Data Show Efficacy for Triplet and Quadruplet Regimens in Transplant-Ineligible Multiple Myeloma

David H. Vesole, MD, PhD, director, Myeloma Program MedStar Georgetown University Hospital, professor of Medicine at Georgetown University in Washington, DC and codirector, Myeloma Division, and director, Myeloma ResearchJohn Theurer Cancer Center at Hackensack University Medical Center, discussed the case of a 82-year old patient with transplant-ineligible multiple myeloma.

Targeted Oncology^TM: What are the approved regimens to treat this patient with multiple myeloma who is ineligible for transplant in the first-line setting, and what do you consider from a toxicity standpoint?

VESOLE: The NCCN [National Comprehensive Cancer Network] guidelines have a lot of options: VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone], DRd [daratumumab (Darzalex), lenalidomide, dexamethasone], Rd [lenalidomide, dexamethasone], CyBorD [bortezomib, cyclophosphamide, dexamethasone].1 I sometimes use Rd in patients with high-risk disease who are older and frail or can’t come in. Then there’s DVMP [daratumumab, bortezomib, melphalan (Alkeran), prednisone]. This is oral melphalan—transplant melphalan—with DVMP, which is FDA approved.^2,3 Daratumumab plus CyBorD is FDA approved for amyloidosis.^4,5 This is to prove to you that triplets are better than doublets.

A SWOG [Southwest Oncology Group S0777 (NCT00644228)] trial published a few years ago studied VRd versus Rd, and then after 8 cycles of therapy patients went on maintenance therapy with Rd—not lenalidomide alone.^6,7

How did these patients do on the triplet compared with the doublet in the SWOG S0777 study?

In non–transplant eligible patients [who just received diagnoses], the triplet beats the doublet. The median PFS [progression-free survival] was 41 months [with VRd] versus 29 months [with Rd] [HR, 0.742; 96% CI, 0.594- 0.928; P = .003].⁷

This was true even for patients over the age of 65 [HR, 1.27; 95% CI, 1.00-1.61; P = .048]. The [median] OS [(overall survival) for VRd] was not reached versus 69 months with a hazard ratio of 0.709 [95% CI, 0.543-0.926; P= .0114]. It’s a 30% improvement in the decrease of disease progression and survival in patients who had VRd versus Rd, and younger patients did better than older [patients]. SWOG S0777 was done with VRd, but it was [IV] intravenous bortezomib, not subcutaneous.⁸ A third of the patients had grade 3 painful, debilitating neuropathy. This is given twice a week, on days 1, 4, 8, and 11, with IV bortezomib.

Are there more recent data in this setting?

A trial that just came out, called the BOSTON trial [NCT03110562], studied bortezomib, selinexor [Xpovio], and [dexamethasone]; in that trial, they gave the bortezomib once a week.9 That’s the only FDA-approved indication for once-weekly bortezomib, even though if I do a poll, probably three-fourths or all of you only give the bortezomib once a week. It was not FDA approved to do that until just recently. In December 2020, BOSTON trial data were approved of giving [bortezomib] once a week.¹⁰ But before that, the standard of care in all of the trials was [bortezomib given] on days 1, 4, 8, and 11. When you give that much bortezomib, and you give it subcutaneously, you can have severe neuropathy. Grade 3 sensory neuropathy and pain are much higher with the triplet versus the doublet.

So, what about modifying it? Giving the bortezomib once a week is one of the VRd or VRd-lite regimens. There are a couple of them out there. This [modified VRd-lite regimen, termed VRd-28] is given on days 1, 8, 15, and I’ve seen 1, 8, 15, 22.11 VRd-28 is lenalidomide given on days 1 through 21; I’ve seen lenalidomide on days 1 through 14 for VRd-lite, and dexamethasone is given on the day of the bortezomib. This is just to [investigate]: Can you give less bortezomib? Can you give it subcutaneously? The answer is yes. The overall response rate [with VRd-28] was 87%, the VGPR [very good partial response] was 63%. So, yes, you can get by with less bortezomib and on a different schedule than the standard [regimen]. [Peripheral] neuropathy, even [with subcutaneous bortezomib] once a week, was still 38%. This is important when [considering] the study of KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone] versus VRd.^12,13

How does carfilzomib play a role for transplant-ineligible patients?

