Assessing Quadruplet vs Triplet Regimens in Up-front Multiple Myeloma Treatment

Triplet drug regimens have become the standard of care for patients with multiple myeloma (MM) as first-line therapy, followed by autologous stem cell transplant (ASCT) for eligible patients.¹ Although some individuals may present with poorer performance status allowing only for a 2-drug regimen, a third agent should be added if and when status improves.¹

Studies show that patients experi-ence improved response rates, depth of response, progression-free survival (PFS), and overall survival (OS) with triplet vs doublet regimens.¹ This is important in newly diagnosed MM because a deeper response, such as achievement of negative measurable residual disease (MRD), can improve long-term survival.²

The most common first-line triplet regimen for transplant-eligible candidates is RVd (lenalidomide [Revlimid; Bristol Myers Squibb], bortezomib [Velcade; Takeda Pharmaceuticals U.S.A.], and dexamethasone), with some institutions favoring other regimens such as KRd (carfilzomib [Kyprolis; Amgen], lenalidomide, and dexamethasone). For nontransplant candidates, the preferred up-front therapy is either RVd or Dara-Rd (dara-tumumab [Darzalex; Janssen Biotech], lenalidomide, and dexamethasone).³

As with other oncological diseases, it is common to add a targeted agent to the standard of care, such as rituximab (Rituxan; Genentech USA) targeting CD20 in lymphoma or midostaurin (Rydapt; Novartis) targeting FLT3 in acute myeloid leukemia. Targeted agents are also seeing increased use with MM treatment. Important targets in MM include CD38, SLAMF7, and BCMA, which are all highly expressed on MM plasma cells. There are multiple studies assessing quadruplet regimens as initial therapy in MM to determine whether a quadruplet regimen is better than a triplet regimen for treatment of patients with MM.³

GRIFFIN, a randomized phase 2 trial (NCT02874742), assessed adding daratumumab, an anti-CD38 monoclonal antibody (MAb), to frontline RVd (D-RVd) for transplant-eligible patients with newly diagnosed MM.³ For 4 cycles, trial patients received either D-RVd or RVd, followed by ASCT, then received D-RVd or RVd consolidation for 2 cycles, with maintenance therapy consisting of lenalidomide or lenalidomide plus daratumumab for 26 cycles.³ Stringent complete response (sCR) following consolidation was the primary end point, in which D-RVd vs RVd showed improved response after consolidation, 42% vs 32% (P = .068), respectively.³ After 22 months, this was statistically significant with D-RVd vs RVd showing sCR of 62.6% vs 45.4% (P = .018).³ During the trial, severe hematologic adverse effects (AEs) were observed to be common for this quadruplet regimen.³ Following publication of these study results, the regimen has been added to the National Comprehen-sive Cancer Network (NCCN) guidelines as an option for initial treatment in transplant-eligible patients.¹

At the American Society of Hematology (ASH) Annual Meeting and Exposition in 2021, updated results from GRIFFIN were presented with a median follow-up of 27.4 months. The data showed that results persisted and deepened at the follow-up point, and after 24 months sCR for D-RVd vs RVd was 66.05% vs 47.4% (P = .0096), respectively.⁴ MRD negativity was higher with D-RVd as well (35.6% vs 14.6%; P = .0007).⁴ This trial is ongoing and more time is needed to determine whether there will be a statistically significant PFS benefit.⁴ However, it is also not clear whether the long-term benefit will be driven from the quadruplet initial regimen or the doublet maintenance, which is not currently the standard of care.

The MASTER trial (NCT03224507) is a nonran-domized study assessing daratumumab added to KRd (Dara-KRd) followed by ASCT and then lenalidomide maintenance in transplant-eligible patients with newly diagnosed MM.⁵ The primary end point was MRD negativity, and 80% of patients achieved this at a median follow-up of 25.1 months.⁵ This trial will also assess whether patients can come off therapy after 2 consecutive MRD negative results, which could have significant impact on quality of life; the current standard of care has been ongoing maintenance therapy.⁵

