Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data

Figures & data

Figure 1. Study design. Abbreviations. LOT, line of therapy; MM, multiple myeloma; TC, triple-class refractory.

Figure 2. Summary of similarities and differences in the determination of refractory status and TCR identification criteria for Algorithms 1-4 using IMWG-derived progressions (a) and HCP-reported progressions (b). Abbreviations. HCP, healthcare provider; IMWG, International Myeloma Working Group; N/A, not applicable; TCR, triple-class refractory.

Figure 3. Patient examples of application of Algorithms 1–4 for TCR identification. Patient example 1 (a) and patient example 2 (b).

Table 1. Summary of algorithms for TCR identification.

Algorithm	IMWG Progressions	HCP Progressions
Algorithm 1 Refractory status was identified using both IMWG- and HCP-reported progressions as recorded in the COTA database	Refractory to all therapies in all regimens in the associated LOT	Refractory to all therapies in the regimen discontinued due to progression
Algorithm 2 Refractory status identified using only IMWG progressions as recorded in the COTA database	Refractory to all therapies in all regimens in the associated LOT	Not considered
Algorithm 3 Refractory status identified using both IMWG and HCP progressions with the modified definition of progression-associated regimens	In a given LOT, refractory only to therapies in regimens occurring before or at the time of progression	Refractory to all therapies in the regimen discontinued due to progression
Algorithm 4 Refractory status identified using both IMWG and HCP progressions with a modified attribution of progression-associated LOT	Based on the reported time of progression, the progression may be re-attributed to a different LOT. Refractory to all therapies in regimens in the attributed LOT that occurred before or at the time of progression.	Refractory to all therapies in the regimen discontinued due to progression

Abbreviations. HCP, healthcare provider; IMWG, International Myeloma Working Group; LOT, line of therapy; TCR, triple-class refractory.

Table 2a. Demographics characteristics of TCR samples identified using four algorithms.

	Algorithm 1	Algorithm 2	Algorithm 3	Algorithm 4	p-value^e
	IMWG and HCP progressions as recorded in the database	Only IMWG progressions as recorded in the database	COTA IMWG progressions with modified timing and HCP progressions	Using IMWG and HCP progression events with a modified attribution of progression-associated LOT/regimen
	N = 404	N = 123	N = 404	N = 375
Age at MM diagnosis, years
Mean (SD)	61.5 (10.5)	60.8 (9.5)	61.5 (10.5)	61.4 (10.5)	0.9144
Median (IQR)	62.0 (55.0–69.0)	62.0 (54.0–68.0)	62.0 (55.0-69.0)	62.0 (55.0–69.0)
Age as of the date of initiation of the post-TCR LOT,^a^,b years	67.0 (60.5–75.0)	67.0 (60.0–74.0)	67.0 (60.5–75.0)	67.0 (60.0–75.0)	0.9693^f
Mean (SD)	67.1 (10.0)	66.7 (9.2)	67.1 (10.0)	67.0 (10.0)
Median (IQR)	67.0 (60.5–75.0)	67.0 (60.0–74.0)	67.0 (60.5–75.0)	67.0 (60.0–75.0)	0.9693^f
Male, n (%)	223 (55.2)	67 (54.5)	223 (55.2)	207 (55.2)	0.9990
Race, n (%)					0.9992
White	296 (73.3)	84 (68.3)	296 (73.3)	273 (72.8)
Black or African American	56 (13.9)	22 (17.9)	56 (13.9)	56 (14.9)
Asian	8 (2.0)	2 (1.6)	8 (2.0)	6 (1.6)
Other	28 (6.9)	9 (7.3)	28 (6.9)	25 (6.7)
Unknown or not assessed	16 (4.0)	6 (4.9)	16 (4.0)	15 (4.0)
CCI score any time before or on the date of initiation of the post-TCR LOT^a^,c,d
Mean (SD)	3.3 (1.5)	3.4 (1.6)	3.3 (1.5)	3.3 (1.4)
Median (IQR)	3.0 (2.0–4.0)	3.0 (2.0–4.0)	3.0 (2.0–4.0)	3.0 (2.0–4.0)	0.9386
CCI score any time before or on the date of initiation of the post-TCR LOT, n (%)^a^,c,d					0.9999
2-3	269 (66.6)	82 (66.7)	269 (66.6)	249 (66.4)
4-5	95 (23.5)	28 (22.8)	95 (23.5)	90 (24.0)
≥6	40 (9.9)	13 (10.6)	40 (9.9)	36 (9.6)

Abbreviations. CCI, Charlson Comorbidity Index; HCP, healthcare provider, IMWG, International Myeloma Working Group; IQR, interquartile range; LOT, line of therapy; MM, multiple myeloma; SD, standard deviation; TCR, triple-class refractory.