The [ENDURANCE (NCT01863550)] trial was recently presented and published.^12,13 They wanted to do an up-front trial for non–transplant-eligible patients comparing bortezomib versus carfilzomib. It’s VRd versus KRd, and this is giving KRd twice a week. You can now give carfilzomib once a week, and you can give it with lenalidomide once a week. A paper we recently published showed efficacy of 97% giving KRd once a week.¹⁴ [In the ENDURANCE trial, they studied] VRd versus KRd, then maintenance therapy with [lenalidomide].^12,13 They found there was no difference in PFS of KRd versus VRd. It was identical between the 2. However, a couple of caveats: Caveat 1, the rapidity of response was quicker with KRd versus VRd. Second caveat, the KRd group had deeper responses. PFS was the same, but the VGPR rate was 65% [with VRd (95% CI, 61%-69%)] versus 74% [with KRd (95% CI, 70%-77%; P = .015)]. So you had faster and deeper responses with KRd, even though the PFS was the same.

Neuropathic toxicities were more common with VRd. Subcutaneous [bortezomib] was given [on days] 1, 4, 8, and 11.12,13 Any-grade peripheral neuropathy was 53% with VRd compared with 24.4% with KRd [P < .001]. Severe [grade 3] neuropathy was 8% with VRd [vs 0.8% with KRd]. There’s no doubt [that] even giving it subcutaneously, patients get neuropathy. That’s the downside of bortezomib.

What about carfilzomib? If you give it for an extended [duration], the likelihood of cardiopulmonary and renal [toxicity], not just cardiac alone, [is significantly higher], 16% [with KRd] versus 5% [with VRd; P < .001]. There’s no doubt that you get more toxicity over an extended [duration] with KRd versus VRd. I personally give all my patients KRd. This is an opinion; I give them all KRd [because] I cannot stand neuropathy. To this day I don’t know how to fix neuropathy after I’ve tried gabapentin or duloxetine. Narcotics, as far as I can tell, are how to manage peripheral neuropathy. In my patients, when I give them KRd, because I transplant all of them, they only get 2 to 4 cycles. We essentially never see cardiopulmonary or renal toxicity when you give short courses of KRd. I’m aware that the cardiopulmonary renal toxicity cumulatively is substantially higher. If you give shorter courses of it, it’s much lower, and it’s tolerated better than the peripheral neuropathy.

What data have been shown with daratumumab combinations?

[Another option is DRd, which was done in the MAIA trial (NCT02252172)].15,16 It was a large trial, 737 patients, DRd versus Rd, 1:1 randomization for non–transplant-eligible patients with a median age of 73. The 48-month PFS rate was estimated to be 60% for the triplet versus 38% [for Rd]; hazard ratio was 0.54 [95% CI, 0.43-0.67; P < .0001].^15-17 It’s a far superior regimen to give the DRd versus the Rd; the triplet beats the doublet.

When you look at the OS, it’s only a 2-year follow-up; there’s no difference. For the depth of response, stringent CR [complete response] was 34% [with the triplet] versus 14% [with the doublet (P < .0001)]. MRD [minimal residual disease] negativity was 31% [with DRd] versus 10% [with Rd (P < .0001)]. There’s no doubt that DRd is superior to Rd. The [projected] PFS with a median follow-up at 4 years is 60% versus 38%, and it’s not age dependent. Essentially, across the board, the DRd beats the Rd; even for the high [cytogenic]-risk group, [those with at least 1 high-risk abnormality], the hazard ratio [for DRd] is 0.57 [95% CI, 0.33-1.00] versus 0.48 for Rd [95% CI, 0.38-0.62].^16,17

As I alluded to before, when you give daratumumab plus [lenalidomide], you get more neutropenia and thrombocytopenia. Grade 3 and 4 neutropenia was 50% [with DRd] versus 35% [with Rd alone].15,16 You have to watch for neutropenia and a bit of thrombocytopenia. The rest of the toxicities are comparable across the board. Infusion reactions [of any grade] in the MAIA trial were seen in 41% [of the participants receiving DRd, but only 3% were grade 3 or 4]. Grade 3 [or higher reactions are] extremely rare in infusion reactions, and they’re almost always just the first infusion—after that it goes away.

How do all the trials you have discussed compare in efficacy?

[There were increased CR rates with combination therapies.] [In SWOG S0777, the CR rate with VRd was] 24% versus 12% with Rd; it’s twice as likely to get CRs.⁷ With VRd-lite [CR rate was 24%] and it causes less toxicities.18 In the ALCYONE [trial (NCT02195479)], when you give daratumumab as a quadruplet with VMP, [the CR rate is 46% versus 25% with VMP alone].^19,20 [In the MAIA trial], the DRd triplet versus doublet [yielded a CR rate of] 51% versus 34%.¹⁷ Across the board we see superior outcomes with combinations versus doublets, and particularly when you add a fourth drug and make it a quadruplet.

