Daratumumab Forms Backbone of Triplet Regimens in Transplant Ineligible Multiple Myeloma

David H. Vesole, MD, PhD, director of the Myeloma Program MedStar Georgetown University Hospital, and professor of Medicine at Georgetown University in Washington, DC, discussed triplet regimens used for the treatment of transplant ineligible multiple myeloma during a Targeted Oncology Case-Based Roundtable event.

Targeted Oncology^TM: What are the first-line options recommended by the National Comprehensive Cancer Network (NCCN) for patients with multiple myeloma who are not eligible for transplant?

VESOLE: There are a variety of regimens available for patients in the NCCN guidelines.1 Particularly in older, frailer people that you don’t want to have to come into the clinic multiple times a month for either bortezomib [Velcade], darolutamide [Darzalex], or similar drugs—they are still rare individuals—I’ll give Rd [lenalidomide (Revlimid) and dexamethasone] so they only have to come in once a month, for [the sake of convenience]. These are the different regimens, including IRd [ixazomib (Ninlaro), lenalidomide, and dexamethasone] for this [setting]. There’s no daratumumab plus IRd regimen. IRd is approved for lines 1 to 3, but it’s listed in the NCCN [guidelines] for frontline use. If you really want to give a proteasome inhibitor, lenalidomide, and dexamethasone as an all-oral regimen, you can do that based on the NCCN guidelines.

What factors do you take into account when determining therapy for patients?

The different issues that you think about and how you decide what treatment to give include age; efficacy, although all these regimens have efficacies that exceed 70%; and convenience: Can the patients get back and forth to the clinic? Do they have caregivers to get them back and forth to the clinic? We’re dealing with patients who are transplant ineligible. Cost is not something to be ignored. Medicare covers these drugs, but their co-pays can be astronomical. There are a number of different places to get financial assistance for the patients. It’s a rare patient [for whom] I can’t find a way to get drugs...based on financial need.

Genetic risks [are also a factor]. Daratumumab helps with the high-risk patients. Most of the studies still show that proteasome inhibitors work better for high-risk patients than immunomodulatory drugs do. So that’s certainly a consideration.

[Physicians have to think about] comorbidities such as kidney function. [Many] of the drugs in this setting can be administered in patients with renal insufficiency. Lenalidomide has to be dose modified; daratumumab, bortezomib, carfilzomib [Kyprolis], dexamethasone, pomalidomide [Pomalyst], and cyclophosphamide all do not need to be dose adjusted. The only one that you really have to be concerned about dose adjusting for renal insufficiency is lenalidomide.

How do doublet and triplet therapies compare?

On occasion, for the convenience of the patient, I’ll give a doublet, but the standard of care across the board is triplet therapy except for specific case scenarios, such as an elderly patient who can’t get back and forth. We could substitute VRd [bortezomib, lenalidomide, and dexamethasone] for IRd.

SWOG S0777 [NCT00644228] was a trial of 3 drugs versus 2 drugs [VRd vs Rd] for 8 cycles; then patients went on Rd maintenance.2 The triplet beat the doublet; the median progression-free survival [PFS] was 41 months versus 29 months, respectively [HR, 0.742; 96% CI, 0.594- 0.928; P = .003].³

Overall survival [OS] was difficult to interpret because this is frontline therapy. I don’t like OS Kaplan-Meier curves, particularly in frontline therapy. It doesn’t mean much to me.

The grade 3 adverse events [AEs] severe neuropathy—was 33% versus 11% [with the triplet vs the doublet].² This was twice-a-week therapy intravenously, but [neuropathy was] still substantial. Even if you change this regimen to subcutaneous [delivery] once a week, it’s still in the 20% to 25% range of getting significant neuropathy. Lenalidomide causes gastrointestinal problems, and when you add bortezomib to it, it’s worse [22% vs 8%, respectively].

What is the role of modified VRd in this space?

VRd lite is a made-up regimen, [but] there are some data to support it. There is a paper on VRd lite, giving bortezomib on days 1, 8, and 15—not 1, 8, 15, and 22—once weekly subcutaneously.4 Lenalidomide was [given] on days 1 through 21, although most people... on VRd lite [who get referred to me] were only getting 14 days of lenalidomide. And there are different recipes. Dexamethasone should be given [on days] 1, 8, 15, and 22. You should give the dexamethasone every time lenalidomide is given.

The response rate to VRd lite with a 28-day cycle was 87%. It does work. Peripheral neuropathy was 11.6% at baseline and 38.2% after 4 cycles.

Which other triplets have been looked at for patients with multiple myeloma?

There was the ENDURANCE trial [NCT01863550] of KRd [carfilzomib, lenalidomide, and dexamethasone] versus VRd that came out at the 2020 American Society of Clinical Oncology Annual Meeting.⁵

The OS data [are] too immature [to evaluate], but the PFS [rates] for KRd and VRd were a wash. The PFS Kaplan-Meier curves were virtually superimposable [HR, 1.04; 95% CI, 0.83-1.31; P = .74]. When the investigators looked at the depth of response and the rapidness of response, KRd was better than VRd. The PFS didn’t change. The likelihood of a deeper response was seen with KRd, and the response rate, as far as how many weeks of therapy [until response], was shorter in KRd versus VRd.

Any-grade peripheral neuropathy was 53.4% [with VRd] versus 24.4% [with KRd], a 30% higher rate of peripheral neuropathy. Severe neuropathy, grade 3, was 8% versus 1%, respectively. I’ve been working in the myeloma setting for 30 years; I still do not know the best way to manage peripheral neuropathy. Peripheral neuropathy is the downside for VRd.

