Weekly Carfilzomib Quadruplet Induces High Rates of MRD Negativity, PFS in Newly Diagnosed Myeloma

C. Ola Landgren, MD, PhD

The quadruplet combination comprised of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D) was linked with high rates of minimal residual disease (MRD) negativity and progression-free survival (PFS) in patients with newly diagnosed multiple myeloma, according to data from the nonrandomized phase 2 MANHATTAN trial.¹

Results, which were published in JAMA Oncology, a MRD negativity rate (10-5 sensitivity in the bone marrow) of 40% or higher following up to 8 cycles of the weekly combination was achieved by 71% of 41 patients (n = 29; 95% CI, 54%-83%), meeting the primary end point of the trial. Moreover, the median time to MRD negativity was 6 treatment cycles (range, 1-8).

Additionally, the 4-drug regimen elicited an overall response rate of 100% (n = 41) and a very good partial response or complete response rate of 95% (n = 39). For individual patients, the response achieved with the regimen was noted to deepen over time. At a median of 11 months of follow-up, the 1-year PFS rate with the combination was 98% (95% CI, 93%-100%), while the 1-year overall survival (OS) rate was 100%.

“In this nonrandomized clinical trial of patients with newly diagnosed multiple myeloma, weekly KRd-D combination therapy was associated with unprecedented high rates of MRD negativity by itself,” lead study author C. Ola Landgren, MD, PhD, of Myeloma Service, Department of Medicine, at Memorial Sloan Kettering Cancer Center (MSKCC), and colleagues, wrote in the paper. “Indeed, we found that 71% of the patients achieved MRD negativity (primary end point of the trial), and therefore the trial is deemed successful.”

To date, clinical guidelines for the first-line treatment of patients with newly diagnosed multiple myeloma call for combination treatment, with or without high-dose melphalan chemotherapy and autologous hemopoietic cell transplant (HDM-AHCT), followed by maintenance treatment.

The combination of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) was introduced to the National Comprehensive Cancer Network guidelines as category 2A evidence in 2008.^2-4 Since then, the triplet has become the most frequently used regimen in the United States for this population.^5,6 Following data from the SWOG S0777 trial (NCT00644228), which compared VRd with Rd alone and showed that the triplet improved PFS and OS, the regimen was upgraded to category 1 evidence in the guidance.⁷ For those who are not undergoing HDM-AHCT, the 3-drug regimen has been shown to produce a median PFS of 50 months.⁷ However, when used with HDM-AHCT, the combination has a 4-year OS rate of 81%.⁸

The addition of daratumumab to VRd in patients with newly diagnosed multiple myeloma who underwent HDM-AHCT was investigated as part of the phase 2 GRIFFIN trial (NCT02874742) and results showed that MRD negativity was achieved in 51% of patients in the intent-to-treat population who received 4 cycles of daratumumab plus VRd, 1 round of HDM-AHCT, and an additional 2 cycles of daratumumab/VRd.⁹

For the nonrandomized phase 2 MANHATTAN trial, investigators set out to evaluate whether the addition of daratumumab to weekly 56-mg/m2 dosing of carfilzomib and Rd would result in high rates of MRD negativity in the absence of HDM-AHCT, and to establish the safety profile of the regimen.

The single-center trial was conducted at the MSKCC and patients were enrolled between October 1, 2018 and November 15, 2019. Key inclusion criteria required that patients be at least 18 years of age, have newly diagnosed multiple myeloma defined via International Myeloma Working Group criteria, and have an ECOG performance status of 0 to 2. Patients who had known underlying cardiac disease and/or clinically significant cardiac abnormalities identified during pretreatment assessment were excluded.

Study participants had a median age of 59 years (range, 30-70), with 29% of patients aged 65 years or older. The majority of patients, or 61%, were female. Additionally, 51% had an ECOG performance status of 0, while 49% had a status of 1. Fifty-one percent of patients had standard cytogenetic risk, while 29% were determined to be high risk.

Moreover, 49% of patients (n = 20) had a high-risk fluorescence in situ hybridization or single-nucleotide variant signature that was defined by 1 or more abnormalities, such as 1q+, t(4;14), t(14;16), t(14;20), and/or 17p-.

