Treatment of Newly Diagnosed Multiple Myeloma

Presentation 

A 62-year-old female with newly diagnosed revised R-ISS stage 1 standard risk IgG kappa multiple myeloma presented with acute low back pain that was progressively worsening. She had a 3-month history of low back pain that was initially treated with NSAIDS and physical therapy. Imaging noted a large L4 lytic lesion and subsequent compression fracture. She underwent a kyphoplasty and was referred for further work up. A PET-CT noted multiple new fluorodeoxyglucose-avid osseous lesions throughout the axial and appendicular skeleton. There were no epidural extensions or masses.   

Labs revealed: 

A bone marrow biopsy noted plasma cells estimated as overall about 15-20% of the marrow cells. Flow cytometry noted a distinct plasma cell population with large cell size comprising about 8% of the total sample, expressed CD56 (bright), and CD138, and exhibited cytoplasmic kappa light chain restriction. Fluorescence in situ hybridization and cytogenetics were negative. The patient’s past medical history is unremarkable with no noted comorbidities and no history of prior thromboembolic events. 

Treatment 

The patient underwent 4 cycles of induction therapy with daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd), with stem cell mobilization following cycle 4 of therapy. She tolerated the treatment well although at the end of mobilization, she had mild grade 1 neuropathy without pain to both feet. She achieved a serum complete response (sCR) with detected minimal residual disease (MRD) at that point. She then moved on to an autologous stem cell transplant (ASCT) achieving sCR, MRD negative, 100 days post-transplant. At day 100 post-transplant, she was initiated on lenalidomide 10 mg for days 1-21 of a 28-day cycle maintenance. She was started on a daily 81 mg aspirin with induction and then again with maintenance. She also started an antiviral with valacyclovir and started on Pneumocystis jirovecii pneumonia (PGP) prophylaxis with the PJP prophylaxis discontinued six months post-transplant. To prevent further skeletal events, she started a bone agent with zoledronic acid with induction and was monthly for the first year with a plan to decrease to every 3 months at 1 year and then discontinue at 2 years post-transplant. 

Discussion 

When selecting a treatment plan selection for a newly diagnosed myeloma patient, the first thing to do is determine if they are transplant-eligible or not. Our patient had no other comorbidities and was very fit with no noted frailties so she was a good candidate for transplant. We chose a quadruplet-based induction therapy based on our standard of care based on the data from the phase 2 GRIFFIN trial data, which compared standard lenalidomide, bortezomib, dexamethasone (RVd) vs. D-RVd in transplant-eligible patients. In the trial, patients were randomized to D-RVd or RVd induction for 4 cycles followed by ASCT, consolidation and lenalidomide, or lenalidomide plus daratumumab maintenance. The primary end point was sCR rate at end of post-ASCT consolidation with D-RVd vs. RVd (42.4% vs 32%) demonstrating a deeper response. At 49.6 months, response rates further improved for D-RVd vs RVd (67% vs 48%); as did MRD negativity. There were no new safety concerns with grade 3/4 infection rates.1,2 

The phase 3 PERSEUS trial further compared D-VRd and VRd in transplant-eligible newly diagnosed MM patients with induction, ASCT, consolidation, and maintenance. The median follow-up of 47.5 months noted a lower risk of progression or death in the quadruplet arm. Progression-free survival (PFS) at 48 months for D-VRd vs VRd was 84.3% vs. 67.7% and for complete response or better rates were 87.9% vs. 70.1%. MRD negativity was 75.2% for D-VRd vs. 47.5% for VRd. Overall, the study demonstrated that the addition of daratumumab conferred a significant benefit in PFS newly diagnosed transplant-eligible patients.3 The GRIFFIN and PERSUS studies show improved sCR and MRD rates that both deepen over time. 

References 

1. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X
2. 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
3. 3. 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
4. 4. Bertamini L, D'Agostino M, Gay F. MRD Assessment in Multiple Myeloma: Progress and Challenges. Curr Hematol Malig Rep. 2021;16(2):162-171. doi:10.1007/s11899-021-00633-5
5. 5. Ramasamy K, Avet-Loiseau H, Hveding Blimark C, et al. Measurable Residual Disease Testing in Multiple Myeloma Routine Clinical Practice: A Modified Delphi Study [published correction appears in Hemasphere. 2023 Nov 02;7(11):e doi: 10.1097/HS9.0000000000000986]. Hemasphere. 2023;7(9):e942. Published 2023 Aug 30. doi:10.1097/HS9.0000000000000942