“Continuous improvement is better than delayed perfection.”
—Mark Twain
Syed Ali Abutalib, MD
Kenneth C. Anderson, MD
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel treatment approaches under study for patients with newly diagnosed multiple myeloma who are candidates for autologous transplantation. For full details of these study abstracts, visit ashpublications.org.
ABSTRACT 549: Phase II GRIFFIN study: Daratumumab plus lenalidomide, bortezomib, and dexamethasone (D-RVd) in patients with transplant-eligible newly diagnosed multiple myeloma: Updated analysis after 12 months of maintenance therapy (ClinicalTrials.gov identifier NCT02874742).1
Background: Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous hematopoietic cell transplantation (auto-HCT) is standard front-line therapy for transplant-eligible patients with newly diagnosed multiple myeloma. In the primary analysis of the phase II GRIFFIN study, the primary endpoint, stringent complete response rate at the end of consolidation (auto-HCT) favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio = 1.57; 95% confidence interval [CI] = 0.87–2.82; one-sided P = .068) and met the prespecified one-sided α of 0.10.2
Methods: Patients were randomly assigned 1:1 to receive 4 cycles of D-RVd (n = 104) or RVd induction (n = 103) then auto-HCT followed by D-RVd or RVd consolidation (2 cycles) and finally lenalidomide or lenalidomide plus daratumumab maintenance (26 cycles or 2 years).
Results:
- At data cutoff for 12 months of maintenance therapy (median follow-up, 26.7 months), the stringent complete response rate still favored D-RVd vs RVd (63.6% vs 47.4%, two-sided P = .0253).
- Measurable residual disease (MRD) negativity (10-5) rates in the intent-to-treat population favored D-RVd vs RVd (62.5% vs 27.2%, P < .0001), as well as among patients who achieved complete response or better at that time (76.5% vs 42.4%, P < .0001). Similarly, MRD negativity (10-6) rates favored D-RVd vs RVd (P = .0140).
- Estimated 24-month progression-free-survival rates were 94.5% and 90.8% for the D-RVd and RVd groups, respectively.
Clinical Implications: The addition of D-RVd induction and consolidation, followed by daratumumab/lenalidomide maintenance, in patients with transplant-eligible newly diagnosed multiple myeloma continued to demonstrate deep and improved responses, including higher stringent complete response and MRD negativity rates than lenalidomide alone. Maintenance therapy increased stringent complete response and MRD negativity rates, compared with rates after consolidation. No new safety concerns were observed with longer follow-up.
This trial, as in other randomized trials evaluating the addition of daratumumab as initial therapy for transplant-eligible and transplant ineligible-patients,3 shows that inclusion of daratumumab may achieve MRD responses and prolong progression-free survival, even in patients with high-risk disease. Although there is not yet an overall survival advantage, recent large meta-analyses showed that MRD negativity may be associated with prolongation of both progression-free and overall survival, both in newly diagnosed and relapsed myeloma.4 However, it is becoming more difficult to demonstrate overall survival differences related to induction treatment, given that therapies for relapsed myeloma can also achieve a high extent and frequency of responses and confound analysis of the independent impact of initial treatment. Nonetheless, incorporation of daratumumab into initial therapy is becoming a standard of care, including in high-risk myeloma, to achieve increased MRD-negative responses and prevent the ongoing DNA damage and clonal evolution of residual myeloma that underlie relapse of disease.
ABSTRACT 143: Randomized phase III IFM 2009 study—Early vs late auto-HCT in newly diagnosed multiple myeloma: Long-term follow-up analysis (NCT01191060).5
Background: The IFM 2009 study prospectively evaluated the combination of eight cycles of RVd vs three cycles of RVd followed by auto-HCT. This was followed by two RVd cycles and then by lenalidomide maintenance for 12 months. RVd followed by auto-HCT was associated with significantly longer progression-free survival (primary endpoint) than RVd alone (P < .001). Overall survival at 4 years was similar in both groups.6
Methods: To evaluate the long-term outcome in the two arms and the impact of second-line treatments on second progression-free-survival and overall survival, investigators performed an extension of patient follow-up of the IFM 2009 study over 4 years (DB-FU-IFM 2009/NCT03679351). A total of 100 patients (50 from each arm) who experienced first disease progression were included in the IFM 2009-02 PCD trial (NCT02244125). The choice of second-line treatment and the decision to perform an auto-HCT at relapse were based on investigator’s discretion. The second progression-free survival was defined as the time from randomization to disease progression on the next line of therapy or death from any cause. This trial was previously reported with a median follow-up of 44 months.
