revised International Staging System (R-ISS) of 3, Callander recommended the 4-drug induction, which is VRd plus daratumumab. This is followed by ASCT and multidrug maintenance with periodic minimal residual disease (MRD) assessment.

“These guidelines proposed by R-ISS were issued in Europe last year and these are in our guidelines that just came out on September 18, 2023,” Callander said. “What we are trying to do is further stratify people,” Callander continued.^2,3 Callander noted that in the updated guidelines, 1q copy number abnormalities, deletion 17p, high lactate dehydrogenase, and translocation 4;14 have been highlighted and emphasized as risk factors to consider when treating patients with multiple myeloma.

For the transplant-ineligible patient, Callander bases her treatment decisions on the patient’s level of fitness. For patients who are fit, she opts for DR (daratumumab, lenalidomide) and dexamethasone until progression, followed by a modified VRd regimen (ie, bortezomib given on days 1, 8, and 15; lenalidomide is given for 21 days; and dexamethasone is given on days 1, 8, and 15).²

If the patient is frail, a regimen of Rd or DR is considered; if fitness improves, she considers adding another agent. For frail or fit patients, the maintenance choice is lenalidomide. In the high-risk but fit patient, she suggests the D-VRd regimen and multidrug maintenance.²

Genetic Risk Factors

Genetic features associated with high-risk disease include translocations at 4;14, 14;16, 14;20, and p53; 1q amplification or gain; deletion 1p32; SKY 92; and 2 or more HRCAs.

“SKY 92 is a commercially available gene expression profiling test. This is a CLIA [Clinical Laboratory Improvement Amendments]–certified test that uses bone marrow aspirate,” Callander said. “It’s not widely used yet, but it does seem to correlate with outcomes.”

Callander said some cancer centers are measuring circulating plasma cells as a risk factor at diagnosis. Extramedullary presentations are also considered high risk. Other risks associated with poor survival include older age, frailty, and comorbidities such as diabetes, coronary artery disease, and a sedentary lifestyle, which are modifiable risks.

ASCT

Transplants have been used as a treatment option for more than 30 years, said Callander. The study by Attal et al⁴ “is the seminal trial that demonstrated that the incorporation of transplant with standard chemotherapy at the time not only improved progression-free survival and overall response rates but quadrupled survival,” Callander said.

Despite the trial’s positive outcome, not all research agrees, however. The phase 3 DETERMINATIONA trial (NCT01208662) showed that RVd plus ASCT was associated with longer progression-free survival (PFS) than RVd alone. However, investigators reported that no overall survival benefit was observed.⁵

After a median follow-up of 76.0 months, investigators reported 328 events of disease progression or death. The risk was 53% higher in the RVd-alone group (n = 357) than in the transplant group (n = 365; HR, 1.53; 95% CI, 1.23-1.91; P < .001.

Median PFS was 46.2 months (RVd-alone group) compared with 67.5 months (transplant group). In the RVd-alone group, 95% of patients had a partial response or better compared with 97.5% in the transplant group. Complete responses or better in the RVD-alone group were 42.0% vs 46.8% in the transplant group.

“If you look at the patients at high risk in this study, they don’t benefit as much as transplant patients who didn’t have a transplant, but their PFS improved 4-fold if they had a transplant,” Callander said. “It underscores that this group of patients need a transplant. One could argue that even the standard risk patients are experiencing a 50% improvement in PFS if they undergo a transplant,” Callander continued (TABLE⁵).

Another study that demonstrated the benefit of ASCT was the phase 2 UNITO-MM-01/ FORTE trial (NCT02203643).⁶ A total of 474 patients were randomly assigned to receive carfilzomib (Kyprolis), lenalidomide, and dexamethasone plus ASCT (KRd; n = 158); KRd for 12 cycles; or carfilzomib, cyclophosphamide, plus dexamethasone and ASCT (KCd; n = 157).

“This study showed that the transplant made a difference,” Callander said. “Those patients with high-risk cytogenetics benefited the most from transplantation."

MRD

MRD is another way to measure risk, according to Callander. Two common methods assess MRD: flow cytometry and next- generation sequencing (NGS).

“We’ve known for a few years that if a patient became MRD negative, they did better than if they were MRD positive,” Callander said.

Efforts to improve MRD include the regimen evaluated in the phase 2, randomized 1:1, GRIFFIN trial (NCT02874742).

GRIFFIN showed that daratumumab when combined with RVd induction and consolidation improved depth of response in patients who were transplant eligible with newly diagnosed multiple myeloma.⁷

Another study of interest is the phase 2, multicenter, single-arm, MASTER trial (NCT03224507), which demonstrated that the daratumumab, KRd, autologous hematopoietic cell transplantation, and the MRD response–adapted consolidation led to high rate of MRD negativity in patients with newly diagnosed multiple myeloma.⁸

“With this approach, MRD negativity kept improving in all patient groups,” Callander said. “But we did discover that those highest- risk patients with 2 or more HCAs did not do as well with this strategy. So, we think this is a signal that patients with 2 or more HCAs are going to need something additional,” Callander said.

In conclusion, Callander said that patients at low risk could consider transplant deferral, but for many patients with new diagnoses, up-front transplant remains appropriate.

“Despite newer therapies, outcomes for patients with multiple myeloma vary. Efforts to address modifiable risks— including improving fitness, such as increasing exercise, smoking cessation, and infection prophylaxis—should be a focus,” Callander said.

REFERENCES:

1. Callander NS. Management of newly diagnosed multiple myeloma based on risk stratification. Presented at: National Comprehensive Cancer Center 2023 Annual Congress: Hematologic Malignancies; September 22-23, 2023; San Francisco, CA, and virtual. Accessed September 23, 2023. https://bit.ly/46pXMQ0

2. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2024. Accessed September 24, 2023. https://bit.ly/3Q0bgwN

3. Latest blood cancer treatment updates presented at annual NCCN event during Blood Cancer Awareness Month. News release. NCCN. September 18, 2023. Accessed September 24, 2023. https://bit.ly/3PR2aCn

4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91-97. doi:10.1056/NEJM199607113350204

5. Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

6. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0

7. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288

8. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935