Progression-Free Survival in Third-Line Treatment of Relapsed/ Refractory Multiple Myeloma Among Patients with Who Have Received Prior Bortezomib and Immunomodulatory Drugs

Background: There are limited data on real-world treatment outcomes for novel agents used in the treatment of relapsed/refractory multiple myeloma (RRMM). These data are particularly important for patients who have already received bortezomib (BTZ) and an immunomodulatory drug (IMiD) given the lack of a standard of care in 3^rd line and the costs of novel therapies including lenalidomide (LEN), carfilzomib (CFZ) and pomalidomide (POM).

Methods: Data including patient and disease characteristics, treatment information and mortality data were collected from electronic medical records. RRMM patients diagnosed between 01/2007-08/2014 having received at least three treatment regimens (not including maintenance) were selected from the International Oncology Network (ION) database. Treatment regimens were aggregated into 8 mutually exclusive categories. Progression-free survival (PFS), based on physician reported date of progression, was calculated by treatment regimen overall and for the subgroup of patients who had prior BTZ and IMiD exposure. A multivariate proportional hazard model was used to estimate the risk of progression or death in the subgroup adjusting for age, gender, race, year of diagnosis, ISS stage, presence of cytogenetic abnormality, immunoglobulin type, receipt of stem-cell transplant (SCT), ECOG status and comorbidities at diagnosis.

Results:  There were 391 patients that met inclusion criteria. Mean age at diagnosis was 68 years, 46.9% being ISS III and 55.5% were classified as IgG.  Median duration of follow-up was 36.1 months with 45% of patients being deceased by the end of follow-up.  SCT information was available for 218 patients: 25.2% were deemed ineligible, 46.8% received an SCT and 28% of eligible patients had no evidence of receiving a SCT. BTZ and an IMiD were received by 239/391 (61.1%) patients prior to 3^rd line. PFS in 3^rd-line for the overall study population and the subgroup are presented in Table 1.  For the subgroup, the median PFS in 3^rd-line among regimens with at least 10 patient was: BTZ monotherapy ± non-IMiD – 7.3 months; LEN monotherapy or ± non-proteasome inhibitor (PI) – 4.9 months; BTZ + IMiD – 7.3 months; CFZ monotherapy ± IMiD –  3.7 months; and POM monotherapy ± PI – 5.8 months. Although not statistically significant, risk of progression or death after adjustment for baseline demographic and clinical characteristics was lower for BTZ + IMiD and other chemotherapies  and higher for LEN monotherapy or ± non-PI, CFZ monotherapy ± IMiD and POM monotherapy ± PI compared to BTZ mono ± non-IMID (Table 1).

Conclusions: These data are the first recent real-world treatment outcomes in RRMM. For BTZ-, LEN-, and POM- containing regimens, PFS was non-significantly shorter in 3^rd-line for those patients with prior BTZ and IMiD treatment compared to the overall study population. For the subgroup, the results of the multivariate proportional hazards model showed no significant difference in the risk of progression or death in 3^rd-line for patients with prior BTZ and IMiD therapy compared to other treatment regimens. As such, there remains a significant unmet need for novel treatment regimens which significantly improve PFS for the subgroup of patients who have received prior treatment with both BTZ and an IMiD.  

Table 1

	Overall		Patients with prior BTZ and IMiD¥
3rd – Line Treatment Regimen	N	PFS (95% CI)	N	PFS (95% CI)	HR	p-value
BTZ mono ± non-IMID	128	9.1 (7.1 – 10.9)	69	7.3 (4.2 – 10.8)	REF	-
LEN mono ± non-PI	88	7.0 (4.7 – 10.6)	45	4.9 (3.0 – 8.6)	1.23	0.43
BTZ + IMID (thalidomide or lenalidomide)	59	9.4 (5.3 – 12.3)	39	7.3 (5.0 – 15.0)	0.84	0.55
THAL mono ± non-PI	12	8.5 (1.4 – 16.4)	7	9.8 (0.1 – 50.4)	0.94	0.89
MEL mono ± non-IMiD, non-PI	19	8.3 (3.4 – 13.2)	7	3.4 (0.6 – NR)	1.16	0.78
MEL + THAL	5	25.2 (0.7 29.4)	4	25.2 (0.7 – 29.4)	*	*
CFZ mono ±IMID / Other †	37	3.6 (2.6 – 8.4)	34	3.7 (2.8 – 8.4)	1.13	0.68
POM mono ± PI / Other	17	9.6 (1.6-13.8)	15	5.8 (1.4 – 13.8)	1.18	0.68
Other Chemotherapies	26	5.6 (2.1 -13.3)	19	7.9 (1.9 – 14.0)	0.95	0.87

¥ Steroids (dexamethasone or prednisone) may have been given in conjunction with any of the therapies per usual standard of care.

† Includes patients treated with combination CFZ + POM.

* Patients combined with “Other Chemotherapies” in model.

Key: BTZ – bortezomib; CI – confidence interval; CFZ – carfilzomib; IMiD – immunomodulatory drug; LEN – lenalidomide; MEL – melphalan; NR – not reached; PI – proteasome inhibitor; POM – pomalidomide; THAL – thalidomide.