A combination of humanized anti-BCMA and murine anti-CD38 CAR-T cell therapy in patients with relapsed or refractory multiple myeloma

Figures & data

Figure 1. Structures of CAR-T cells and response to combination therapy. (A,B) The construct of anti-BCMA/CD38 CAR-T. (C) Response assessment after combination therapy.

Table 1. Baseline characteristics in 22 relapsed/refractory multiple myeloma patients.

Median age (range), years	56 (47–68)
Sex
Female	13 (59.1%)
Male	9 (40.9%)
Karnofsky Performance Score
60–80	7 (31.8%)
80–100	15 (68.2%)
Bone marrow plasma cells
10–60%	18 (81.8%)
>60%	4 (18.2%)
Monoclonal globulin
IgG	12 (54.5%)
IgA	4 (18.2%)
IgD	1 (4.5%)
Light chain	5 (22.7%)
Durie-Salmon staging system
I	0 (0.0%)
II	10 (45.5%)
III	12 (54.5%)
A	20 (90.9%)
B	2 (9.1%)
International staging system
I	0 (0%)
II	17 (77.3%)
III	5 (22.7%)
High risk cytogenetics*	19 (86.4%)
Extramedullary disease	3 (13.6%)
Numbers of prior therapy	8 (4–12)
Previous therapies
Proteasome inhibitor	22 (100.0%)
Immunomodulatory drugs	18 (81.8%)
Anthracyclines/Cyclophosphamide	14 (63.6%)
Autologous stem-cell transplantation	19 (86.4%)

*High-risk cytogenetics were defined as del(17p), t(14;16), t(4;14).

Figure 2. Changes in monoclonal immunoglobulin and light chain from baseline and survival in R/RMM to CAR-T. (A) The change in plasma M-protein concentration from baseline after CAR-T cell infusion. (B) The change in light chain concentration from baseline after CAR-T cell infusion. (C) The curve shows the time to progression after infusion of CAR-T cells. (D) The curve shows overall survival data censored at the time of the last follow-up.

Table 2. Adverse event associated with treatment.

Adverse event, n%	All grade	Grades 1–2	Grade ≥ 3
Constitutional symptom
Fever	22 (100.00)	14 (63.6)	8 (36.4)
Fatigue	9 (40.9)	8 (36.4)	1 (4.5)
Myalgia	3 (13.6)	3 (13.6)	0 (0.0)
Hematologic
Leukopenia	22 (100.00)	14 (63.6)	8 (36.4)
Anemia	9 (40.9)	3 (13.6)	6 (27.3)
Thrombocytopenia	4 (18.2)	4 (18.2)	0
Cardiopulmonary
Hypotension	6 (27.3)	4 (18.2)	2 (9.0)
hypoxemia	5 (22.7)	4 (18.2)	1 (4.5)
Heart failure	4 (18.2)	2 (9.0)	2 (9.0)
Arrhythmology	4 (18.2)	3 (13.6)	1 (4.5)
Gastrointestinal
Nausea	6 (27.3)	6 (27.3)	0 (0.0)
Diarrhea Coagulopathy	4 (18.2)	4 (18.2)	0 (0.0)
APTT prolonged	6 (27.3)	2 (9.0)	4 (18.2)
D-dimer elevated	12 (54.5)	10 (45.5)	2 (9.0)
Electrolyte disorder
Hypokalemia	4 (18.2)	4 (8.2)	0 (0.0)
Hyponatremia	3 (13.6)	3 (13.6)	0 (0.0)
Hypoalbuminemia	5 (22.7)	4 (18.2)	1 (7.14)
Liver insufficiency	6 (27.3)	4 (18.2)	2 (9.0)
Renal insufficiency^a	3 (13.6)	2 (9.0)	0 (0.0)
CRS^b	22 (100.00)	16 (72.7)	6 (27.3)
ICANS^c	3 (13.6)	3 (13.6)	0 (0.0)

^aRenal insufficiency is caused by CAR-T cells infusion, excluding patients with renal insufficiency before CAR-T cells infusion.

^bCRS Cytokine release syndrome.

^cICANS Immune effector cell associated neurotoxic syndrome.

Figure 3. Serum cytokines associated with CRS severity. The chart shows the peak levels of serum cytokines over baseline in the first 30 days after infusion of CAR-T cells in patients with grade 1–2 CRS (n = 16) compared with patients with grade ≥3 CRS (n = 6). (A–C). Peak levels of IL-6, CRP and ferritin in the 1–2 grade CRS group were higher than those in the ≥3 grade CRS group (p < 0.001). (D–H) There was no significant difference in peak levels of IL-1β, IL-2R, IL-8, IL-10, and TNF-α between 1–2 grade and the ≥3 grade CRS groups (p = 0.643, p = 0.573, p = 0.064, p = 0.146, p = 0.462).

Table 3. Management of patients with CRS ≥ grade 3.

	CRS grading	Glucocorticoid	Tocilizumab	ICU*
Patient 4	4	Yes	Yes	Yes
Patient 6	5	Yes	Yes	Yes
Patient 8	3	Yes	Yes	No
Patient 14	3	Yes	No	No
Patient 20	5	Yes	Yes	Yes
Patient 22	4	Yes	Yes	Yes

*The two patients transferred to ICU received plasmapheresis therapy.

Table 4. Factors possibly associated with CRS.

Characteristic	Grade 1–2	Grade ≥3	p value
Case (n)	16	6
Age
Mean value, years	55	57	0.964^a
KPS			0.837^b
90–100	8	3
60–80	2	1
ISS stage			0.124^b
II	7	1
III	3	3
Lactate dehydrogenase
Mean value, U/L	246.62	307.14	0.563^a
Hemoglobin
Mean value, g/L	85.49	93.26	0.631^a
Serum M protein
Mean value, g/L	25.0	41.5	0.156^a
Clonal BM plasma cells
Mean value, %	15.90	74.25	<0.001^a
High-risk cytogenetics			>0.999^b
Yes	5	2
No	5	2
Lines of prior therapy
Mean value	5.5	11.5	0.050^a

^ap value is calculated by t test.

^bp value is calculated by χ² test.

Figure 4. Expansion of CAR-T cells after infusion. CAR-T cell levels over time in peripheral blood are depicted, as measured by quantitative PCR for CAR sequence. (A) The absolute number of BCMA CAR⁺ cells/µl in peripheral blood within 28 days of infusion. (B) The absolute number of CD38 CAR⁺ cells/µl in peripheral blood within 28 days of infusion.