Results:
- More patients in the nontransplant arm than in the transplant arm experienced disease progression, 270 (77.1%) vs 227 (64.9%), respectively.
- In the nontransplant arm, 76.7% (201 of 262) received an auto-HCT at first relapse.
- In the transplant arm, 22.6% (49 of 217) received a second auto-HCT at first relapse.
- Second progression-free survival was significantly increased in patients who received an auto-HCT at first relapse.
- At 8 years, the overall survival rate was 60.2% and 62.2% in the nontransplant and transplant arms (hazard ratio [confidence interval (CI)] = 1.03 [0.80–1.32], P = .81), respectively.
- MRD was a strong predictor of outcome: progression-free survival (HR [CI] = 0.28 [0.22–0.36], P < .001), second progression-free survival (HR [CI] = 0.27 [0.20–0.37], P < .001) and overall survival (HR [CI] = 0.35 [0.25–0.49], P < .001) were longer in patients achieving MRD negativity, in comparison with those who did not.
Clinical Implications: At first relapse, before the systematic use of daratumumab- or carfilzomib-based combinations, almost half of the patients received pomalidomide-based treatment, and about three-quarters of patients who had not received front-line auto-HCT underwent delayed (first) transplant. MRD status in this trial predicts for outcome, regardless of whether patients received transplant or not. Notable in this study was that the opportunity for delayed transplant was missed in a quarter of the patients, and it is plausible that this number would further increase in the real-world “nonclinical trial” practice. With a follow-up of almost 8 years, median overall survival was not reached, and there was no difference between the two strategies with respect to second progression-free survival and overall survival. Moreover, the incidence of invasive second primary cancer was not significantly different between the two groups (P = .38). Of note, ongoing and future clinical trials are evaluating MRD status to inform the type of therapy needed, if any, in patients who are MRD-negative at various important points (eg, after induction, after transplant, after consolidation, and during maintenance).
ABSTRACT 550: Randomized phase III EMN02/HO95 study—Report of progression-free survival from R2 (consolidation) with RVd followed by maintenance therapy vs maintenance alone in transplant eligible patients (aged ≤ 65 years) with newly diagnosed multiple myeloma (NCT01208766).7
Background: The role of auto-HCT with bortezomib/melphalan/prednisone (VMP) as intensification therapy and RVd consolidation therapy compared to no consolidation demonstrated that median progression-free survival was significantly improved with auto-HCT compared with VMP (56.7 months [CI = 49.3–64.5 months] vs 41.9 months [37.5–46.9 months]; HR = 0.73, 0.62–0.85; P = .0001). In the same study, at a median follow-up of 42.1 months (interquartile range = 32.3–49.2 months), consolidation therapy with RVd significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0 months to not estimable] vs 45.5 months [39.5–58.4 months]; HR = 0.77, 0.63–0.95; P = .014).8
Methods: The EMN02/HO95 trial was designed to compare intensification therapy (first randomization, or R1) with either four cycles of VMP (n = 495) or single or double auto-HCT (n = 702), after induction with bortezomib/cyclophosphamide/dexamethasone (BoCyD).8 A second randomization (R2) was performed after intensification for consolidation treatment with two cycles of RVd (n = 451) vs no RVd (n = 427; R2), followed by lenalidomide (10 mg) maintenance until disease progression or unacceptable toxicity. Primary study endpoints were progression-free survival from R1 and progression-free survival from R2. For R2, 894 patients were eligible, of whom 878 had also been included in R1. Median follow-up from R2 was 71.3 months.
Results:
- Progression-free survival from R2 with adjustment for R1 was prolonged in patients randomly assigned to RVd consolidation (HR = 0.80; 95% CI = 0.67–0.95; P = .013) vs no consolidation—which is consistent with the results of the first and second interim analyses.
