Blood Cancers Today recently spoke with several clinicians familiar with the use of quadruplet regimens to find out more about how the new approach is changing the treatment landscape.
“Historical research on the treatment of newly diagnosed multiple myeloma (MM) has shown that “more tends to be better,” according to Nisha Joseph, MD, associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine.
“If we hit myeloma cells from different angles using different mechanisms of action,” Dr. Joseph said, “it often results in a better depth of response.”
This approach initially started with the use of doublets—typically immunomodulatory drugs—in combination with a steroid. The approach evolved to triplet regimens, which added proteasome inhibitors (PIs) to the mix.
In 2024, the National Comprehensive Cancer Network Clinical Practice Guidelines for MM included a quadruplet regimen—adding an anti-CD38 monoclonal antibody—as a category 1 recommendation and a preferred first-line option for patients with transplant-eligible or transplant-ineligible newly diagnosed MM.1
Building on Therapy
“MM is a clonally heterogenic type of disease,” explained Amrita Krishnan, MD, director of the Judy and Bernard Briskin Multiple Myeloma Center at City of Hope, Duarte, California. “The thought process is that if you use different drugs, you may be able to target different clones with varying sensitivity to each class of agent.”
“In addition to their varying targets, the other reason these classes of drugs seem to work well together is that they have non-overlapping toxicities … for the most part,” Dr. Krishnan said.
One of the first trials to tackle the question of quadruplet regimens was the phase II GRIFFIN trial. GRIFFIN tested consolidation with lenalidomide, bortezomib, and dexamethasone (RVd) with or without daratumumab followed by maintenance with lenalidomide with or without daratumumab in transplant-eligible newly diagnosed MM.2 At the end of post-transplant consolidation, stringent complete response rate favored daratumumab (42.4% vs 32.0%; P=.068), and with a longer median follow-up of about 22 months, it was significantly better with daratumumab (62.6% vs 45.4%; P=.0177). Measurable residual disease (MRD) negativity was also significantly improved.
These data were further confirmed by results from two phase III trials. The CASSIOPEIA trial, which tested bortezomib, thalidomide, and dexamethasone (VTd) with or without daratumumab before and after transplantation, showed improved depth of response and progression-free survival (PFS) with daratumumab.3
Most recently, the PERSEUS trial comparing VRd with or without subcutaneous daratumumab in transplant-eligible patients again confirmed the significant PFS benefit of adding daratumumab.4 These results led to the July 2024 FDA approval of the drug combination for transplant-eligible patients.
Uptake in Transplant-Eligible Population
“Following PERSEUS, I think a quadruplet regimen with RVd and an anti-CD-38 monoclonal antibody should be the standard of care for transplant-eligible patients,” Dr. Joseph said. “We have been using daratumumab-RVd since 2018.”
In fact, Dr. Joseph and colleagues recently published data from 326 patients at their institution who received induction therapy with daratumumab plus RVd with intent to transplant. The data showed a PFS benefit favoring the quadruplet regimens among standard- and high-risk patients; the 2-year PFS was 93% with daratumumab/RVd compared with 82% for RVd alone (P<.001). The 2-year overall survival was 94% with daratumumab/RVd compared with 91% without (P<.034). There was also improved depth of response favoring the addition of daratumumab.5
“Clinical trial populations aren’t always representative of the real world,” Dr. Joseph said. “Here we are seeing the benefit translate to a real-world setting; for that reason, we think it is the standard of care in this population, and we have been using it for a long time.”
Timothy Schmidt, MD, assistant professor of Hematology, Medical Oncology and Palliative Care at University of Wisconsin School of Medicine and Public Health, agreed that the use of quadruplet regimens in the transplant-eligible population is being broadly adopted, at least across the US.
“My vantage point as a myeloma specialist at an academic center may be different from other regions,” Dr. Schmidt said. “Here in the Midwest, I think perhaps there was a bit of a later uptake of quadruplet regimens compared to what was seen on the coasts, but over the last two to three years, there has been increasing utilization of quadruplet regimens in academic centers as well as in the community.”
