Evolving Roles of Transplant and Quadruplet Therapy in Multiple Myeloma

Adam D. Cohen, MD

Director, Myeloma Immunotherapy

Associate Professor of Medicine (Hematology-Oncology)

Hospital of the University of Pennsylvania

Penn Medicine

Philadelphia, PA

CASE SUMMARY

• A 54-year-old woman presented with the following:
  • Complaints of back pain, fatigue, and occasional, but recurring dizziness
  • Nausea, constipation
• 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: 1.5 mg/dL
• Bone marrow: 22% monoclonal plasma cells
• Serum κ free light chains: 240 mg/L; λ 2.0 mg/L; κ/λ ratio 120
• Serum monoclonal protein: 5 g/dL
• Serum immunofixation electrophoresis: IgG-kappa present
• 24-hour urine: monoclonal protein spike of 50 mg – free κ
• Cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities: hyperdiploidy (gain 9 and 11)
• ECOG performance status: 1
• PET/CT scans: multiple bone lesions in vertebrae without extramedullary disease
• Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG-κ myeloma; identified as transplant eligible

Targeted Oncology: What are some considerations you would have for this patient in terms or triplet vs quadruplet therapy?

ADAM D. COHEN, MD: We [at Penn Medicine] were one of the late adopters of getting quadruplets to everybody when it became [common] to do so. I was still sometimes thinking maybe [for] is a patient with standard risk, I’d start with VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone], and I’ll add in the daratumumab [Darzalex] later, [when] I have more data. But now we’re seeing multiple trials over and over between the phase 2 GRIFFIN trial [NCT02874742], phase 3 PERSEUS trial [NCT03710603], and all of these quadruplet regimens showing that starting with daratumumab leads to deeper responses and now improved progression-free survival [PFS], with a tradeoff to me that seems acceptable in terms of toxicity.^1,2 I have evolved and I’m moving, especially for my younger transplant eligible patients, to quadruplets for everyone.

What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for a patients such as this with transplant-eligible multiple myeloma?

The NCCN guidelines haven’t quite been updated yet to reflect the PERSEUS trial, which was presented at 2023 American Society of Hematology Annual Meeting.^2,3 They still have the triplets listed as preferred VRd or KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone]. Dara-VRd is an “other recommended regimen,” but I think this will change to a category 1 recommendation because now we have a phase 3 trial. They have a lot of others that you can choose from, particularly cyclophosphamide-based [treatment for] somebody with renal failure. Then there is another [anti-CD38 antibody] called isatuximab [Sarclisa].

Which trials support the current category 1 recommended regimen of VRd with transplant?

There were 2 studies that looked at this. In DETERMINATION [NCT01208662] and an older trial called IFM 2009 [NCT01191060], the question was the role of transplant with VRd induction and does transplant still have a role.^4,5 All the patients got VRd as induction [in DETERMINATION] and then 1 arm was randomly assigned to no transplant or delayed transplant, got 5 cycles of consolidation, and went right to lenalidomide maintenance. The other arm got melphalan 200 mg/m2 [conditioning with] transplant and then got 2 cycles of consolidation and then maintenance; so it’s 5 vs 8 cycles of the VRd with a transplant in 1 arm. In DETERMINATION, lenalidomide maintenance was given indefinitely until progression.

The bottom line is that the addition of the transplant had a significant improvement in PFS, close to 2 years’ additional benefit at 67.5 vs 46.2 months median PFS, but no difference in overall survival [OS].4 This was seen in the French study, IFM 2009, as well.⁵ They saw at 8 years’ follow-up no difference in OS. That’s because in the French study, 70% of the patients who were assigned to the control arm got a transplant at relapse.

Interestingly, in the United States, only about 25% to 30% had a transplant so far in the control arm, and yet there’s still no difference in OS.⁴ It shows how many options we have in the United States, and also how challenging it is to look at OS in an upfront setting in the transplant-eligible population. These patients have median OS probably stretching [up to] 10 to 12 years in some cases. But this is to tell you what to expect and why we say that we still prefer upfront transplant, because there is still this PFS benefit. But for patients who don’t want to do it, we can collect stem cells and offer transplant later and you’ll probably have equivalent OS even though their disease is likely to relapse sooner. So at least with the triplets, I still think there’s a role for transplant.

REFERENCES:

1. 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

2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

3. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma; version 4.2024. Accessed July 15, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

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

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