^a TCR status date is defined as the end of the line of therapy in which the patient meets the TCR definition.

^b If not available on the date of initiation of the post-TCR LOT, the measurement closest to the date of initiation of the post-TCR LOT was used.

^c As defined by M. E. Charlson et al. A New Method of Classifying Prognostic Comorbidity in Longitudinal Studies: Development and Validation, Journal of Chronic Diseases, Volume 40, Number 5, pp. 373–383, 1987 and using the diagnosis codes listed in H. Quan et al. Coding Algorithms for Defining Comorbidities in ICD-9-CM and ICD-10-CM Administrative Data, Medical Care, Volume 43, Number 11, November 2005.

^d Any malignancy, including the lymphoma and leukemia category that includes multiple myeloma diagnoses, which all patients have before the date of initiation of the post-TCR LOT.

^e All dichotomous and categorical variables were compared across the four cohorts of TCR patients using the Chi-square test or Fisher’s exact test when the number of observations was less than five. Continuous variables were compared across the four cohorts of TCR patients using the Kruskal-Wallis test when not normally distributed or the analysis of variance test when normally distributed.

^f Not normally distributed.

Table 2b. Disease characteristics of TCR samples identified using four algorithms.

	Algorithm 1	Algorithm 2	Algorithm 3	Algorithm 4	p-value^a
	IMWG and HCP progressions as recorded in the database	Only IMWG progressions as recorded in the database	COTA IMWG progressions with modified timing and HCP progressions	Using IMWG and HCP progression events with a modified attribution of progression-associated LOT/regimen
	N = 404	N = 123	N = 404	N = 375
Derived ISS stage within 90 days prior to or on the date of initiation of the post-TCR LOT, n (%)					0.9989
I: Patients with Sβ2M <3.5 mg/L; serum albumin ≥3.5 g/dL	52 (12.9)	19 (15.4)	52 (12.9)	48 (12.8)
II: Patients with Sβ2M <3.5 mg/L; serum albumin <3.5 g/dL; or Sβ2M 3.5–5.5 mg/L irrespective of serum albumin	45 (11.1)	15 (12.2)	45 (11.1)	41 (10.9)
III: Patients with Sβ2M >5.5 mg/L	24 (5.9)	6 (4.9)	24 (5.9)	24 (6.4)
Unknown or not assessed	283 (70.0)	83 (67.5)	283 (70.0)	262 (69.9)
ECOG PS closest value within 90 days prior to or on the date of initiation of the post-TCR LOT, n (%)					0.9993
0	99 (24.5)	28 (22.8)	99 (24.5)	93 (24.8)
1	182 (45.0)	62 (50.4)	182 (45.0)	166 (44.3)
2	46 (11.4)	14 (11.4)	46 (11.4)	41 (10.9)
3	8 (2.0)	2 (1.6)	8 (2.0)	8 (2.1)
4	1 (0.2)	0 (0.0)	1 (0.2)	1 (0.3)
Unknown or not assessed	68 (16.8)	17 (13.8)	68 (16.8)	66 (17.6)
≥1 bone lesion during the baseline period or on the date of initiation of the post-TCR LOT, n (%)	248 (61.4)	75 (61.0)	248 (61.4)	228 (60.8)	0.9979
≥1 extramedullary plasmacytoma during the baseline period or on the date of initiation of the post-TCR LOT, n (%)	76 (18.8)	21 (17.1)	76 (18.8)	71 (18.9)	0.9719
Laboratory results
High-risk cytogenetics, closest value during the baseline period, n (%)	89 (22.0)	24 (19.5)	89 (22.0)	78 (20.8)	0.9124
Presence of t(4;14) marker	40 (9.9)	12 (9.8)	40 (9.9)	36 (9.6)	0.9989
Presence of t(14;16) marker	24 (5.9)	6 (4.9)	24 (5.9)	20 (5.3)	0.9534
Presence of del(17p) marker	45 (11.1)	10 (8.1)	45 (11.1)	39 (10.4)	0.7895
Unknown or not assessed	34 (8.4)	9 (7.3)	34 (8.4)	34 (9.1)	0.9436
SPEP within 90 days prior to or on the date of initiation of the post-TCR LOT, g/dL, n (%)
≥1 assessment	290 (71.8)	112 (91.1)	290 (71.8)	266 (70.9)	<0.0001
Mean (SD)	1.2 (1.3)	1.8 (1.1)	1.2 (1.3)	1.2 (1.3)
Median (IQR)	0.8 (0.2-1.8)	1.9 (1.0-2.6)	0.8 (0.2-1.8)	0.8 (0.2-1.9)	< 0.0001^b
UPEP within 90 days prior to or on the date of initiation of the post-TCR LOT, mg/24 h, n (%)
≥1 assessment	141 (34.9)	53 (43.1)	141 (34.9)	130 (34.7)	0.3443
Mean (SD)	256.6 (486.7)	257.6 (327.9)	256.6 (486.7)	289.8 (502.5)
Median (IQR)	82.0 (9.0-245.6)	89.9 (12.8-391.0)	82.0 (9.0-245.6)	116.0 (11.9-308.4)	0.7412^b
Serum immunoglobulin kappa to lambda FLC ratio within 90 days prior to or on the date of initiation of the post-TCR LOT, ratio, n (%)
≥1 assessment	305 (75.5)	115 (93.5)	305 (75.5)	278 (74.1)	0.0001
Mean (SD)	274.8 (1 447.3)	202.8 (529.0)	274.8 (1 447.3)	230.4 (1 156.6)
Median (IQR)	10.1 (0.1-106.0)	11.5 (0.0-136.6)	10.1 (0.1-106.0)	10.5 (0.0-114.9)	0.9983^b