- The secondary endpoint of response ≥ complete response after consolidation vs no consolidation and before the start of maintenance was 34% vs 18%, respectively (P < .001).
- At 6 years, overall survival was 75% (CI = 71%–79%) in the RVd arm vs 69% (CI = 64%–73%) without RVd.
- Toxicity associated with RVd was reported to be acceptable and manageable, with 5% Common Terminology Criteria for Adverse Events grade 4, mainly neutropenia (2%) and thrombocytopenia (2%).
Clinical Implications: Consolidation RVd followed by continuous lenalidomide maintenance improved progression-free survival and quality of response in newly diagnosed patients with multiple myeloma compared with lenalidomide maintenance alone in patients treated with BoCyD induction and auto-HCT or VMP intensification. The cumulative incidence of second primary malignancies at 6 years from R2, excluding superficial skin cancer, was 5% to 6% in both arms. The STAMINA trial9 has compared three strategies (lenalidomide maintenance, RVd consolidation and lenalidomide maintenance, or second auto-HCT with lenalidomide maintenance) in patients who had already received an auto-HCT. It did not find an overall difference in outcome in these three patient cohorts. In both the EMN02/HO957 and STAMINA9 trials, a second auto-HCT conferred benefit in patients with high-risk disease. Ongoing trials are now evaluating the need for and value of consolidation therapy predicated upon MRD status.
ABSTRACT 141: Randomized phase II FORTE study—Progression-free and overall survival analysis of transplant-eligible (aged ≤ 65 years) patients with newly diagnosed multiple myeloma (NCT02203643).10
Background and Methods: Patients were randomly assigned (R1) to receive 4 cycles of carfilzomib/lenalidomide/dexamethasone (KRd) induction followed by auto-HCT and 4 cycles of KRd consolidation (n = 158) vs 12 cycles of KRd (KRD) (n = 157) vs carfilzomib/cyclophosphamide/dexamethasone × 4 cycles (KCd) induction followed by auto-HCT and 4 cycles of KCd consolidation (n = 159).
After consolidation, patients underwent second randomization (R2) to carfilzomib/lenalidomide (KR; n = 178) × 2 years then lenalidomide until disease progression vs lenalidomide (n = 178) maintenance until disease progression.
The aims of the analysis were to evaluate the progression-free survival of first 4 cycles of KRd followed by auto-HCT and 4 cycles of KRd vs 12 cycles of KRd vs 4 cycles of KCd followed by auto-HCT and 4 cycles of KCd and second KR vs lenalidomide maintenance.
MRD evaluation (eight-color second-generation flow cytometry, sensitivity 10–5) was performed in patients achieving at least a very good partial response before maintenance and every 6 months during maintenance.
Results: After a median follow-up from R1 of 45 months: Median progression-free survival was not reached with 4 cycles of KRd followed by auto-HCT and 4 cycles of KRd; 57 months with 12 cycles of KRd; and 53 months with 4 cycles of KCd followed by auto-HCT and 4 cycles of KCd. The benefit of 4 cycles of KRd/auto-HCT/4 cycles of KRd vs both 12 cycles of KRd and 4 cycles of KCd/auto-HCT/4 cycles of KCd was observed in most subgroups. The 3-year overall survival was 90% with 4 cycles of KRd/auto-HCT/4 cycles of KRd and 12 cycles of KRd vs 83% with 4 cycles of KCd/auto-HCT/4 cycles of KCd.
After a median follow-up from R2 of 31 months and a median duration of maintenance of 27 months in both arms: By intention-to-treat analysis, 3-year progression-free survival from R2 was 75% with KR vs 66% with lenalidomide alone (HR = 0.63; P = .026). The benefit of KR vs lenalidomide was observed in most subgroups. The 3-year overall survival was 90% in both arms. In all, 46% of MRD-positive patients at randomization became MRD-negative with KR vs 32% with lenalidomide (P = .04). Four patients developed a second primary malignancy with KR vs one patient with lenalidomide.
