Predictors of Second-Line Treatment Choice with Triplet Therapy in Routine Care Among Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Romanus Dorothy , Jhaveri Mehul , Labotka Richard , Henk Henry , Seal Brian 
Published: October 2019

Abstract
Background
Beginning with the IFM 2005-04/MMVAR trial, three-drug combinations (TCs) have demonstrated superior clinical outcomes compared with two-drug regimens among patients with RRMM (Garderet JCO 2012). TCs are emerging as the standard of care at first relapse. We assessed factors that influenced treatment choice with TCs in a cohort of patients with RRMM who were managed in routine care.
Methods
We identified adult patients with MM between January 2008 and February 2014 in a large, national, US healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed patients were followed from the first claim with an ICD-9 code for MM (with a 12-month wash-out period). To ensure completeness of claim history, patients with continuous enrollment from 12 months pre-diagnosis through at least initiation of second-line therapy (SLT) for RRMM were included. Those with claims for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 months of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 months between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with a treatment gap of >3 and up to 6 months after end of FLT, or 3) a switch to another drug combination after FLT regimen. The first claim for SLT was the index date. SLT ended at the earliest of: start of a new drug, death, or end of study period (February 2014). Patients were grouped into those receiving one-/two-(1-2) vs three-/four-drug (3+) combinations based on the number of unique cancer therapy agents received within the start and end date of SLT. A logistic multivariable model was used to identify factors independently associated with receipt of 1-2 vs 3+ SLT regimens.
Results
Baseline characteristics among 249 RRMM patients on SLT are shown in Table 1 according to receipt of 1-2 vs 3+ SLT regimens. Among 62 patients who initiated SLT in 2013-14, 14 (23%) received a 3+ SLT regimen (vs 19 (10%) prior to 2013). Adjusting for gender and CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone disease), predictors of 3+ SLT included: younger age (<65 years), early relapse (time to next therapy [TTNT], interval from start of FLT to start of SLT, <6 months), 3+ agents in FLT and index year of SLT initiation (in 2013-14). Charlson Comorbidity Index (CCI) was not independently associated with receipt of 3+ SLT.
Conclusions
A majority of patients do not receive triplet-based SLT in routine care. Younger age, and not comorbidity status, appears to be the discriminatory patient characteristic for triplet therapy choice. Introduction of triplets with a favorable toxicity profile and assessment for comorbidity status in routine practice represent steps towards optimizing treatment choices in RRMM.
Table 1. Baseline Characteristics among Patients with RRMM According to SLT Type (N=249) N (%) Monotherapy/Doublet (1-2) (N=216) Triplet/Quadruplet (3+) (N=33) Total (N=249) TTNT <6 months 44 (20.4%) 14 (42.4%) 58 (23.3%) ≥6 months 172 (79.6%) 19 (57.6%) 191 (76.7%) Age, years <65 53 (24.5%) 17 (51.5%) 70 (28.1%) 65-74 64 (29.6%) 8 (24.2%) 72 (28.9%) ≥75 99 (45.8%) 8 (24.2%) 107 (43%) Male 105 (48.6%) 16 (48.5%) 121 (48.6%) CCI 0 60 (27.8%) 10 (30.3%) 70 (28.1%) 1 52 (24.1%) 3 (9.1%) 55 (22.1%) 2+ 104 (48.1%) 20 (60.6%) 124 (49.8%) CRAB symptoms 147 (68.1%) 26 (78.8%) 173 (69.5%) Number of agents in FLT regimen 1-2 147 (68.1%) 12 (36.4%) 159 (63.9%) 3+ 69 (31.9%) 21 (63.6%) 90 (36.1%)
Table 2. Predictors of 3+ SLT in RRMM (N=249) Odds Ratio (OR) for 3+ vs 1-2 SLT (95% CI for OR) Age, years <65 65-74 ≥75 3.10 1.36 Reference (1.13 - 8.51)* (0.45 - 4.09) - Male 1.13 (0.51 - 2.51) Index year 2008-2012 ≥2013 Reference 3.42 - (1.42 - 8.21)** TTNT, months ≥6 <6 Reference 2.54 - (1.05 - 6.17)* CRAB symptoms at baseline 1.69 (0.63 - 4.58) CCI 0 1 2+ Reference 0.41 0.98 - (0.10 - 1.62) (0.39 - 2.46) Number of agents in FLT regimen 1-2 3+ Reference 2.77 - (1.20 - 6.42)* *significant at 5%; **significant at 1%

Disclosures
Romanus: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.