For those of you who are elotuzumab [Empliciti] fans, they did a trial of elotuzumab plus VRd versus VRd alone, and there was no advantage of elotuzumab and VRd versus VRd.21 Elotuzumab is approved in the relapse [setting] with [lenalidomide] and with pomalidomide [Pomalyst], but when you give it up front as a quadruplet, elotuzumab plus VRd did not improve outcomes.^21,22

[Another consideration is that] patients always hate dexamethasone. We have 5%, maybe 10% [of patients, where] it gets rid of their arthritis and gives them a sensation of well-being. But 90% of the patients hate dexamethasone. We never, until this time, did a trial of looking at lenalidomide with dexamethasone or without dexamethasone.²³ The EMN01 trial [NCT01093196] studied elderly patients with new diagnoses who were given an induction regimen with Rd. Everyone got Rd standard dosing, except for the dexamethasone, [which] was decreased because of age, for 9 cycles. Then it was randomized after 9 cycles to continue Rd or to [switch to] lenalidomide alone. It was randomized to see if you could drop the dexamethasone. The answer is that you can drop the dexamethasone. When you give Rd continuous versus Rd followed by single-agent lenalidomide, the PFS is a wash. The hazard ratio is 0.93 [95% CI, 0.64- 1.34; P = .681]. The OS is not statistically significant, with a P value of .306 [HR, 0.73; 95% CI, 0.40-1.33]. Yes, you can ultimately drop the dexamethasone and end up with the same outcomes.

In your practice, what is the most common reason for discontinuation of therapy?

A lot of times safety concerns or second cancers; intolerance to toxicity, particularly with lenalidomide; diarrhea and fatigue are big issues. Most of the patients can find financial coverage by some ways or means. Patient preferences—they just don’t want to be on drugs, or something else.

[I’ve been asked about subcutaneous daratumumab [(Darzalex Faspro) versus the IV daratumumab.] The COLUMBA [(NCT03277105) trial studied] relapse or refractory multiple myeloma using a single-agent daratumumab; it was to prove a point.20 It was subcutaneous daratumumab at 1800 mg versus the IV [at 16 mg/kg], both given on the same exact schedule that you’re familiar with. Response rates were identical, 41% versus 37% [odds ratio, 1.11; 95% CI, 0.89-1.37], but the infusion reactions were 34% [for the IV route] versus 13% with the subcutaneous [route] [odds ratio, 0.28; 95% CI, 0.18- 0.44; P < .0001]. Efficacy was the same.

[About] 99% of our patients are on subcutaneous [regimens]. We still have about 1% who are on IV who say, “Well, why should I change it? Because I’m doing fine on this.” There are some financial considerations about daratumumab, and the other thing that I didn’t cover is isatuximab [Sarclisa], another anti-CD38 monoclonal antibody.²⁴ It only comes in an IV formulation now, but it’s the same anti-CD38 monoclonal antibody. We’ve got 30% using it, and 50% think they’re going to use it, and the other 20% are not convinced.

What has your experience been with COVID-19 for your patients with myeloma? Has it affected your practice?

One, [patients are] opting for oral therapy over IV. This is a moving target because a lot of our patients are in the process of getting vaccinated. How well they get vaccinated—and immunized, I should say—is a complete unknown. There’s no one in the world who can tell you that a patient with multiple myeloma off therapy generates a good antibody response.

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_{12. 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}

_{13. Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. Abstract presented: 2020 American Society of Clinical Oncology Annual Meeting. J Clin Oncol. 2020;38(suppl 18). doi:10.1200/JCO.2020.38.18_suppl.LBA3}

_{14. Alsina M, Landgren O, Raje N, et al. A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Am J Hematol. 2021;96(2):226-233. doi:10.1002/ajh.26041}

_{15. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132(suppl 1):LBA-2. doi:10.1182/blood-2018-120737}

_{16. 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}

_{17. Kumar SK, Facon T, Usmani SZ, et al. 2276 updated analysis of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 Maia study. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 6, 2020; virtual. Accessed May 14, 2021. https://bit.ly/2S65BJG}

_{18. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230. doi:10.1111/bjh.15261}

_{19. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3}

_{20. 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}

_{21. Usmani SZ, Hoering A, Ailawadhi S, et al; SWOG1211 Trial Investigators. Bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in patients with untreated, high-risk multiple myeloma (SWOG-1211): primary analysis of a randomised, phase 2 trial. Lancet Haematol. 2021;8(1):e45-e54. doi:10.1016/S2352-3026(20)30354-9}

_{22. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811- 1822. doi:10.1056/NEJMoa1805762}

_{23. 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}

_{24. Sarclisa. Prescribing information. Sanofi-Aventis; 2021. Accessed May 16, 2021. https://bit.ly/2RkvXbc}