Abbreviations. ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; HCP, healthcare provider, IMWG, International Myeloma Working Group; IQR, interquartile range; ISS, International Staging System; LOT, line of therapy; MM, multiple myeloma; Sβ2M, serum beta-2 microglobulin; SD, standard deviation; SPEP, serum protein electrophoresis; TCR, triple-class refractory; UPEP, urine protein electrophoresis.

^a All dichotomous and categorical variables were compared across the four cohorts of TCR patients using the Chi-square test or Fisher’s exact test when the number of observations was less than five. Continuous variables were compared across the four cohorts of TCR patients using the Kruskal-Wallis test when not normally distributed or the analysis of variance test when normally distributed.

^b Not normally distributed.

Table 2c. Treatment history of TCR samples identified using four algorithms.

	Algorithm 1	Algorithm 2	Algorithm 3	Algorithm 4	p-value^a
	IMWG and HCP progressions as recorded in the database	Only IMWG progressions as recorded in the database	COTA IMWG progressions with modified timing and HCP progressions	Using IMWG and HCP progression events with a modified attribution of progression-associated LOT/regimen
	N = 404	N = 123	N = 404	N = 375
SCT during the baseline period, n (%)					0.9978
1 SCT	232 (57.4)	74 (60.2)	232 (57.4)	214 (57.1)
>1 SCT	30 (7.4)	9 (7.3)	30 (7.4)	30 (8.0)
SCT within 12 months before or on the date of initiation of the post-TCR LOT, n (%)	26 (6.4)	7 (5.7)	26 (6.4)	25 (6.7)	0.9857
Radiation therapy within 12 months before or on the date of initiation of the post-TCR LOT, n (%)	87 (21.5)	20 (16.3)	87 (21.5)	83 (22.1)	0.5630
Time from initial MM diagnosis to the date of initiation of the post-TCR LOT (years)
Mean (SD)	5.7 (4.3)	6.1 (4.5)	5.7 (4.3)	5.7 (4.4)
Median (IQR)	4.5 (2.5–7.5)	5.4 (2.9–8.3)	4.5 (2.5–7.5)	4.6 (2.5–7.5)	0.5500^b
Number of LOTs used prior to the date of initiation of the post-TCR LOT
Mean (SD)	6.3 (2.6)	6.7 (2.9)	6.3 (2.6)	6.4 (2.6)
Median (IQR)	6.0 (4.0-8.0)	6.0 (5.0–8.0)	6.0 (4.0–8.0)	6.0 (5.0–8.0)	0.4998^b
Total duration of LOTs prior to the date of initiation of the post-TCR LOT (years)
Mean (SD)	3.9 (2.9)	4.2 (3.0)	3.9 (2.9)	3.9 (2.9)
Median (IQR)	3.2 (1.8–5.1)	3.5 (1.9–5.7)	3.2 (1.8–5.1)	3.3 (1.9–5.1)	0.8105^b
Received BCMA therapy prior to the date of initiation of the post-TCR LOT, n (%)	0 (0.0)	1 (0.8)	0 (0.0)	1 (0.3)	0.0629

Abbreviations. BCMA, B-cell maturation antigen; HCP, healthcare provider, IMWG, International Myeloma Working Group; IQR, interquartile range; LOT, line of therapy; MM, multiple myeloma; SCT, stem cell transplant; SD, standard deviation; TCR, triple-class refractory.

