Syed Ali Abutalib, MD
Kenneth C. Anderson, MD
Here is an update on several different studies focusing on novel treatments for patients with newly diagnosed multiple myeloma presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition. Featured therapeutics include daratumumab plus lenalidomide and dexamethasone, carfilzomib plus lenalidomide and dexamethasone, as well as maintenance therapy with ixazomib or lenalidomide after autologous stem cell transplantation. (See part 2, with more abstracts on newer treatments under study for relapsed or refractory multiple myeloma presented at the 2018 ASH Annual Meeting & Exposition.)
Treatments for Newly Diagnosed Myeloma
Abstract LBA-2: Multicenter phase III randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd; n = 368) vs lenalidomide and dexamethasone (Rd; n = 369) in patients with newly diagnosed multiple myeloma ineligible (protocol-defined age ≥ 65 years or comorbidities) for transplant1
Primary Study Endpoint: Progression-free survival
Key Findings: The prespecified interim analysis occurred after 239 progression-free survival events, with a median follow-up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% confidence interval [CI] = 0.43–0.72; P < .0001), representing a 45% reduction in the risk of disease progression or death in patients treated with D-Rd. The median progression-free survival for the Rd arm was 31.9 months and not reached for the D-Rd arm. The D-Rd regimen resulted in deeper responses with a complete response or better rate of 47.6% in the D-Rd arm compared with 24.7% in the Rd arm (odds ratio = 2.75, 95% CI = 2.01–3.76; P < .0001). A total of 19% of patients have died, and the hazard ratio for overall survival was 0.78 (95% CI = 0.56–1.1); follow-up is ongoing. Higher rates (5% or more difference) of grade 3 to 5 pneumonia, neutropenia, and leukopenia were observed in the D-Rd arm. The safety profile is consistent with previously reported daratumumab studies.
These data support the addition of daratumumab to standard-of-care combinations in patients with newly diagnosed multiple myeloma who are ineligible for autologous hematopoietic cell transplantation.— Syed Ali Abutalib, MD, and Kenneth C. Anderson, MD
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Clinical Implications: D-Rd in patients with transplant-ineligible newly diagnosed multiple myeloma significantly reduced the risk of disease progression or death by 45%. There were no new safety signals observed with this regimen. These data, together with the phase III ALCYONE study (D-VMP [daratumumab plus bortezomib, melphalan, prednisone] vs VMP), support the addition of daratumumab to standard-of-care combinations in patients with newly diagnosed multiple myeloma who are ineligible for autologous hematopoietic cell transplantation (auto-HCT).2
Of note, regimens containing melphalan and prednisone are rarely used in North America, where lenalidomide, bortezomib, and dexamethasone (RVD) in reduced doses (RVD-lite) is a common initial triplet regimen in transplant-ineligible patients with newly diagnosed multiple myeloma. Although RVD-lite and D-Rd have not yet been directly compared in a randomized trial, D-Rd already has achieved remarkable prolongation of progression-free survival. It represents a major advance and a new therapeutic option to treat transplant-ineligible patients with newly diagnosed multiple myeloma.
Abstract 121: Carfilzomib/lenalidomide/dexamethasone (KRd) induction auto-HCT KRd consolidation (4; n = 158) vs KRd 12 cycles (n = 157) vs carfilzomib/cyclophosphamide/dexamethasone (KCd) inductionauto-HCT KCd consolidation (4; n = 159). Following completion of planned therapy, patients were randomly assigned to maintenance with lenalidomide alone or plus carfilzomib.3
Primary Study Endpoints and Methods: The primary aim was to evaluate the efficacy and safety of different therapeutic platforms. Endpoints were premaintenance stringent complete response and minimal residual disease (MRD) negativity in intent-to-treat analysis. Centralized MRD evaluation—8-color second-generation flow cytometry, sensitivity 10-5—was performed in patients achieving at least a very good partial response.
Key Findings: The median follow-up was 20 months. By intent-to-treat analysis, the rate of premaintenance stringent complete response was similar between KRd auto-HCT KRd (41%) and KRd12 (42%) and significantly higher than with KCd auto-HCT KCd (30%; P for KRd auto-HCT KRd vs KCd auto-HCT KCd = .047; P for KRd12 vs KCdauto-HCTKCd = .028). In multivariate analysis, the main factor affecting the probability of achieving at least a very good partial remission, at least a complete response, or a stringent complete response was treatment with KRd auto-HCT KRd or KRd12 vs KCd, with no significant impact of International Staging System stage or fluorescence in situ hybridization abnormalities.
In the intent-to-treat analysis (MRD missing [31 of 395 patients achieving a very good partial response, 8%] and less than a very good partial response were considered to be MRD-positive), MRD negativity was again similar with KRd auto-HCT KRd (58%) and KRd12 (54%) and significantly higher than with KCd auto-HCT KCd (41%; P for KRd auto-HCT KRd vs KCd auto-HCTKCd = .004; P for KRd12 vs KCd auto-HCT KCd = .023); 82% vs 78% vs 88% of patients in the three groups, respectively, could maintain extended MRD-negative status with 2 MRD-negative results obtained apart at least 6 months (either pretransplant and postconsolidation or postconsolidation and during maintenance). The rates of grade 3 to 4 cardiac adverse events and thrombosis were below 5% in all arms. Treatment discontinuation due to adverse events was similar in the three arms.
