14 CLINICAL STUDIES

14.1 Multiple Myeloma in Patients Who Have Received at Least One Prior Therapy

The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.

A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of NINLARO, lenalidomide and dexamethasone (N=360; NINLARO regimen) or the combination of placebo, lenalidomide and dexamethasone (N=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve). Twenty three percent (N=166) of the patients had light chain disease and 12% (N=87) of patients had free light chain-measurable only disease.

Thromboprophylaxis was recommended for all patients in both treatment groups according to the lenalidomide prescribing information. Antiemetics were used in 19% of patients in the NINLARO regimen and 12% of patients in the placebo regimen; antivirals in 64% and 60%, respectively, and antihistamines in 27% and 19%, respectively. These medications were given to patients at the healthcare provider's discretion as prophylaxis and/or management of symptoms.

Patients received NINLARO 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renal impairment received a starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities.

Table 6 summarizes the baseline patient and disease characteristics in the study. The baseline demographics and disease characteristics were balanced and comparable between the study regimens.

Table 6: Baseline Patient and Disease Characteristics
	NINLARO + Lenalidomide and Dexamethasone (N = 360)	Placebo + Lenalidomide and Dexamethasone (N = 362)
* Primary refractory, defined as best response of stable disease or disease progression on all prior lines of therapy, was documented in 7% and 6% of patients in the NINLARO regimen and placebo regimens, respectively.
Patient Characteristics
Median age in years (range)	66 (38, 91)	66 (30, 89)
Gender (%) Male/ Female	58/42	56/44
Age Group (% [<65/ ≥65 years])	41/59	43/57
Race n (%)
White	310 (86)	301 (83)
Black	7 (2)	6 (2)
Asian	30 (8)	34 (9)
Other or Not Specified	13 (4)	21 (6)
ECOG performance status, n (%)
0 or 1	336 (93)	334 (92)
2	18 (5)	24 (7)
Missing	6 (2)	4 (1)
Creatinine clearance, n (%)
<30 mL/min	5 (1)	5 (1)
30-59 mL/min	74 (21)	95 (26)
≥60 mL/min	281 (78)	261 (72)
Disease Characteristics
Myeloma ISS stage, n (%)
Stage I or II	315 (87)	320 (88)
Stage III	45 (13)	42 (12)
Prior line therapies n (%)
Median (range)	1 (1, 3)	1 (1,3)
1	224 (62)	217 (60)
2 or 3	136 (38)	145 (40)
Status at Baseline n (%)
Relapsed	276 (77)	280 (77)
Refractory*	42 (12)	40 (11)
Relapsed and Refractory	41 (11)	42 (12)
Type of Prior Therapy n (%)
Bortezomib containing	248 (69)	250 (69)
Carfilzomib containing	1 (<1)	4 (1)
Thalidomide containing	157 (44)	170 (47)
Lenalidomide containing	44 (12)	44 (12)
Melphalan containing	293 (81)	291 (80)
Stem cell transplantation	212 (59)	199 (55)
High risk (deletion (del) 17, t(4:14) and/or t(14:16)	75 (21)	62 (17)
deletion del (17)	36 (10)	33 (9)

The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results. Response was assessed every four weeks until disease progression.

The approval of NINLARO was based upon a statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in Table 7 and shown in Figure 1.

Table 7: Progression-Free Survival and Response Rate
	NINLARO + Lenalidomide and Dexamethasone (N = 360)	Placebo + Lenalidomide and Dexamethasone (N = 362)
NE: Not evaluable.
* Hazard ratio is based on a stratified Cox's proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen. † P-value is based on the stratified log-rank test.
Progression-free Survival
PFS Events, n (%)	129 (36)	157 (43)
Median (months) (95% CI)	20.6 (17.0, NE)	14.7 (12.9, 17.6)
Hazard Ratio* (95% CI)	0.74 (0.59, 0.94)
p-value†	0.012
Response Rate
Overall Response Rate, n (%)	282 (78)	259 (72)
Complete Response	42 (12)	24 (7)
Very Good Partial Response	131 (36)	117 (32)
Partial Response	109 (30)	118 (33)

The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in the placebo regimen for responders in the response evaluable population.

Figure 1: Kaplan-Meier Plot of Progression-Free Survival

A non-inferential PFS analysis was conducted at a median follow up of 23 months with 372 PFS events. Hazard ratio of PFS was 0.82 (95% confidence interval [0.67, 1.0]) for NINLARO regimen versus placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and 15.9 months in the placebo regimen.

At the final analysis for OS at a median duration of follow up of approximately 85 months, median OS in the ITT population was 53.6 months for patients in the NINLARO regimen and 51.6 months for patients in the placebo regimen (HR = 0.94 [95% CI: 0.78, 1.13]).

14.2 Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting

In C16019 (NCT02181413), newly diagnosed multiple myeloma patients who underwent autologous stem cell transplantation, continued on maintenance therapy for 24 months. There were 27% (105/395) deaths in the NINLARO arm compared with 26% (69/261) in the placebo arm. The hazard ratio for overall survival was 1.008 (95% CI: 0.744 - 1.367).

In C16021 (NCT02312258), newly diagnosed multiple myeloma patients, not treated with a stem cell transplant who achieved a partial response or better, continued on maintenance therapy for 24 months. There were 30% (127/425) deaths in the NINLARO arm compared with 27% (76/281) in the placebo arm. The hazard ratio for overall survival was 1.136 (95% CI: 0.853 - 1.514).

NINLARO is not recommended for use in the maintenance setting for multiple myeloma outside of controlled clinical trials [see Indications and Usage (1) and Warnings and Precautions (5.9)].

14.3 Lack of Efficacy in Patients with Newly Diagnosed Multiple Myeloma

Lack of efficacy in patients with newly diagnosed multiple myeloma was determined in a prospective randomized clinical trial.

In C16014 (NCT01850524), in newly diagnosed multiple myeloma patients, the study did not meet the prespecified primary endpoint for PFS. There were 136 (39%) deaths in the NINLARO, lenalidomide, and dexamethasone arm compared to 148 (42%) in the lenalidomide and dexamethasone arm. The hazard ratio for overall survival was 0.998 (95% CI: 0.79 - 1.261).

NINLARO is not recommended for use in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma outside of controlled clinical trials [see Indications and Usage (1)].