Trial Outcomes & Findings for Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65 (NCT NCT01208662)

NCT ID: NCT01208662

Last Updated: 2026-01-22

Results Overview

PFS was estimated using the Kaplan-Meier (KM) method and defined as time from randomization to the earlier of disease progression (PD) as determined by central review or death from any cause (events). Patients who started non-protocol therapy (NPT) were censored at the date of NPT initiation if available or date treatment ended if date of NPT was missing. Deaths occurring beyond 1 year from the date last known progression-free are not counted as events and censored at date of last disease evaluation. Patients who had not started NPT, progressed, or died were censored at the date of last disease evaluation. PD was based upon the International Myeloma Working Group (IMWG) uniform response criteria. \[Kumar S, et al Lancet Oncol 2016;17(8):e328-e346\].

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

729 participants

Primary outcome timeframe

On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months.

Results posted on

2026-01-22

Participant Flow

Participants were enrolled at 56 clinical sites in the U.S. from Oct 1, 2010 to January 30, 2018.

Participant milestones

Participant milestones
Measure	RVD Alone All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Cycle 1 Only Some participants started cycle 1 lenalidomide (R), bortezomib (V) and dexamethasone (D) therapy but were not randomized. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1) on days 1, 2, 4, 5, 8, 9, 11, and 12
Induction and Consolidation STARTED	357	365	7
Induction and Consolidation Randomized	357	365	0
Induction and Consolidation Underwent Stem Cell Mobilization	324	330	0
Induction and Consolidation COMPLETED	291	289	0
Induction and Consolidation NOT COMPLETED	66	76	7
Maintenance STARTED	291	289	0
Maintenance Minimal Residual Disease (MRD) Evaluable at Maintenance Start	108	90	0
Maintenance COMPLETED	0	0	0
Maintenance NOT COMPLETED	291	289	0

Reasons for withdrawal

Reasons for withdrawal
Measure	RVD Alone All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Cycle 1 Only Some participants started cycle 1 lenalidomide (R), bortezomib (V) and dexamethasone (D) therapy but were not randomized. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1) on days 1, 2, 4, 5, 8, 9, 11, and 12
Induction and Consolidation Disease Progression	23	13	0
Induction and Consolidation Adverse Event	16	18	2
Induction and Consolidation MD or Participant Decision	16	34	4
Induction and Consolidation Death	1	3	1
Induction and Consolidation Discontinued for other reasons	10	8	0
Maintenance Disease Progression	156	102	0
Maintenance Adverse Event	12	28	0
Maintenance MD or Participant Decision	24	36	0
Maintenance Death	0	3	0
Maintenance Discontinued for other reasons	21	31	0
Maintenance Still on Treatment	78	89	0

