Larson Reviews Combination Therapy Plus Transplant in Newly Diagnosed Multiple Myeloma

Sarah M. Larson, MD

Assistant Professor of Medicine

Hematologic Malignancies and Stem Cell Transplant Program

Director, Hematology/Oncology Fellowship Program

Division of Hematology and Oncology

David Geffen School of Medicine at UCLA

Los Angeles, CA

CASE

• A 54-year-old woman presented with Revised International Staging System stage II IgG-κ multiple myeloma, based on her laboratory results. Hemoglobin: 7.0 g/dL
  • β2-Microglobulin: 6 mg/dL
  • Albumin: 3.2 g/dL
  • Calcium: 11.3 mg/dL
  • Lactate dehydrogenase: 200 U/L
  • Creatinine clearance: 45 mL/min
  • Bone marrow: 22% clonal plasma cells
  • Serum κ free light chains: 24 mg/dL
  • Serum monoclonal protein: 5 g/dL
  • Cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities: none
  • ECOG performance status: 1
  • PET/CT: multiple bone lesions in vertebrae without extramedullary disease
• She was identified as being transplant eligible.

Targeted Oncology: What are the available therapy options for patients with transplant-eligible newly diagnosed multiple myeloma (NDMM)?

LARSON: The NCCN [National Comprehensive Cancer Network] guidelines, which are always in the process of revision because of all the new data that are always coming out, list the preferred regimens. They are bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd]; or carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]. Another recommended regimen is daratumumab [Darzalex], lenalidomide, bortezomib, and dexamethasone [D-VRd].¹

What role does autologous stem cell transplant (ASCT) play in transplant-eligible patients with NDMM?

The IFM/DFCI2009 study [NCT01191060] compared VRd with or without ASCT in transplant-eligible patients with NDMM. It is important to note that these patients were [younger than] 65 years, which is younger compared with many of our patient populations. We would certainly consider patients [older than] 65 years transplant eligible. This trial randomly assigned patients to VRd for 3 cycles, collection of stem cells but not proceeding to transplant, followed by 5 cycles of VRd. In the transplant arm, patients underwent 3 cycles of VRd, stem cell collection, ASCT with MEL200 [melphalan (Alkeran) 200 mg/ m²], followed by 2 cycles of VRd consolidation.

The patients then had lenalidomide maintenance for a fixed duration of 12 months. After 44 months of follow-up, the median PFS [progression-free survival] benefit for ASCT vs no ASCT was 50 months vs 36 months.² At the 90-month follow-up, it was 47.3 months vs 35 months. There was no difference in OS [overall survival], with an 8-year OS rate of 62% in the ASCT arm compared with 60% in the no-ASCT arm.³ The standard risk group showed clear ASCT benefits, but the high-risk group showed a very wide confidence interval. Patients were not prestratified as far as risk.²

The MRD [minimal residual disease] status is so important for patients. In the subgroup analyses, MRD negativity was a favorable prognostic factor. The transplant arm had a higher MRD-negativity rate of 30% compared with 20% for VRd alone.³

Are there more recent data regarding ASCT plus VRd in patients with NDMM?

The more updated DETERMINATION study [NCT01208662] was first presented at ASCO [American Society of Clinical Oncology Annual Meeting] in 2022. It also had VRd with or without transplant in transplant-eligible patients with NDMM. The patients were randomly assigned to 3 cycles of VRd, stem cell collection, followed by 5 cycles of VRd or 3 cycles of VRd, transplant with MEL200, followed by 2 cycles of consolidation.

Patients on this trial underwent continuous lenalidomide maintenance, so more consistent with our practice. At the 76-month follow-up point, the median PFS was 67 months in the transplant arm compared with 46 months in the VRd alone arm. But the OS rate had no difference at 5 years with 80.7% in the transplant arm vs 79.2% in the control arm.⁴

What trial looked at ASCT with other therapy combinations in this setting?

The FORTE trial [NCT02203643] had 3 arms that were randomized 1:1:1. The first arm was carfilzomib, cyclophosphamide, and dexamethasone; mobilization of stem cells; transplant; 4 cycles of consolidation. The second arm was 4 cycles of KRd, mobilization, transplant, 4 cycles of consolidation. The third arm was 4 cycles of KRd, mobilization of stem cells, but delayed transplant, so just collection and storage for the stem cells, and then 8 cycles of KRd. At the end of consolidation, all patients underwent a subsequent 1:1 randomization of lenalidomide vs carfilzomib and lenalidomide maintenance.⁵

The benefit of transplant with carfilzomib induction was further proven with an improved PFS rate of 69% in the KRd plus transplant arm compared with 56% for KRd alone. Across subgroups, the favoring of KRd plus transplant was less in patients who were 60 years or older.

