Carfilzomib weekly 20/56 mg/m<sup>2</sup> , lenalidomide and dexamethasone for early relapsed refractory multiple myeloma
Authors: Valentine Richez, Cecile Gruchet, Stephanie Guidez, Guillemette Fouquet, Isabelle Azais, Geraldine Durand, Vincent Javaugue, Antoine Brigaud, Florent Plasse, Jéremie Diolez, Antoine Machet, Niels Moya, Helene Gardeney, Paul Franques, Arthur Bobin, Anthony Levy, Florence Sabirou, Anthony Bonnin, Celine Dieval, Sylvain Primault, Jocelyn Barrier, Emmanuel Fleck, Sabrina Bouyier, Claire Daras, Isabelle Princet, Delphine Bauwens, Laurence Legros, Jean‐Gabriel Fuzibet, Angela Gil, Frank Bridoux, Hervé Avet‐Loiseau, Xavier Leleu
Journal: American Journal of Hematology (2018)

Triplet-based lenalidomide plus dexamethasone combinations have become a new standard of care for early relapsed refractory multiple myeloma (RRMM),1 improving the outcome of MM over the past 15 years. Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively and irreversibly to the constitutive proteasome and immunoproteasome.2 Carfilzomib has been approved in combination with dexamethasone or lenalidomide plus dexamethasone for patients with RRMM, based on Endeavor and Aspire phase 3 studies.3, 4 In either study, Carfilzomib was given twice a week infused over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28 days based cycle, at 20/56 mg/m2 and 20/27 mg/m2, respectively. Although active and overall safe, including on the long run, the twice a week scheme is very cumbersome to patients. We hypothesized that carfilzomib plus lenalidomide/dexamethasone (KRd) on a weekly basis, with three visits per 28-days' cycle but using a more intense dosing at 20/56 mg/m2, maintained dose intensity although at a reduced dose density scheme, and was far less inconvenient to patients. The aim of this study was to evaluate the efficacy and toxicity of carfilzomib weekly plus lenalidomide/dexamethasone regimen in early RRMM. We have recruited 28 RRMM and measurable disease who had received more than one prior treatment. Patients exposed sensitive or refractory to bortezomib were eligible. Patients previously treated with lenalidomide and dexamethasone were eligible so long as they did not discontinue therapy because of adverse effects or progression. Patients received KRd until disease progression or until occurrence of unacceptable toxic effects. Carfilzomib was administered as a 30-minute infusion on days 1, 8, 15 (starting dose, 20 mg/m2 on day 1 of cycle 1; target dose, 56 mg/m2 thereafter). Lenalidomide (25 mg) was given on days 1 through 21. Dexamethasone (20/40 mg) was administered on days 1, 8, 15, 22. During infusion carfilzomib, intravenous hydration was limited at 250 mL. Patients had to control their blood pressure every day during the first cycle of KRd; antihypertensive treatment could be prescribed in case of hypertension. Patients received antiviral and antithrombotic prophylaxis. Treatment responses and disease progression were assessed according to the International Myeloma Working Group Uniform Response criteria.5 For patients who achieved a complete response, minimal residual disease measurement was studied by next-generation sequencing (sensitivity level 10−6, Pr Avet-Loiseau, Oncopole Toulouse, France). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Statistical analyses were performed with SPSS v.22 (SPSS Inc., Chicago, IL, USA). The median age was 64 years (range 45-80 years) with 14% of patients older than 70 years. 57% of patients were male and 36% had prior cardiac history. Patient's characteristics are presented in Supp Table 1. The median of previous lines of therapy before KRd line was 1 (range 1-3). The median number of KRd cycles received was 15.5 (range 1-23), and patients were on carfilzomib for a median of 17 months (range 1-24 months). The ≥ VGPR rate was 75% (n = 21), with ≥ CR rate in 35.7% (n = 10) (Supporting Information Table S2). MRD was negative at 10−6 in 6/7 studied RRMM all of them PET CT normalized, the latter being negative by flow cytometry at 10−5. With a median follow up of 19.5 months, the median duration of response (≥ PR) is 12 months (range 1-20 months), and 12 (43%) patients had more than 15 months duration, including patients in CR and particularly MRD negativity. At the time of data cutoff, 10 (35%) patients have relapsed, 4 (14%) died and 3 more (10%) patients had clinically significant adverse event responsible for the interruption of the treatment. The median PFS and OS survivals are not reached, and the 26 months-projected rates are 62.7% and 85.2%, respectively (Figure 1A,B). The median EFS, which end-points are relapse or death or any adverse event of particular significance that would be responsible for the permanent interruption of the studied treatment, is 20 months with 46.7% of patients event free at 26 months. We further observed that depth of response had a significant impact on either median PFS or OS survivals. The responders had a median PFS and OS not reached vs 3 and 9.3 months for the nonresponders, respectively. The 26 months-expected PFS and OS were at 69.3% and 91.3%, respectively (P = .036 and .017). The responders had a median OS not reached, vs 9.3 months for non-responders, and a 26 months-expected survival at (Figure 1C,D). We anticipated a lower impact of KRd in high-risk RRMM given the lack of dose density by having a weekly design, despite the increased dose intensity. We first analyzed the patients with high risk determined