A Phase II Study of the Efficacy and Safety of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RVD) Combination Therapy for Patients with Newly Diagnosed Multiple Myeloma: Promising Activity and Manageable Toxicity, Including in High Risk Disease
Authors: Laubach Jacob , Yee Andrew J , Rosenblatt Jacalyn , Matous Jeffrey V , Farber Charles M. , Openshaw Thomas H. , Maegawa Rodrigo O. , Tsai Michaela L. , Ghobrial Irene M. , Bianchi Giada , Rawal Bhupendra , Dipietro Heidi , Cummings Kristen , Harran John , O'Gorman Peter , Scott Kathleen , Fitzpatrick Kathleen , Abovich Jennifer , Baker Hannah , Savell Alexandra , Hansen Joshua , Richardson Paul 
Published: October 2019

Abstract
Introduction:
Patients (pts) with newly diagnosed multiple myeloma (MM) are commonly treated with the standard of care combination of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex), also known as RVD. A recent randomized phase 3 study found that the addition of Bz to Len and Dex significantly increased median overall and progression free survival as well as response rate (Durie et al. Lancet 2017). Mild to moderate peripheral neuropathy (PN) is commonly reported with Bz use, although lower rates of PN have been reported with subcutaneous (SC) administration of single agent Bz compared with IV Bz (Moreau et al. Lancet Oncol 2011). Here we present preliminary results of a multi-center, open-label, single arm phase II trial of Len, SC Bz, and Dex in pts with newly diagnosed MM. Maintenance was risk-stratified, with high risk patients (defined as those with high risk cytogenetics (del17p, t(4:14), t(14;16)) or ISS stage II or III) receiving Bz in addition to Len. Primary endpoints included 1) overall response rate (ORR) after 4 induction cycles, 2) best response to induction therapy, and 3) rate and severity of PN during induction therapy.
Methods:
Patients enrolled in this study were newly diagnosed with active MM as defined by the revised IMWG criteria (Rajkumar et al. Lancet Oncol 2014). Protocol specified induction treatment consisted of 21-day cycles with Len 25 mg on days 1-14, SQ Bz 1.3 mg/m2 days 1, 4, 8, and 11, and Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Stem cell mobilization followed induction cycle 4 and patients subsequently proceeded to either high dose melphalan and autologous stem cell transplant (ASCT) or 4 additional cycles of induction therapy based on patient preference with provider input. Following ASCT or completion of the 8th induction cycle pts proceeded to risk-stratified maintenance therapy. Maintenance consisted of 28-day cycles of therapy with Len on days 1-21 for all patients, while those pts defined as high-risk also received SC bortezomib Bz on days 1 and 15. Patients remained on maintenance therapy until progression, unacceptable toxicity, or withdrawal from protocol-directed treatment. Response was based on the IMWG uniform criteria (Rajkumar et al. Lancet Oncol 2011) and toxicities were graded based on the NCI-CTCAE V4. Correlative samples of blood and bone marrow for genomics and proteomics were collected from baseline and then throughout the study, and are currently being analyzed.
Results:
Forty-five pts were enrolled across 8 US sites between December 2015 and June 2017. Median age at enrollment was 61 years (range: 43 to 79) and 60% of the patients were male, 40% female. FISH cytogenetics found del 17p in 8% of pts tested, t(14;16) in 9%, and t(4;14) in 14%. At baseline, 60% of pts were ISS II/III. High risk pts comprised 62% of the study population overall. 80% of pts (36/45) collected stem cells and 31% of pts (14/45) continued to ASCT. The median number of CD34+ stem cells collected was 9.67 x 10^6. The median number of induction cycles completed was 8 (1 to 8 cycles) and 43 of 45 pts were evaluable for the primary endpoint of response after 4 induction cycles, with preliminary results indicating an ORR of 91% (39/43). Three pts did not reach the end of cycle 4 and 1 patient had stable disease. ORR at any point up to the beginning of maintenance was 98% (42/43). Any grade PN was reported by 80% of patients, including 38% with grade 1 and 36% with grade 2 PN. There were two cases of Grade 3 PN and one case of Grade 4 PN. Among the three patients with Grade ≥ 3 PN, symptoms improved to Grade ≤ 2 with dose reduction, modification of treatment schedule, or discontinuation of Bz. Importantly, given the higher than expected rate of all and high-grade PN, hydration with IV normal saline 500-1000 ccs prior to Bz administration as part of supportive care in selected patients was instituted and a comprehensive evaluation of the impact of this intervention on PN is in process.
Conclusions:
The combination of RVD with SC Bz is a highly effective treatment regimen for patients with newly diagnosed MM, including high risk pts. However, rates of all- and high-grade PN were greater than expected despite the use of SC Bz. Prompt dose reduction and/or change in schedule of Bz administration to weekly administration is recommended, with careful attention to supportive care in order to further improve tolerability.

Disclosures
Rosenblatt: Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Farber:Charles M. Farber, MD, PhD, LLC-Medical legal consulting: Consultancy; Gilead: Honoraria; Genentech: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; ummit Medical Group-MD Anderson Cancer Center: Employment; BeiGene: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Speakers Bureau; Acerta: Research Funding. Ghobrial:Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.