The downside for KRd was the cardiac, pulmonary, and renal AEs combined, at 16.1% [with KRd] versus 4.8% [with VRd]. There is no doubt that patients get more cardiac problems with carfilzomib than with bortezomib. Grade 4 [cardiac, pulmonary, and renal AEs were] 2.5% versus 0%, really not much different. To me, the question [concerns] the trade-off: cardiac, pulmonary, and renal AEs versus peripheral neuropathy. I only give 2 or 3 cycles of KRd in my patients who are transplant eligible. This trial allowed transplant. We almost never see the cardiac toxicity in 2 or 3 cycles. Therefore, I don’t use bortezomib.

My preference, even after this trial, is still KRd. There were a couple of other problems with this trial. They only allowed for [translocation (4;14)]. They didn’t allow high-risk patients in this trial. So it wasn’t really a good overview of the entire population of patients with multiple myeloma.

How has daratumumab been evaluated in this setting?

The MAIA trial [NCT02252172] looked at DRd [daratumumab, lenalidomide, and dexamethasone] versus Rd.⁶ A number of [participants] picked DRd [in the poll], 38%.

This trial was for transplant-ineligible patients. The 48-month PFS rate was 60% versus 38% [for DRd vs Rd, respectively]. The hazard ratio was 0.54 [95% CI, 0.43- 0.67; P < .0001]. DRd was far more efficacious. The stringent complete response rate was 34% versus 14%. Minimal residual disease negativity was [observed in] 31% versus 10%. DRd was superior to Rd.

There was a 46% improvement in PFS. High-risk groups don’t [have as good efficacy] as the standard-risk groups. When you look at the high-risk group as study entry for MAIA, 48 of patients receiving DRd [and 44 receiving Rd] had high-risk disease. Efficacy still favors the DRd, but the hazard ratio is not much different from what it is with the standard risk: 0.57 versus 0.48. There wasn’t a lot of impact on high-risk disease with the addition of daratumumab versus Rd alone—though daratumumab in itself is not a fantastic drug for high-risk patients.

In this case, I really would like to give a proteasome inhibitor to the high-risk patients versus just DRd. You have to pick and choose based on the patient’s demographics and decide how you want to handle that.

Any-grade neutropenia was 57% versus 42% [for DRd versus Rd, respectively]. It’s higher in grade 3 to 4, 50% versus 35%. Daratumumab can cause more problems. When you look at the other parameters, [there are] potential infusion reactions, which almost go away completely with subcutaneous daratumumab. Secondary malignancy was similar between the 2 regimens. The likelihood of dying from a treatment-emergent complication was also similar. The main safety profile issue was neutropenia.

How does maintenance therapy affect the patients’ survival?

Once patients started maintenance therapy on some of these trials, like the SWOG S0777 trial, it was given continuously. They got VRd for 8 cycles versus Rd for 8 cycles; then they went on Rd for an indefinite period of time.²

A trial in Europe looked at if patients need dexamethasone.⁷ Can patients get by with lenalidomide alone versus with dexamethasone? The trial was of 200 older individuals with new diagnoses. Everyone received induction with Rd; then they randomized the patients after 9 cycles to either Rd continuous or lenalidomide alone.

The answer is that you can drop the dexamethasone. You’ll make your patients extraordinarily happy. The PFS was identical whether the patient stayed on the doublet or got lenalidomide alone after 9 cycles of therapy.

What do you think of these poll results?

There’s a concern of secondary malignancies. It increases the risk about 4% to 5% over baseline if a patient goes on lenalidomide after a transplant. Financial risks are a problem with people that have high co-pays. There’s no doubt about that whatsoever.

Intolerance is usually fatigue and diarrhea. These are certainly the most common reasons for intolerance of toxicity.

Is there a difference between using subcutaneous and intravenous (IV) daratumumab?

Darzalex Faspro [subcutaneous daratumumab] was investigated in the COLUMBA trial [NCT03277105].⁸ It was comparing the subcutaneous formulation versus the IV, and it was a large phase 3 trial with over 500 patients; this led to the approval. [Both were given on the] same exact schedule.

This was given to patients with relapsed or refractory disease as a single agent. This wasn’t a combination. This was just to prove that subcutaneous was not inferior to IV. There was a 37.1% response rate [with IV] versus a 41.1% response rate [with subcutaneous].

My practice has switched 98% of our patients to subcutaneous daratumumab. We still have a few people that either think it’s fun to chat with the nurses when they get their IV or they think that if IV is working fine, why would they want to change it? But we’ve changed 98% of our practice to the subcutaneous formulation.

For our first [subcutaneous dose], we’re watching the patients for 4 hours. The median time to reaction is 3 to 3.5 hours. We watch them for 4 hours the first time they get it, 2 hours the second week they get it, and after that, we just give them their injection, watch them for 15 minutes, and send them out. We give the IV premedications for the first 2 [times], and then we switch them to everything oral—usually just the Tylenol and steroids—give them their shot, and let them go out the door.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 6.2021. Accessed April 20, 2021. https://bit.ly/3x8THip}

_{2. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stemcell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X}

_{3. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase 3 trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/ s41408-020-0311-8}

_{4. Rodriguez C, Lantz J, Akbar F, Lantz L, Dressler E. Assessing efficacy and tolerability of a modified lenalidomide/bortezomib/dexamethasone (VRd-28) regimen using weekly bortezomib in multiple myeloma. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA.}

_{5. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6}

_{6. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249}

_{7. Bringhen S, D’Agostino M, Paris L, et al. Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial. Haematologica. 2020;105(7):1937- 1947. doi:10.3324/haematol.2019.226407}

_{8. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370-e380. doi:10.1016/S2352-3026(20)30070-3}