by cytogenetic markers (n = 7), del17p and/or t(4;14). The median PFS was 17 months (IC95% 7;27) for the high-risk group, and not reached otherwise, expected at 26 months at a rate of 67%. The median OS for the 2 groups was not reached and expected above 70% at 26 months (Figure 1E,F). We then considered high-risk any patient with presence of either high-risk cytogenetic or ISS 3 (n = 11, 39%). The median PFS remained 17 months for the high-risk group, and expected at a rate of 73% at 26 months for the nonhigh-risk group. The median OS for the 2 groups was not reached and expected above 70% at 26 months. Interestingly, the median PFS and OS were similar across groups with EMD (n = 8) or without, 75% and 87.5% (P = ns), respectively (data not shown). We have also studied the impact of KRd weekly according to the time from the start of the last line prior to KRd to the start of KRd; considering the patients with <1 year as carrying a poor prognosis. Interestingly, we noticed that the projected PFS at 26 months was 68.4% and 75% in patients with longer vs short interval between lines (P = ns). Similarly, we have observed no difference in median and estimated 26 months PFS, and OS, according to exposure to lenalidomide or not, 65% and 60% for PFS (P = ns), and 83% and 86% for OS (P = ns), respectively. In multivariate analysis for survival, it seemed that prolonged exposure to KRd weekly, favored by the more convenient weekly K administration, allowed a prolonged treatment exposure in RRMM and possibly improved the survival of these patients. Indeed, ability to obtain a response (ORR, ≥PR; HR 0.017 [0.002-0.171], P = .001) for PFS, and depth of response (≥VGPR; HR 13.2 [2.1-82.9], P = .006) were the only variables identified for PFS and OS, respectively; and none of the other variables related to any prognostication. Although all patients experienced some adverse events, mainly hematological, rarely greater than grade 2, 3 (10%) patients had significant adverse event responsible for the interruption of the treatment. No patient died related to adverse events. Adverse events are listed in Supporting Information Table S3. Of note, no patient experienced any severe cardiovascular adverse event and one patient required an increase of antihypertensive treatment on carfilzomib. The benefit of carfilzomib lies into the rescue carfilzomib brings to bortezomib-exposed/refractory RRMM, but also from that a dose intense and dense approach can be proposed to patients compared to bortezomib. One would anticipate that trying to administer carfilzomib at a once a week schedule might improve the long run exposure and the quality of life but at the cost of the dose density and therefore lesser activity. In our study we demonstrated that dose intensity could compensate for dose density with KRd on a weekly basis but using carfilzomib on a greater dose intensity to compensate for the loss of dose density, a unique dose concentration possibility given by carfilzomib across proteasome inhibitors. The treatment appeared manageable, and in a certain extent much more manageable for certain AEs of interest including cardiovascular AEs. This data was similar to Aspire data, and confirmed triplet-based carfilzomib combinations better than doublet regimens as a whole 3, 4. These data are confirmed, although indirectly, by the phase 3 ARROW study of once-weekly carfilzomib regimen at 70 mg/m2, that demonstrated superior efficacy with a median PFS of 11.2 months compared to 7.6 months for those treated with the twice-weekly carfilzomib regimen (HR = 0.69, 95%CI, 0.54-0.88), and comparable safety.6 One important aspect of the treatment of myeloma is to improve the treatment paradigm of high-risk myeloma (HR), whatever high-risk definition applies. We found that weekly 20/56 mg/m2 KRd performed well, but to a lesser extent to HR than other RRMM.3, 4 In conclusion, we demonstrated that KRd 20/56 mg/m2 on a weekly basis, with 3 visits per cycle at 56 mg/m2 rather than 6 visits at 27 mg/m2 at hospital, was far less inconvenient to patients and reported superior health-related quality of life. It allowed managing triplet-based regimen on a very safe run, particularly anticipating patients will have prolonged exposure to carfilzomib, likely up to progression. Further studies are warranted to confirm this data on a larger MM population, and study cost effectiveness. CRCs. Fanny Biais Sauvetre, Myriam Pansard, Marie Thibaud; Transplant Coordinator. Laurie Charleux, Evelyne Maury, Coraline Emambux; Secretary. Claudine Decourchelle, for their contribution to the study. All authors read and approved the final version of this manuscript. Conception and design: VR, CG, XL. Conduction of Trial: VR, CG, GF, SG, IA, GD, VJ, AB, AP, JD, AM, NM, HG, PF, AB, AL, FS, AB, CD, SP, JB, EF, SB, CD, IP, DB, LL, JGF, AG, FB, HAL, XL. Collection and assembly of data: VR, CG, GF, SG, IA, GD, VJ, AB, AP, JD, AM, NM, HG, PF, AB, AL, FS, AB, CD, SP, JB, EF, SB, CD, IP, DB, LL, JGF, AG, FB, HAL, XL. Data analysis and interpretation: VR, CG, XL, SG. Article writing: VR, CG, XL. XL received honorarium from Janssen, Celgene, Amgen, Novartis, Takeda, Sanofi, Merck, BMS, Pierre Fabre, Karyopharm, Abbvie, Gilead, Roche, Mundipharma, Incyte. TABLE S1. Characteristics of the patients at baseline (n = 28) TABLE S2. Treatment responses of the patients at baseline (n = 28) TABLE S3. Adverse events, grade ≥ 3, n(%).* Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.