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S. Bringhen et al.
The incidence of at least one hematologic adverse event was similar in fit, intermediate-fit and frail patients. The rate of non-hematologic adverse events as well as the rate of discontinuation due to adverse events increased with worsening of fitness status (Online Supplementary Table S2). Data from each induction treatment group are pre- sented in Table 3. Frail patients receiving the alkylating- containing regimens had the highest rate of discontinua- tion due to adverse events.
In our trial, both maintenance regimens improved the quality of response and produced a time from biochemical to clinical relapse of approximately 10 months. Indeed, as recently described, even when neoplastic plasma cells become lenalidomide-refractory, the immunomodulatory effect of lenalidomide on immune cells may help prolong disease control.12 A trend toward a slight improvement of PFS in the RP arm was noted as compared to R alone, while OS data were still immature after only 170 deaths (42% of patients).
Regarding safety, maintenance treatment with both reg- imens was feasible with grade ≥3 non-hematologic adverse event rates of less than 15%. The only difference
During maintenance, the most frequent grade ≥3 toxi- city was neutropenia, which occurred in 10% of RP and 21% of R patients (P=0.001) (Table 2). Grade ≥3 non- hematologic adverse events were rare and occurred in <15% of patients. The proportion of patients requiring dose discontinuation due to adverse events during main- tenance was 18% in the R arm and 21% in the RP arm. The proportion of patients requiring dose reduction dur- ing maintenance was 9% in the RP arm and 16% in the R arm (P=0.05). Fifteen cases of second primary malig- nancies were recorded: six (3%) in the RP group and nine (4%) in the R group. All second primary malignancies were solid tumors.
Table 2. Grade ≥3 adverse events during maintenance treatment.
Grade ≥3 adverse events
Hematologic
At least one event
Anemia Neutropenia Thrombocytopenia
Non-hematologic
At least one event
Cardiological
Acute myocardial infarction Other
Vascular
Deep vein thrombosis/
thromboembolism Renal
Dermatological
Infectious Pneumonia Bronchitis
Sepsis
Other/not specified
Nervous
Second primary malignancies Hematologic
Solid
Other
Discontinuation due to adverse events
In the RP group, 133 patients required a second line of therapy: 94 (71%) received bortezomib, 3 (2%) thalido- mide or lenalidomide, 17 (13%) other chemotherapy, 16 (12%) died before starting treatment and 3 (2%) were lost to follow-up. In the R group, 138 patients required a sec- ond line of therapy: 102 (74%) received bortezomib, 3 (2%) thalidomide or lenalidomide, 21 (15%) other chemotherapy, 7 (5%) died before starting treatment and 5 (4%) were lost to follow-up.
The incidences of at least one hematologic and non- hematologic grade ≥3 adverse events were similar in fit, intermediate-fit and frail patients. Frail patients had the highest rate of discontinuation due to adverse events; a trend towards a higher discontinuation due to adverse events was found in frail vs. fit patients (Online Supplementary Table S2). Data in each maintenance treat- ment group are presented in Table 4.
Discussion
One of the aims of this analysis was to compare RP vs. R alone as maintenance treatment after induction therapy. While the use of maintenance therapy is a standard approach in young ASCT-eligible patients with newly diagnosed MM, its use in elderly MM patients after induc-
tion treatment is more debated.
Lenalidomide (R) (n=204)
46 (23%)
4 (2%) 43 (21%) 4 (2%)
22 (11%)
2 (1%) 1
1
5 (2%) 2 (1%)
1
2 (1%)
2 (1%) 0
1
0
1
2 (1%)
9 (4%) 0
9 (4%)
9 (4%) 36 (18%)
Lenalidomide-prednisone (RP) (n=198)
26 (13%)
4 (2%) 19 (10%) 5 (3%)
28 (14%)
1 1 0
4 (2%) 3 (2%)
2 (1%) 3 (2%) 4 (2%)
1 1 1 1
7 (4%)
6 (3%) 0
6 (3%)
5 (3%) 41 (21%)
Table 3. Grade ≥3 hematologic adverse events, non-hematologic adverse events, treatment discontinuation due to adverse events and toxic deaths during induction treatment according to patients’ frailty status.
Treatment arm (n)
Frailty Score class (n)
Hematologic AE G ≥3, n (%)
Non-hematologic AE G ≥3, n (%)
Discontinuation due to AE, n (%)
DeathduetoAE,n(%) 1(1) 0 7(13) 1(1) 2(3) 2(4) 1(1) 1(2) 4(7)
CPR: cyclophosphamide-prednisone-lenalidomide; MPR: melphalan-prednisone-lenalidomide; Rd: lenalidomide-dexamethasone; AE: adverse events; G: grade; n: number; %: per- centage.
Fit (98)
CPR (n=220)
Intermediate -fit (69)
Frail (53)
Fit (88)
MPR (n=211)
Intermediate- fit (76)
Frail (47)
Fit (94)
Rd (n=212)
Intermediate- fit (57)
Frail (61)
31 (32) 22 (22) 8 (8)
23 (33) 22 (32) 9 (13)
17 (32) 22 (42) 16 (30)
62 (70) 22 (25) 10 (11)
46 (61) 22 (29) 17 (22)
35 (74) 22 (45) 10 (21)
26 (28) 24 (26) 9 (10)
13 (23) 15 (26) 9 (16)
22 (36) 24 (39) 12 (20)
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