Elotuzumab (Empliciti; Bristol Myers Squibb), a MAb directed against SLAMF7, is approved in the relapsed/refractory setting in combination with lenalidomide or pomalidomide (Pomalyst; Bristol Myers Squibb) plus dexamethasone. At ASH 2021, results were presented that showed the addition of elotuzumab to the RVd backbone did not result in improved outcomes in the frontline setting for transplant-eligible patients.⁶ The quadruplet regimen compared with RVd showed no difference in PFS, with the OS and AEs showing similar results.⁶

Another study presented at ASH 2021 added isatux-imab (Sarclisa; Sanofi-Aventis)—which is approved in the relapsed/refractory setting in combination with dexamethasone and either pomalidomide or carfilzomib—to RVd. This study is one of the first trials to use MRD as the primary end point in transplant-eligible patients with newly diagnosed MM.⁷ Isatuximab is a MAb directed at CD38 and differs from daratumumab in that it induces apoptosis of the MM cells more directly.⁸ The study met its primary end point and isatuximab plus RVd was superior to RVd alone.⁷ MRD negativity rates after induction for RVd were 35.6% and 50.1% for isatuximab plus RVd (odds ratio [OR], 1.83; 95% CI, 1.34-2.51; P < .001).⁷ The trial is ongoing, and PFS and OS have not been reported. However, serious AEs have been observed to be similar between the 2 groups.

In transplant-eligible patients with newly diagnosed MM, a quadruplet regimen has been added to the NCCN guidelines, known as D-VTd (daratumumab, bortezomib, thalidomide [Thalomid; Celgene).¹ The CASSIOPEIA trial (NCT02541383) randomized patients to bortezomib, thalidomide, and dexametha-sone (VTd) with or without daratumumab followed by ASCT in part 1 of the trial.⁹ This trial was conducted in Europe, where thalidomide is used more commonly. In the United States, lenalidomide is used to a greater extent than thalidomide, in part to avoid added toxicity of neuropathy with thalidomide combined with bortezomib. The primary end point of CASSIOPEIA was sCR 100 days after ASCT in which 29% of the D-VTd group vs 20% of the VTd group achieved sCR (OR, 16; 95% CI, 1.21-2.12; P = .0010). MRD negativity was also assessed, showing 64% in the D-VTd group vs 44% in the VTd group (P < .0001). In part 2 of the trial, maintenance therapy was analyzed with either observation or daratumumab, results of which demon-strated that daratumumab maintenance every 8 weeks for 2 years reduced risk of disease progression at a median follow-up of 35.4 months.¹⁰

Investigators are continually seeing improved response rates with novel therapies in MM. Whether quadruplet vs triplet regimens offer improved outcomes remains a question, but some studies have shown promising results in such comparisons. Quadruplets are becoming an option for patients with MM and hopefully time will determine which patients benefit most from these new regimens.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed February 3, 2022. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
2. Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160
3. 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
4. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 24 months of maintenance. Blood. 2021;138(suppl 1):79.
   doi:10.1182/blood-2021-149024
5. Costa LJ, Chhabra S, Callander NS, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. Final primary end point analysis of the Master trial. Blood. 2021;138(suppl 1):481. doi:10.1182/blood-2021-145494
6. Goldschmidt H, Mai EK, Bertsch U, et al. Elotuzumab in combination with lenalidomide, bortezomib, dexamethasone and autologous transplantation for newly-diagnosed multiple myeloma: results from the randomized phase III GMMG-HD6 trial. Blood. 2021;138(suppl 1):486. doi:10.1182/blood-2021-147323
7. Goldschmidt H, Mai EK, Nievergall E. et al. Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma patients: The phase III GMMG-HD7 trial. Blood. 2021;138(suppl 1):463. doi:10.1182/blood-2021-145097
8. Deckert J, Wetzel MC, Bartle LM, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014;20(17):4574-4583. doi:10.1158/1078-0432.CCR-14-0695
9. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1
10. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet. 2021;22(10):1378-1390. doi:10.1016/S1470-2045(21)00428-9

About the Author

Sarah Schmidt, PharmD, BCOP, is an oncology clinical specialist in malignant hematology and stem cell transplantation and the PGY2 oncology program director at the University of Oklahoma Health Stephenson Cancer Center.