In the maintenance arm, there was a PFS benefit to the combination. This is all the patients who underwent a second 1:1 randomization to carfilzomib plus lenalidomide vs lenalidomide alone. The subgroup analysis was less clear than with the KRd with ASCT vs KRd alone, and this is impacted by the high-risk cytogenetics included.5 A subgroup that did not benefit in this group to the KRd plus ASCT was patients with amplified 1q, so not just a gain 1q but patients who have 4 or more copies of 1q, which is part of what skews the high-risk cytogenetics. But overall, the FORTE trial showed a benefit of KRd plus transplant compared with KRd alone, as well as the benefit of carfilzomib plus lenalidomide vs lenalidomide maintenance.

So we’ve looked at transplants, and carfilzomib vs bortezomib as the proteasome inhibitor. But what the field is moving toward is the incorporation of a CD38-directed antibody in the up-front setting.

Which data support the addition of a CD38-directed antibody to triplet therapy in the transplant-eligible NDMM population?

The phase 2 GRIFFIN trial [NCT02874742] compared D-VRd with VRd in transplant-eligible patients with NDMM in the United States. The age of these patients is 18 to 70 years, with a performance status of 0 to 2, creatinine clearance of 30 mL/min or greater, and stratification factors for stage and kidney function. Patients were randomly assigned to either D-VRd vs VRd for 4 cycles. They underwent mobilization [with G-CSF (granulocyte colony-stimulating factor) and plerixafor (Mozobil)], which are frequently used now. The other trials did use cyclophosphamide. I know our center and others have moved away from that to G-CSF plus a CXCR4 antagonist.⁶

Both arms underwent transplant then consolidation for 2 cycles, then maintenance for cycles 7 to 32 on either daratumumab/lenalidomide or lenalidomide alone. The primary end point of this trial was sCR [stringent complete response] rate by the end of consolidation. The other end points were MRD negativity, overall response rate [ORR], PFS, and OS. The median age on this trial was 60 years, and approximately 15% of patients were high risk. There was a lower rate of ASCT in the VRd arm because of early discontinuations.

What was the efficacy reported in the GRIFFIN trial?

Both arms experienced a deepening of response throughout the study. At the end of induction, end of consolidation, at 1 year of maintenance, and then at end of the study, both arms showed an increase in CR rate. The [combined sCR and] CR rate at the end of induction was 19% for the D-VRd arm and 13% for the VRd arm. At the end of the study, the [combined] CR rate was 83% in the D-VRd arm compared with 60% in the VRd arm.⁶

Because we follow these patients for so long, MRD negativity can be our surrogate end point for OS. At the end of induction, 22% of patients in the D-VRd arm were MRD negative, whereas only 8% of the patients in the VRd arm were MRD negative to 10^–5. At the end of the study, in the D-VRd arm, 64% of patients achieved MRD negativity, including 36% who made it to the 10^–6 MRD-negativity state, and for VRd alone it was 30% and 16%, respectively.

The median PFS was not yet reached in either group in the intention-to-treat population by the 4-year mark. Patients with MM are having a much more favorable outcome as far as PFS goes. There was a benefit in the D-VRd arm with a 4-year PFS rate of 87% compared with 70% in the VRd arm. As I already mentioned, these patients are doing well. The median OS rate had not yet been reached. No new safety signals were identified. Increased rates of neutropenia, including grade 3/4 neutropenia, occurred with the addition of daratumumab.⁷ We’ve all seen that when treating patients. Most patients tend to tolerate the combination of D-VRd with minimal myelosuppression, but I do have patients who have difficulty and can have a rather rapid drop in their neutrophil count.

How do the 4 studies in transplant-eligible patients with NDMM compare?

The IFM/DFCI2009 study had VRd plus transplant vs VRd alone with 1 year of lenalidomide maintenance in both arms. The median PFS was 47 months in the VRd plus ASCT arm vs 35 months in the VRd alone arm, but no difference in OS in both arms.^2,3

The DETERMINATION trial had VRd plus ASCT vs VRd alone. Both arms received lenalidomide until progressive disease. The median PFS benefit was 68 months for the VRD plus ASCT arm vs 46 months for the VRd alone arm. Again, there was no difference in OS, and both arms are doing quite well.⁴

The FORTE trial had KRd plus ASCT vs KRd alone. The median PFS benefit was not yet reached for the transplant arm vs 55.3 months for KRd, and neither arm reached median OS.⁵

The GRIFFIN study was D-VRd vs VRd and maintenance of 2 years with daratumumab/lenalidomide or lenalidomide alone. Patients per investigator decision after the 2-year maintenance period were able to stay on treatment. But 2 years was the point at which [data were reported]. The 4-year PFS rate was 87% for D-VRd vs 70% for VRd, but neither median OS nor PFS have been reached.⁶

_REFERENCES

_{NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 2.2023. Accessed March 20, 2023. https://bit.ly/3Tug2T1}

_{Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;136(suppl 1):39. doi:10.1182/blood-2020-134538}

_{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}

_{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}

_{Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057}

_{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}