Baseline Characteristics

ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RVD Alone n=357 Participants All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Cycle 1 Only n=7 Participants Some participants started cycle 1 lenalidomide (R), bortezomib (V) and dexamethasone (D) therapy but were not randomized. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	Total n=729 Participants Total of all reporting groups
Age, Continuous	57 years n=357 Participants	55 years n=365 Participants	59 years n=7 Participants	56 years n=729 Participants
Sex: Female, Male Female	155 Participants n=357 Participants	150 Participants n=365 Participants	3 Participants n=7 Participants	308 Participants n=729 Participants
Sex: Female, Male Male	202 Participants n=357 Participants	215 Participants n=365 Participants	4 Participants n=7 Participants	421 Participants n=729 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	19 Participants n=357 Participants	23 Participants n=365 Participants	0 Participants n=7 Participants	42 Participants n=729 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	336 Participants n=357 Participants	332 Participants n=365 Participants	7 Participants n=7 Participants	675 Participants n=729 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=357 Participants	10 Participants n=365 Participants	0 Participants n=7 Participants	12 Participants n=729 Participants
Race/Ethnicity, Customized White	268 Participants n=357 Participants	272 Participants n=365 Participants	5 Participants n=7 Participants	545 Participants n=729 Participants
Race/Ethnicity, Customized Black	66 Participants n=357 Participants	66 Participants n=365 Participants	2 Participants n=7 Participants	134 Participants n=729 Participants
Race/Ethnicity, Customized Asian	8 Participants n=357 Participants	12 Participants n=365 Participants	0 Participants n=7 Participants	20 Participants n=729 Participants
Race/Ethnicity, Customized Other	9 Participants n=357 Participants	9 Participants n=365 Participants	0 Participants n=7 Participants	18 Participants n=729 Participants
Race/Ethnicity, Customized Unknown	6 Participants n=357 Participants	6 Participants n=365 Participants	0 Participants n=7 Participants	12 Participants n=729 Participants
Region of Enrollment United States	357 participants n=357 Participants	365 participants n=365 Participants	7 participants n=7 Participants	729 participants n=729 Participants
ISS Multiple Myeloma Stage I	178 Participants n=357 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	184 Participants n=365 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	—	362 Participants n=722 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.
ISS Multiple Myeloma Stage II	130 Participants n=357 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	134 Participants n=365 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	—	264 Participants n=722 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.
BMI >/= 30	136 Participants n=357 Participants	157 Participants n=365 Participants	4 Participants n=7 Participants	297 Participants n=729 Participants
ISS Multiple Myeloma Stage III	49 Participants n=357 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	47 Participants n=365 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	—	96 Participants n=722 Participants • ISS Multiple Myeloma staging data collected at randomization and therefore data was not collected for the seven participants who were not randomized.
Cytogenetic Risk Category High risk	66 Participants n=357 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	66 Participants n=365 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	—	132 Participants n=722 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.
Cytogenetic Risk Category Standard risk	268 Participants n=357 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	274 Participants n=365 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.	—	542 Participants n=722 Participants • Cytogenetic risk category data collected at randomization and therefore data was not collected for the seven participants who were not randomized.
BMI <25	80 Participants n=357 Participants	81 Participants n=365 Participants	1 Participants n=7 Participants	162 Participants n=729 Participants
BMI 25 to <30	141 Participants n=357 Participants	127 Participants n=365 Participants	2 Participants n=7 Participants	270 Participants n=729 Participants
ECOG Performance Status 0	153 Participants n=357 Participants	164 Participants n=365 Participants	4 Participants n=7 Participants	321 Participants n=729 Participants
ECOG Performance Status 1	177 Participants n=357 Participants	161 Participants n=365 Participants	3 Participants n=7 Participants	341 Participants n=729 Participants
ECOG Performance Status 2	27 Participants n=357 Participants	39 Participants n=365 Participants	0 Participants n=7 Participants	66 Participants n=729 Participants
ECOG Performance Status Unknown	0 Participants n=357 Participants	1 Participants n=365 Participants	0 Participants n=7 Participants	1 Participants n=729 Participants

PRIMARY outcome

Timeframe: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months.

Population: The analysis population is comprised of all randomized participants.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Median Progression-Free Survival (PFS)	46.2 months Interval 38.1 to 53.7	67.5 months Interval 58.6 to 95% CI upper bound not estimable because data not mature enough. Specifically, with the follow-up observed as of data extraction, there were not enough events.

SECONDARY outcome

Timeframe: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.

Population: The analysis population is comprised of all randomized participants.

The PR rate is the percentage of participants achieving PR or better on treatment and was evaluated based on the IMWG criteria. PR was defined as \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a \> 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \> 30%. In addition to the above listed criteria, if present at baseline, a \> 50% reduction in the size of soft tissue plasmacytomas was also required. Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Partial Response (PR) Rate	95 percentage of participants Interval 91.0 to 97.5	97.5 percentage of participants Interval 94.5 to 99.2

SECONDARY outcome

Population: The analysis population is comprised of all randomized participants.

The VGPR rate is the percentage of participants achieving VGPR or better on treatment and was evaluated based on IMWG criteria. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hours.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Very Good Partial Response (VGPR) Rate	79.6 percentage of patients Interval 73.3 to 85.0	82.7 percentage of patients Interval 76.8 to 87.7

SECONDARY outcome

Population: The analysis population is comprised of all randomized patients.

The CR rate is the percentage of participants achieving CR or better on treatment and was evaluated based on IMWG criteria. CR was defined as the negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Confirmation with repeat bone marrow biopsy was not needed.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Complete Response (CR) Rate	42.0 percentage of patients Interval 35.0 to 49.3	46.8 percentage of patients Interval 39.8 to 54.0

SECONDARY outcome

Population: The analysis population is comprised of all randomized participants who achieved PR.

DOR PR was estimated using the KM method and defined as the time from documented best response as CR to documented disease progression per IMWG criteria. Patients who have not progressed or died were censored at the date last known progression-free.

Outcome measures

Outcome measures
Measure	RVD Alone n=339 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=356 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Median Duration of Response: Partial Response (DOR PR)	38.9 months Interval 30.8 to 45.6	56.4 months Interval 47.4 to 75.8

SECONDARY outcome

Population: The analysis population is comprised of all randomized participants.

TTP was estimated using the KM method and defined as time from randomization to time of documented IMWG disease progression or censoring time (time of last disease evaluation for those alive, time to death among those who died). Patients initiating non-protocol therapy prior to progression or death were censored at the date of non-protocol therapy in the TTP analysis. The 5-year TTP endpoint is a probability.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
5-Year Time to Progression (TTP)	41.6 percent probability Interval 35.8 to 47.3	58.4 percent probability Interval 52.2 to 64.2

SECONDARY outcome

Timeframe: In long-term follow-up, survival follow-up every 2 months until death. Median (maximum) OS follow-up was 76 and 129 months.The probability estimate is at 5 years.