All patients received the following weekly KRd-D schedule: 28-day cycles of intravenous (IV) carfilzomib at 20/56 mg/m2 on days 1, 8, and 15; oral lenalidomide at 25 mg on days 1 through 21; and oral or IV dexamethasone at 40 mg on a weekly basis for cycles 1 through 4 and 20 mg after cycle 4. Daratumumab was given intravenously at 16 mg/kg on days 1, 8, 15, and 22 for cycles 1 and 2; days 1 and 15 for cycles 3 to 6; and day 1 of cycles 7 and 8. Treatment was given for a total of 8 cycles.

After cycle 8, each patient received counseling to proceed with standard-of-care treatment. Some participants were given up-front HDM-AHCT followed by maintenance therapy, while others delayed HDM-AHCT and proceeded directly to maintenance treatment. The latter group were largely comprised of those who achieved MRD negativity with the quadruplet regimen.

Notably, investigators optimized the amount of IV fluids given during combination treatment to decrease the risk of volume overload, which could lead to congestive heart failure, pulmonary edema, and other complications. Only 250 mL of saline was given before cycle 1 dose 1 of carfilzomib. No additional IV fluids were given per the trial protocol for the 8 cycles of treatment, unless a direct medical reason required this. The protocol also called for standard thromboprophylaxis, which was based on each patient’s risk profile.

All patients completed treatment and their end-of-treatment assessments. The median follow-up from treatment initiation was 20.3 months (95% CI, 19.2-21.9).

Additional data from subgroup analyses revealed that the rate of MRD negativity did not significantly differ between those with high- vs standard-risk disease (odds ratio [OR], 1.7; 95% CI, 0.36-8.6; P = .50). No significant difference in MRD status and age was reported either (less than 60 yrs vs 60 years or older; OR 0.48; 95% CI, 0.08-2.3; P = .32).

Of 29 patients who had MRD negativity at the end of treatment with the quadruplet, 1 patient experienced disease progression 9 months later. Of the 29 patients, 8 have been evaluated for MRD at 1 year of follow-up; 88% of these patients (n = 7) demonstrated sustained MRD negativity at this time point.

The participant who converted from MRD negative to positive at 1 year of follow-up was reported to have maintained complete response to treatment in the peripheral blood without onset of clinical symptoms; the patient continued to received maintenance treatment.

Regarding safety, the most frequently experienced grade 3 or 4 adverse effects (AEs) with the 4-drug regimen included neutropenia (27%), rash (9%), lung infection (7%), and increased alanine aminotransferase level (4%).

One patient who had a normal echocardiogram at baseline went on to experience chest discomfort and cardiac catherization which indicated evidence of coronary disease during the trial. This patient was diagnosed with acute coronary syndrome, and so they withdrew consent and continued to receive treatment with standard-of-care therapy. Notably, no patients experienced peripheral neuropathy that was grade 3 or higher in severity.

Forty percent of patients (n = 18) reported infusion-related reactions to daratumumab, but all cases were grade 2. All participants who reported these reactions experienced them during the first infusion. None of these reactions resulted in treatment discontinuation. Serious toxicities associated with study treatment were reported in 18% of patients (n = 8) and most of these cases were lung infections (7%).

Moreover, 45 dose reductions were needed for 41 patients. Most of these reductions were with regard to lenalidomide (n = 17) and dexamethasone (n = 22). A total of 2 patients discontinued treatment; 1 did so because of a new malignant neoplasm in the form of lung carcinoma and the other did so because of COVID-19. None of the patients died during the trial.

To build off of these results, the investigators have launched the large randomized multicenter ADVANCE trial (NCT04268498), which is comparing weekly KRd-D with current standard-of-care therapy for patients with newly diagnosed multiple myeloma; the trial is open for enrollment.

References

1. Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. Published online April 15, 2021. doi:10.1001/jamaoncol.2021.0611
2. Engelhardt M, Terpos E, Kleber M, et al; European Myeloma Network. European Myeloma Network recommendations on the evaluation and treatmentof newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2):232-242. doi:10.3324/haematol.2013.099358
3. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37(14):1228-1263. doi:10.1200/JCO.18.02096
4. Moreau P, San Miguel J, Sonneveld P, et al; ESMO Guidelines Committee. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv52-iv61. doi:10.1093/annonc/mdx096
5. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119(19):4375-4382. doi:10.1182/blood-2011-11-395749
6. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-686. doi:10.1182/blood-2010-02-268862
7. 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 stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X
8. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750
9. 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