Triplets and Quadruplets Now Play Role in Transplant-Ineligible NDMM

Andrzej Jakubowiak, MD, PhD

Professor of Medicine

Director, Myeloma Program

UChicago Medicine

Chicago, IL

KEY TAKEAWAYS FROM ANDRZEJ JAKUBOWIAK, MD, PHD

1. Patients over 75 years old with newly diagnosed multiple myeloma (NDMM) are usually not eligible for transplant but their fitness as well as age should be considered.
2. Quadruplet therapies have been shown to be active and tolerated in these patients as well as younger patients.
3. National Comprehensive Cancer Network (NCCN) guidelines have recently been updated to include new preferred triplet and quadruplet options in both transplant-eligible and -ineligible patients.

CASE SUMMARY

• The patient is a 79-year-old man with a medical history of hypertension controlled with lisinopril​.
• He presented to his physician with complaints of back pain, fatigue, and occasional, but recurring dizziness, nausea, and constipation.​
• ECOG performance status: 1​
• Diagnosed with R-ISS [Revised International Staging System] stage 2/R2-ISS stage 3IgG-kappa multiple myeloma​

Targeted Oncology: What are your thoughts on the GEM2017FIT study (EudraCT 2017-000044-18) of carfilzomib (Kyprolis), lenalidomide (Revlimid) and dexamethasone (KRd) plus/minus daratumumab (Darzalex) vs bortezomib (Velcade), melphalan and prednisone, and is it relevant to this case because of this patient’s age?

Andrzej Jakubowiak, MD, PhD:This is an important study published recently [with a] protocol in which all the patients were [between 65 and 80 years old]. I agree that this regimen can potentially be a very active and well tolerated nontransplant regimen.

In this study and in some other studies, it has been shown that quadruplet regimens can be tolerated in older patients, and maybe, at least in this particular Spanish study, it is more effective than triplet regimens, so that's something that may play a factor in our decision making, which I hope over time we will evolve into discussing more.¹

What treatment considerations are there for this patient?

…This patient is most likely not a candidate for autologous stem cell transplant, although some people would argue a patient aged 79 with this performance status can still take transplant in our center. We don't have age as a limitation, but in many places, 75 or 70 years is the age factor. I've transplanted people as old as 80 years or older, but retrospectively, I have to say that I have become humbler in the context of age, because I've seen in these cases that age [was a factor] posttransplant. Not that they didn't tolerate it; they tolerated it OK, but they came out of the transplant, to some extent, not in as good shape as they were. I'm not as big a proponent of taking patients who are over 75 for the most part, and then they have to meet the criteria, so there is agreement.

But a discussion point is whether we should choose a triplet regimen—among them, Dara-Rd [daratumumab, lenalidomide, and dexamethasone] is one of the top choices—or quadruplet regimens. I would add to this point that at a number of meetings at the last American Society of Hematology committee where I was a participant, there was a very important point made by a few of my colleagues that maybe we are at the stage that we should be less focused on [whether] the patient is a transplant candidate vs nontransplant candidate. A different question is, is the patient quadruplet eligible vs non-quadruplet eligible.

Can you discuss the recent studies looking at quadruplet vs triplet combinations in newly diagnosed multiple myeloma?

I will review a number of key studies which have been recently presented or published. PERSEUS [NCT03710603]…is in transplant-[eligible] patients, and the results are outstanding for Dara-VRd [daratumumab, bortezomib, lenalidomide, and dexamethasone]. The progression-free survival [PFS] rate at 4 years is 84% [vs 67.7% for VRd] which is really [impressive], because it is the best result you have seen from randomized trials in the modern era, and clearly superior to triplets [HR, 0.42].²

A [study that was] a little bit under the radar, IsKia [NCT04483739], was with Isa-KRd [isatuximab (Sarclisa), carfilzomib (Kyprolis), lenalidomide, and dexamethasone], whereas PESEUS was Dara-VRd. It is a similar regimen that had a fantastic difference in terms of MRD [minimal residual disease], this was the primary end point at the end of consolidation [77% vs 67% for KRd].³ So it is potentially an alternative, maybe for high-risk patients. We'll see how it plays out once the study has more follow-up. But these are the top 2 contenders at the moment, because there is no randomized trial at this time with Dara-KRd, so Isa-KRd and Dara-VRd probably are also the best trials vs respective triplets.

The FDA recently [approved] Dara-VRd, and NCCN guidelines [updated it to category 1 preferred in September 2024].⁴ Isa-KRd is not yet approved [in the transplant-eligible setting]; the data are still not mature. There was an Oncology Drugs Advisory Committee meeting a few months ago, which unanimously voted to use MRD as a primary end point for 9 or 12 months, so to some extent, IsKia [could have] earlier...approval even before PFS [benefit] is read out, but at the moment they didn't get approval.

Until recently, VRd was the top choice [in transplant-ineligible patients]. Since MAIA [NCT02252172], there was a period of time where we have not known which one was better, but now we have data that by indirect comparison [with SWOG-0777 (NCT00644228)], from specific numbers, in terms of overall response rates and complete response rates, it appears that Dara-Rd is superior relative to VRd.⁵ These are key randomized trials which provide the basis for top choices in the NCCN guidelines for triplets in patients who are non-transplant candidates [Editor’s note: Isa-KRd was approved for use on September 20, 2024 and is also a preferred regimen in NCCN guidelines for non-transplant candidates.]

CASE UPDATE

• During consultation, the patient stated that he is the caregiver for his wife who has chronic rheumatoid arthritis.​
• After discussion, it was determined that it would not be feasible for him to receive autologous stem cell transplant.
• Dara-Rd induction therapy was initiated.​
• He achieved very good partial response post-induction therapy.

REFERENCES:

1. Mateos MV, Paiva B, Romero MTC, 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. doi:10.1182/blood-2023-179866

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. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized IsKia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/blood-2023-177546

4. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2025. Accessed October 2, 2024. https://tinyurl.com/54p5jtf7

5. Durie BGM, Kumar SK, Ammann EM, et al. Adjusted indirect treatment comparison of progression-free survival with D-Rd and VRd based on MAIA and SWOG S0777 individual patient-level data. Adv Ther. 2024;41(5):1923-1937. doi:10.1007/s12325-024-02807-y