Population: The analysis population is comprised of all randomized participants.

OS was estimated using the KM method and defined as time from randomization to death due to any cause. Patients alive were censored at date last known alive. The 5-year OS endpoint is a probability.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
5-Year Overall Survival (OS)	79.2 percent probability Interval 74.3 to 83.3	80.7 percent probability Interval 76.1 to 84.6

SECONDARY outcome

Timeframe: AEs was assessed every cycle on treatment. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.

Population: The analysis population comprised of all randomized participants.

Safety was evaluated throughout trial treatment, including ASCT, and through 30 days after receipt of the last dose of a trial drug. Treatment attribution and grade were based on the NCI CTCAE v4. The Grade 3 or Higher Treatment-Related Non-Hematologic AE Rate is percentage of participants who experienced any grade 3-5 treatment-related (possible, probable or definite attribution) non-hematologic adverse event based on CTCAEv4 as reported on case report forms. The difference in the rate of all grade 3 or higher toxicities was compared between the two groups using Fisher's exact test.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate	78.2 percentage of participants Interval 73.5 to 82.3	94.2 percentage of participants Interval 91.3 to 96.4

SECONDARY outcome

Timeframe: 5 years

Population: The analysis population is comprised of all randomized participants.

Second primary malignancy (SPM) is defined as the development of another new, unrelated cancer, regardless of treatment for previous malignancy attribution. The cumulative incidence of SPMs was estimated with death as a competing risk. SPMs were collected using an SAE form or MEDWATCH 3500A form, with intensity determined by using the NCI CTCAE version 4 as a guideline.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
5-year Cumulative Incidence of Second Primary Malignancy (SPM)	4.9 percentage of patients	6.5 percentage of patients

SECONDARY outcome

Timeframe: Up to 134 months

Population: The analysis population is comprised of all randomized participants.

Treatment duration estimated using the KM method is defined as the time from registration (C1) to the time off treatment (event) or censored at date of last treatment.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Median Treatment Duration	28.2 months Interval 21.2 to 37.1	36.8 months Interval 29.0 to 42.2

SECONDARY outcome

Timeframe: Up to 128 months

Population: The analysis population is comprised of all patients that started maintenance treatment.

Maintenance treatment duration estimated using the KM method is defined as the time from start of maintenance to the time off maintenance (event) or censored at date of last maintenance treatment.

Outcome measures

Outcome measures
Measure	RVD Alone n=291 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=289 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Median Maintenance Treatment Duration	36.4 months Interval 25.7 to 40.8	41.5 months Interval 34.0 to 47.1

SECONDARY outcome

Timeframe: Up to 129 months

Population: All participants off treatment per protocol.

Subsequent therapy rate was the percentage of participants who discontinued treatment and initiated subsequent non-protocol therapy.

Outcome measures

Outcome measures
Measure	RVD Alone n=279 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=276 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Subsequent Therapy Rate	222 Participants	192 Participants

SECONDARY outcome

Timeframe: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline

Population: The analysis population is comprised of all randomized participants who completed the assessment both at baseline and at the respective timepoint on treatment.

The FACT/GOG-NTX assessment consists of 11 questions that are all used to construct 1 subscale to summarize symptoms of peripheral neuropathy, including sensory, motor, and auditory problems and cold sensitivity. (https://www.facit.org/measures/FACT-GOG-NTX) Each question has 4 possible responses from 0 (Not at all) to 4 (Very Much) which are reverse-scored and summed. This sum is then scaled by the number of questions answered by multiplying by 11 and then dividing by the number of questions that are non-blank, in order to keep all final scores proportional to one another even if some questions are left blank. The aggregate score ranges from 0 to 44, with higher scores indicating less neurotoxicity and lower scores indicating more neurotoxicity. Change from baseline is the difference

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Cycle 2	-1.8 units on a scale Standard Deviation 4.8	-1.3 units on a scale Standard Deviation 5.0
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Pre-Mobilization	-3.9 units on a scale Standard Deviation 6.9	-3.5 units on a scale Standard Deviation 7.4
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Cycle 5 Arm A / Post Auto-HSCT Arm B	-4.4 units on a scale Standard Deviation 6.5	-4.4 units on a scale Standard Deviation 7.5
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Cycle 8 Arm A /Cycle 5 Arm B	-4.7 units on a scale Standard Deviation 6.7	-2.5 units on a scale Standard Deviation 6.5
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) Maintenance Day 1	-3.7 units on a scale Standard Deviation 6.9	-2.3 units on a scale Standard Deviation 6.4
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) 2 years from baseline	-4.9 units on a scale Standard Deviation 6.8	-2.6 units on a scale Standard Deviation 6.1
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) 3 years from baseline	-4.6 units on a scale Standard Deviation 7.4	-3.2 units on a scale Standard Deviation 7.2

SECONDARY outcome

Timeframe: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline

Population: The analysis population is comprised of all randomized participants who completed the assessment both at baseline and at the respective timepoint on treatment.