Transplant-Ineligible Population
Transplant-ineligible patients are typically those who are older, frail, have poor performance status, or have high comorbidity burdens.6 However, there are now multiple phase III trials supporting the use of quadruplet regimens in this population as well.
Results of GEM2017FIT, presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, compared two experimental consolidation arms—carfilzomib, lenalidomide, and dexamethasone (KRd) with and without daratumumab—against bortezomib-melphalan and prednisone (VMP) followed by lenalidomide and dexamethasone (Rd) in transplant-ineligible patients. MRD negativity was highest in the daratumumab-KRd arm at 79%.7
The phase III CEPHEUS trial showed that daratumumab-VRd significantly improved MRD negativity, PFS, and complete response rate compared with VRd alone in patients “for whom transplant was not planned as initial therapy.”8
Finally, the international IMROZ trial randomly assigned 446 patients 3:2 to VRd with or without isatuximab. The estimated 5-year PFS was 63.2% with isatuximab-VRd, compared with 45.2% with VRd alone, a 40% reduction in the risk for progression or death with the quadruplet regimen (98.5% CI, 0.41-0.88; P<.001). Significantly more patients assigned to receive isatuximab achieved MRD negativity as well (55.5% vs 40.9%; P=.003).9
“The biggest difference between the regimens in these trials is the percentage of patients achieving not just a very good partial response but a complete response and MRD negativity,” Dr. Schmidt said. “We are seeing significantly higher rates in the groups of patients treated with a quadruplet regimen.”
Dr. Schmidt acknowledged that these studies can be hard to interpret as a group because of differences in ongoing use of one drug versus two drugs, as well as other differences; but overall, they indicate that patients treated with quadruplet regimens have not just better depth of response but also durability of response manifested as PFS.
Unlike the uptake of quadruplet regimens in transplant-eligible patients, the uptake in the transplant-ineligible population is more complicated, Dr. Krishnan and the others said.
“The uptake in the nontransplant–eligible population is likely still not over 50%,” Dr. Krishnan said. “Use of quadruplet regimens in the transplant-ineligible population is a more nuanced discussion that has to be based on a geriatric assessment and a risk-benefit discussion with the patient.”
Dr. Joseph agreed that quadruplet regimens are not yet the standard for all patients who are transplant ineligible, particularly not in community practices.
“I have gotten a lot of questions about it, but it is not yet routine,” Dr. Joseph said. “People are doing it in select patients, but not for everybody.”
Dr. Joseph has also discussed the use of a daratumumab-RVd “light” approach with community oncologists. This approach involves reducing the dose of the drugs to make the regimen more tolerable. This could mean reducing the dose of lenalidomide or bortezomib to only once a week or reducing the dose of steroid.
More Drugs, More Toxicities
Dose reduction may be necessary for some patients because there is always the concern that adding more drugs will result in more toxicity, Dr. Schmidt said.
“Myeloma is a disease that primarily affects older patients—with a median age at diagnosis of 70—and that could prove to be difficult from a tolerability standpoint,” he said.
It was for this reason that quadruplet regimens were first tested in the transplant-eligible population.
“What we found was that the addition of the anti-CD38 monoclonal antibody to the backbone treatment didn’t result in much more toxicity,” Dr. Schmidt said. “Patients didn’t feel that different, and, in fact, when studies reported on quality of life, it had improved.”
A meta-analysis of quadruplet regimens in the treatment of newly diagnosed MM found “light to no difference” in the rate of serious adverse events and a “slight increase” in the rates of grade 3 or 4 infections (relative risk, 1.22; 95% CI, 1.07-1.39) with quadruplet compared with triplet regimens. Quadruplets also appeared to be associated with increased risk for grade 3 to 4 neutropenia (risk ratio [RR], 1.81; 95% CI, 1.42-2.31) and grade 3 to 4 thrombocytopenia (RR, 1.30; 95% CI, 1.07-1.58). The authors also noted that “additional studies may be needed particularly among frail older adults.”10
“Daratumumab is an injection, so there may be injection site reactions,” Dr. Joseph said. “There is also a slightly increased rate of infections with daratumumab, but otherwise, the toxicities we see with the quadruplet tend to be more associated with the other agents in the regimen.”