^a All dichotomous and categorical variables were compared across the four cohorts of TCR patients using the Chi-square test or Fisher’s exact test when the number of observations was less than five. Continuous variables were compared across the four cohorts of TCR patients using the Kruskal-Wallis test when not normally distributed or the analysis of variance test when normally distributed.

^b Not normally distributed.

Table 3. Treatment patterns of the first LOT initiated post TCR in TCR samples identified using four algorithms.

	Algorithm 1 IMWG and HCP progressions as recorded in the database	Algorithm 2 Only IMWG progressions as recorded in the database	Algorithm 3 COTA IMWG progressions with modified timing and HCP progressions	Algorithm 4 Using IMWG and HCP progression events with a modified attribution of progression-associated LOT/regimen	p-value^a
	N = 404	N = 123	N = 404	N = 375
Received SCT in the LOT initiated on the date of initiation of the post-TCR LOT, n (%)	16 (4.0)	4 (3.3)	16 (4.0)	15 (4.0)	1.0000
Received selinexor in the LOT initiated on the date of initiation of the post-TCR LOT, n (%)	19 (4.7)	10 (8.1)	19 (4.7)	18 (4.8)	0.4530
Received BCMA therapy in the LOT initiated on the date of initiation of the post-TCR LOT, n (%)
Belantamab mafodotin	3 (0.7)	1 (0.8)	3 (0.7)	2 (0.5)	0.9650
Idecabtagene vicleucel	1 (0.2)	1 (0.8)	1 (0.2)	1 (0.3)	0.7007
Top 10 treatments received in the LOT initiated on the date of initiation of the post-TCR LOT, n (%)
Daratumumab, dexamethasone, pomalidomide	29 (7.18)	7 (5.69)	29 (7.18)	27 (7.20)
Dexamethasone, elotuzumab, pomalidomide	21 (5.20)	–	21 (5.20)	20 (5.33)
Carfilzomib, cyclophosphamide, dexamethasone	20 (4.95)	9 (7.32)	20 (4.95)	18 (4.80)
Carfilzomib, daratumumab, dexamethasone	19 (4.70)	7 (5.69)	19 (4.70)	16 (4.27)
Carfilzomib, dexamethasone, pomalidomide	18 (4.46)	7 (5.69)	18 (4.46)	16 (4.27)
Investigational agent	18 (4.46)	7 (5.69)	18 (4.46)	18 (4.80)
Carfilzomib, dexamethasone	14 (3.47)	–	14 (3.47)	14 (3.73)
Carfilzomib, daratumumab, dexamethasone, pomalidomide	13 (3.22)	–	13 (3.22)	13 (3.47)
Carfilzomib, cyclophosphamide, dexamethasone, pomalidomide	12 (2.97)	3 (2.44)	12 (2.97)	12 (3.20)
Dexamethasone, pomalidomide	9 (2.23)	4 (3.25)	9 (2.23)	8 (2.13)
Bortezomib, daratumumab, dexamethasone	–	4 (3.25)	–	–
Dexamethasone, panobinostat, pomalidomide	–	4 (3.25)	–	–
Dexamethasone, pomalidomide, selinexor	–	3 (2.44)	–	–

Abbreviations. BCMA, B-cell maturation antigen; HCP, healthcare provider, IMWG, International Myeloma Working Group; LOT line of therapy; SCT, stem cell transplant; TCR, triple-class refractory.

^aAll dichotomous and categorical variables were compared across the four cohorts of TCR patients using the Chi-square test or Fisher’s exact test when the number of observations was less than 5. Continuous variables were compared across the four cohorts of TCR patients using the Kruskal-Wallis test when not normally distributed or the ANOVA test when normally distributed.

Data availability statement

The data that support the findings of this study are available from COTA, Inc, but restrictions apply to the availability of these data, which were used under a license agreement for the current study and, accordingly, are not publicly available. Access to the data can be requested by contacting COTA, Inc.