The EORTC QLQ-C30 assessment consists of 30 questions that are used to construct 15 distinct sub-scales (five function scales, nine symptom scales, and a global health status/QoL scale). The global health status/QoL scale is comprised of two questions each with a range of 6 (1=Very Poor to 7=Excellent). Scores on all sub-scales range from 0 to 100 after linear transformation of the raw scores, with higher scores representing better global health status and quality of life.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale Cycle 2	0.1 units on a scale Standard Deviation 20.8	4.3 units on a scale Standard Deviation 21.8
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale Pre-Mobilization	0.4 units on a scale Standard Deviation 21.7	4.4 units on a scale Standard Deviation 23.8
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale Cycle 5 Arm A / Post Auto-HSCT Arm B	3.0 units on a scale Standard Deviation 24.8	-11.1 units on a scale Standard Deviation 28.9
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale Cycle 8 Arm A /Cycle 5 Arm B	1.2 units on a scale Standard Deviation 23.5	8.3 units on a scale Standard Deviation 25.2
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale Maintenance Day 1	5.3 units on a scale Standard Deviation 23.0	9.9 units on a scale Standard Deviation 23.6
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale 2 years from baseline	5.1 units on a scale Standard Deviation 22.4	11.1 units on a scale Standard Deviation 26.0
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale 3 years from baseline	3.5 units on a scale Standard Deviation 23.6	12.7 units on a scale Standard Deviation 27.4

SECONDARY outcome

Timeframe: Maximum observation of survival for this study cohort was 129.4 months.

QALYs were estimated with a model beginning at initiation of first-line therapy by arm. A lifetime horizon, as well as subsequent lines of therapy, was examined using open-source Amua 0.3.0 software. Base case analysis was performed using 10,000 first-order Monte Carlo simulations. Conditional probabilities were extracted from Kaplan-Meier curves from pivotal clinical trials using WebPlotDigitizer. Costs were estimated from RED BOOK and DFCI charge reporting in US Dollars ($) after inflation adjustment to 2022 and 3% discounting, and QALYs effects were measured using EQ-5D data from Hatswell et al.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Quality-Adjusted Life Years (QALYs)	5.67 years gained Standard Deviation 3.52	6.10 years gained Standard Deviation 3.59

POST_HOC outcome

Timeframe: Maintenance treatment occurred after induction, up to 11.5 months.

Population: The analysis population is comprised of the participants with evaluable samples at baseline and start of maintenance.

Bone marrow aspirate samples were obtained from patients prior to the start of lenalidomide maintenance. NGS MRD- rate is the percentage of evaluable participants with MRD level of \<1 x 10-5 (indicating detection of 1 malignant plasma cell in 100,000 bone marrow cells) using the validated, US Food and Drug Administration approved clonoSEQ® NGS platform (Adaptive Biotechnologies) with a minimum sensitivity of 1 x 10-5.

Outcome measures

Outcome measures
Measure	RVD Alone n=108 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=90 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Next Generation Sequencing (NGS) Minimal Residual Disease Negative (MRD-) Rate at Maintenance Start	39.8 percentage of participants Interval 30.5 to 49.7	54.4 percentage of participants Interval 43.6 to 65.0

POST_HOC outcome

Timeframe: Assessed up to approximately 130 months.

Population: The analysis population is comprised of all randomized participants.

EFS was estimated using the KM method and defined as the time from randomization to the earliest of IMWG disease progression, death, or initiation of non-protocol therapy (events); patients were censored date of last disease evaluation.

Outcome measures

Outcome measures
Measure	RVD Alone n=357 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12	RVD Plus ASCT n=365 Participants All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
Median Event Free Survival (EFS)	32.0 months Interval 23.5 to 42.0	47.3 months Interval 41.3 to 55.5

Adverse Events

RVD Alone

Serious events: 279 serious events

Other events: 343 other events

Deaths: 89 deaths

RVD Plus ASCT

Serious events: 344 serious events

Other events: 345 other events

Deaths: 88 deaths

RVD Cycle 1 Only

Serious events: 4 serious events

Other events: 7 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Ajantha Nithi

Dana-Farber Cancer Institute

Phone: 857-215-2829

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place