In fact, if clinicians were going to limit treatment to a triplet regimen for some patients, one question that has been asked is whether the drug class to be eliminated should be the PI and not the newcomer anti-CD38 monoclonal antibody.
Bortezomib is associated with a higher risk for falls, Dr. Schmidt said, which can be devastating for older patients. An alternative PI, carfilzomib, carries an increased risk for cardiovascular side effects.
The phase III BENEFIT trial was designed to examine the question of eliminating the PI. The trial randomly assigned 270 transplant-ineligible patients to treatment with isatuximab lenalidomide and dexamethasone with (Isa-VRd) and without (Isa-Rd) weekly bortezomib.11 The primary endpoint of MRD negativity at 18 months was reported in 26% of patients assigned Isa-Rd compared with 53% assigned the quadruplet.
“In BENEFIT, the arm with bortezomib had more neuropathy, which was not a surprise,” Dr. Krishnan said. “That was, in part, why they used weekly bortezomib.”
Nuances
As with any clinical research, there are nuances to interpreting the data from the trials examining use of quadruplet regimens.
For example, in the IMROZ trial, Black patients were underrepresented, the trial only enrolled patients aged up to 80 years, and the majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.9 The CEPHEUS trial allowed only patients with a frailty score of 0 or 1 as classified by the International Myeloma Working Group (IMWG) frailty scale.12
Exclusion of older adults or frail patients means that use of quadruplet regimens in these populations is left to the discretion of the clinician. The IMWG frailty score is recommended to assess whether a patient is fit or frail, but Dr. Joseph said it is not often used in clinical practice.
“We often use clinical gestalt or experience,” Dr. Joseph said. “We discuss functional status, if the patient can climb stairs, can walk a couple of miles, if their comorbidities are managed, if they have a history of heart disease.”
There has also been some research looking into whether transplant is still necessary for transplant-eligible patients who achieve deep and durable responses to therapy.
“If you ask this question to 10 MM specialists who are also transplanters, you will get a variety of answers,” Dr. Schmidt said.
“We have been asking this question for 20 years with the introduction of each new class of drugs,” he said. “The studies have been done over and over again, and the answer remains the same, even with the addition of new drugs, if you incorporate autotransplant you are going to have a better PFS, better rates of MRD negativity, and depth of response.”
However, Dr. Schmidt admitted that the field may be closer to the point at which the use of transplant could be more tailored, when studies could look at deferring transplant for patients with standard-risk disease who achieve MRD negativity after initial therapy.
Another question being asked is whether the use of chimeric antigen receptor (CAR) T-cell therapy will replace stem cell transplant. The answer is still unknown, according to Dr. Joseph. In the ongoing phase III EMagine/CARTITUDE-6 trial, daratumumab-VRd followed by ciltacabtagene autoleucel (cilta-cel) followed by lenalidomide will be compared with daratumumab-VRd followed by autotransplant, daratumumab-VRd, and lenalidomide in the treatment of newly diagnosed MM.13
In addition to these nuances, there are also inherent challenges associated with administering (or receiving) a quadruplet regimen.
“One challenge might include logistics of adding more drugs,” Dr. Schmidt said. “That said, adding the anti-CD38 antibody doesn’t add any extra visits really, maybe one or two over the course of the first six months.”
When quadruplets were first incorporated into treatment algorithms, Dr. Joseph noted that insurance coverage could sometimes be a challenge.
“Now though, I see about 30 to 40 new patients with MM per year, and I can think of one or two examples where insurance came back with questions,” Dr. Schmidt said. “It is becoming more of a nonfactor, especially as more long-term data back up their use.”
Finally, although cost is something that clinicians don’t consider when making day-to-day decisions in the clinic, it can’t be entirely ignored.