Clinical Implications: In patients with newly diagnosed multiple myeloma, treatment with 4 cycles of KRd/auto-HCT/4 cycles of KRd significantly improved progression-free survival compared with the other two experimental arms. Also, maintenance with KR was superior in terms of progression-free survival compared with lenalidomide alone. Of note, KR vs lenalidomide significantly prolonged progression-free survival, even in patients who were MRD-negative before starting the R2 phase of the protocol, highlighting the current limitation of MRD-based therapeutic decisions.11 This randomized FORTE trial therefore supports 4 cycles of KRd/auto-HCT/4 cycles of KRd followed by KR × 2 years and then lenalidomide maintenance until disease progression or intolerability. Importantly, it further establishes auto-HCT as a standard of care; demonstrates the superiority of KRd over KCd; and supports the use of combination lenalidomide proteasome inhibitor maintenance.
A recent study of KRd vs RVd followed by auto-HCT in non–high-risk12 newly diagnosed transplant-eligible patients with multiple myeloma demonstrated that these induction treatments were equivalent; however, the FORTE study demonstrated a benefit with KRd in all patients, including those with high-risk disease, and may therefore be especially useful in this subgroup of patients. As in the FORTE study, the use of a proteasome inhibitor in risk-adapted maintenance therapy (RVd) has been shown to abrogate early relapses characteristic of high-risk disease.13 Of note, those patients who received 4 cycles of KRd/auto-HCT/4 cycles of KRd and KR maintenance had higher rates of persistent MRD negativity, which has been associated with improved outcome. Ongoing studies are evaluating whether maintenance can be tailored depending on MRD status, as well as whether more stringent thresholds (10-6) may have even greater clinical significance.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy. Dr. Anderson is Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics and Kraft Family Professor of Medicine at the Harvard Medical School.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Anderson has been an advisor or consultant for Amgen, Janssen, Pfizer, Sanofi, Oncopeptides, and Precision Biosciences.
REFERENCES
1. Kaufman JL, Laubach JP, Sborov D, et al: Daratumumab plus lenalidomide, bortezomib, and dexamethasone in patients with transplant-eligible newly diagnosed multiple myeloma: Updated analysis of GRIFFIN after 12 months of maintenance therapy. 2020 ASH Annual Meeting & Exposition. Abstract 549. Presented December 7, 2020.
2. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 136:936-945, 2020.
3. Giri S, Grimshaw A, Bal S, et al: Evaluation of daratumumab for the treatment of multiple myeloma in patients with high-risk cytogenetic factors: A systematic review and meta-analysis. JAMA Oncol 6:1759-1765, 2020.
4. Munshi NC, Avet-Loiseau H, Anderson KC, et al: A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv 4:5988-5999, 2020.
5. Perrot A, Lauwers-Cances V, Cazaubiel T, et al: Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: Long-term follow-up analysis of the IFM 2009 trial. 2020 ASH Annual Meeting & Exposition. Abstract 143. Presented December 5, 2020.
6. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.
7. Sonneveld P, Beksac M, Van Der Holt B, et al: Consolidation treatment with VRD followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant-eligible patients with multiple myeloma: A randomized phase 3 trial of the European Myeloma Network (EMN02/HO95). 2020 ASH Annual Meeting & Exposition. Abstract 550. Presented December 7, 2020.
8. Cavo M, Gay F, Beksac M, et al: Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): A multicentre, randomised, open-label, phase 3 study. Lancet Haematol 7:e456-e468, 2020.
9. Stadtmauer EA, Pasquini MC, Blackwell B, et al: Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J Clin Oncol 37:589-597, 2019.
10. Gay F, Musto P, Scalabrini DR, et al: Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized FORTE trial. 2020 ASH Annual Meeting & Exposition. Abstract 141. Presented December 5, 2020.
11. Oliva S, Genuardi E, Petrucci MT, et al: Impact of minimal residual disease by multiparameter flow cytometry and next-generation sequencing on outcome: Results of newly diagnosed transplant-eligible multiple myeloma patients enrolled in the FORTE trial. 2020 ASH Annual Meeting & Exposition. Abstract 491. Presented December 6, 2020.
12. Kumar SK, Jacobus SJ, Cohen AD, et al: Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): A multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 21:1317-1330, 2020.
13. Joseph NS, Kaufman JL, Dhodapkar MV, et al: Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol 38:1928-1937, 2020.