In a piece published before the widespread use of these regimens, Vincent Rajkumar, MD, wrote that the addition of daratumumab would create quadruplet regimens “that could cost in excess of $300,000 to $500,000 per year.”14
A more recent study looking at data from GRIFFIN and CASSIOPEIA estimated that first-line daratumumab used with RVd or VTd was cost-effective for transplant-eligible MM when considering improved outcomes.15 However, the long-awaited availability of a generic form of lenalidomide has not turned out to be the cost-saving event anticipated because the generic form is “volume-limited” until 2026.16
“There is no question that by adding drugs we are increasing the cost of care,” Dr. Schmidt said. “We need to find ways to reduce those costs either by limiting how long patients are treated or bringing down the cost of drugs by other measures.”
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple myeloma. Version 1.2025 — September 17, 2024. Accessed December 16, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
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.
3. 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.
4. 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.
5. Joseph NS, Kaufman JL, Gupta VA, et al. Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients. Blood Cancer J. 2024;14(1):159. doi:10.1038/s41408-024-01120-9.
6. Grant SJ, Mian HS, Giri S, et al. Transplant-ineligible newly diagnosed multiple myeloma: current and future approaches to clinical care: a Young International Society of Geriatric Oncology Review Paper. J Geriatr Oncol. 2020;12(4):499-507.
7. Mateos M-V, Paiva B, Cedena Romero MT, et al. GEM2017FIT trial: induction therapy with bortezomib-melphalan and prednisone (VMP) followed by lenalidomide and dexamethasone (Rd) versus carfilzomib, lenalidomide and dexamethasone (KRd) plus/minus daratumumab (D), 18 cycles, followed by consolidation and maintenance therapy with lenalidomide and daratumumab: phase III, multicenter, randomized trial for elderly fit newly diagnosed multiple myeloma (NDMM) patients aged between 65 and 80 years. Blood. 2023;142(suppl 1):209-211.
8. Johnson & Johnson. DARZALEX FASPRO®-based quadruplet regimen significantly improves minimal residual disease negativity for newly diagnosed multiple myeloma patients for whom transplant is not planned. September 27, 2024. https://www.jnj.com/media-center/press-releases/darzalex-faspro-based-quadruplet-regimen-significantly-improves-minimal-residual-disease-negativity-for-newly-diagnosed-multiple-myeloma-patients-for-whom-transplant-is-not-planned
9. Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609.
10. Ebraheem MS, Chakraborty R, Rochwerg B, et al. Quadruplet regimens for patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis. Blood Adv. 2024;8(23):5993-6002.
11. Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nature Med. 2024; 30:2235-2241.
12. Zweegman S, Facon T, Hungria V, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide and dexamethasone (VRd) versus alone in patients with transplant-ineligible newly diagnosed multiple myeloma or for whom transplant is not planned as initial therapy: analysis of minimal residual disease in the Cepheus trial. Blood. 2024;144(suppl 1):362.
13. Broijl A, San-Miguel J, Suzuki K, et al. P23 EMagine/Cartitude-6: a randomized phase 3 study of DVRD followed by ciltacabtagene autoleucel versus DVRD followed by autologous stem cell transplant in transplant-eligible patients with newly diagnosed multiple myeloma. Hemasphere. 2023;7(suppl):22-23.
14. Rajkumar SV. Value and Cost of Myeloma Therapy. American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology;2018. https://doi.org/10.1200/EDBK_200867
15. Yamamoto C, Minakata D, Koyama S, et al. Daratumumab in first-line is cost-effective in transplant-eligible newly diagnosed myeloma patients. Blood. 2022. doi:10.1182/blood.2021015220
16. Beechinor RJ, Mohyuddin GR, Mitchell DE, Aaron D, Mahmoudjafari Z. The story of the development of generic lenalidomide: how one company thwarted the Waxman-Hatch Act to generate billions of dollars in revenue. J Cancer Policy. 2023;38:100446. doi:10.1016/j.jcpo.2023.100446
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