Clinical Implications: The rates of MRD negativity, stringent complete response, at least a complete response, and at least a very good partial response were significantly higher with KRd auto-HCT KRd and KRd12 vs KCd. This study shows that incorporation of an immunomodulatory drug such as lenalidomide is superior to adding cyclophosphamide to the carfilzomib and dexamethasone platform to increase the depth of response, as evidenced by achievement of MRD negativity. At present, no differences in MRD and overall best response (stringent complete response, at least a complete response, at least a very good partial response) were noticed between KRd auto-HCT KRd and KRd12; longer follow-up is needed to assess the comparative duration of response and to evaluate survival.
Abstract 799: KRd (n = 149) vs =RVD (n = 460) in patients with newly diagnosed multiple myeloma: A nonrandomized, historical comparison4
Study Endpoint: Event-free survival (defined as the time from the start of treatment until disease progression, death, or the initiation of new therapy)
Key Findings: With a median follow-up of 11.5 months for KRd and 41.9 months for RVD, 12-month event-free survival rates (95% CI) were 95% (90%–99%) for KRd vs 84% (78%–90%) for RVD (12-month hazard ratio = 0.28; 95% CI = 0.10–0.75; P = .0043). By 12 months, 87% (95% CI = 81%–93%) of patients treated with KRd vs 68% (95% CI = 60%–76%) of patients treated with RVD had a partial response or better (P = .0029) and 35% (95% CI = 25%–45%) of patients treated with KRd vs 14% (95% CI = 8%–20%) of patients treated with RVD achieved a complete response or better (P = .0054). Treatment discontinuation rates due to adverse events were similar between KRd and RVD.
Clinical Implications: KRd demonstrated significant improvements in 12-month event-free survival compared with RVD. With limitations of nonrandomized evaluation and a relatively short median follow-up in the KRd arm, these results are consistent with previous single-arm studies that KRd is not only effective but potentially superior compared with RVD. As noted previously, the nonrandomized comparison and short follow-up limit any conclusions from this study, and we await results from ongoing randomized head-to-head comparative studies.
Abstract 301: Maintenance therapy with ixazomib (n = 395) prolongs progression-free survival after auto-HCT in patients with newly diagnosed multiple myeloma—Results of phase III, double-blind, placebo-controlled (n = 261), multicenter Tourmaline-MM3 trial5
Primary Study Endpoint: Progression-free survival
Key Findings: After a median follow-up of 31 months with 54% of progression-free survival events, there was a 28% reduction in the risk of disease progression/death, corresponding to a 39% improvement in progression-free survival with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio = 0.72; 95% CI = 0.582–0.890; P = .002). In a landmark analysis of auto-HCT, the progression-free survival was 30.7 vs 24.9 months (hazard ratio = 0.684; 95% CI = 0.551–0.848; P < .001). The median progression-free and overall survival have not yet been reached in either arm. Ixazomib maintenance led to higher rates of deepened response compared with placebo (relative risk = 1.41; 95% CI = 1.10–1.80; P = .004). Conversion from documented MRD positivity at study entry to MRD negativity occurred at a higher rate with ixazomib than placebo (12% vs 7%). The rate of peripheral neuropathy was 19% vs 15% (< 1% vs 0 grade 3). The rate of second primary malignancies was 3% in both arms.
Clinical Implications: The study supports ixazomib maintenance therapy in patients who are not candidates for lenalidomide maintenance therapy. Although oral ixazomib maintenance was well tolerated, there was only a 5.2-month prolongation of progression-free survival and no impact on overall survival. This result is in marked contrast to lenalidomide maintenance, which doubled progression-free survival and also demonstrated a survival advantage. Heterogeneity in induction therapy prior to transplant and maintenance treatment with ixazomib for 2 years in this study are among the variables that may have limited the benefit of therapy. Prior studies have shown the benefit of proteasome inhibitor bortezomib maintenance, alone or in combination with lenalidomide, in decreasing the early relapses characteristic of high-risk myeloma; data using ixazomib in high-risk patients in the current study are too limited to draw conclusions. We therefore await the results of ongoing studies, such as those combining lenalidomide with ixazomib maintenance in patients with high-risk disease.
Abstract 4737: Survival analysis from the Cancer and Leukemia Group B (CALGB) study of lenalidomide maintenance therapy in newly diagnosed multiple myeloma after auto-HCT adjusted for crossover6
The data reported here provide further insight into the survival benefits of lenalidomide maintenance therapy after [autologous hematopoietic cell transplantation] and support guideline recommendations.— Syed Ali Abutalib, MD, and Kenneth C. Anderson, MD
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Key Findings: A total of 76 patients with newly diagnosed multiple myeloma who did not experience disease progression, as determined by central adjudication, crossed over from placebo to lenalidomide and were included in the analysis. The landmark analysis of overall survival from the date of unblinding indicated that the treatment effect for the crossover vs the non-crossover placebo group was a hazard ratio of 0.57 (95% CI = 0.29–1.15). This also provided a measure of the benefit of lenalidomide maintenance in patients who started maintenance therapy after the trial-specified 90- to 100-day window after auto-HCT (median 11.5 months post-randomization; range = 3.2–51.0 months). Adjustment for crossover using the rank-preserving structural failure time model or iterative parameter estimation resulted in an increase in the relative treatment effect of lenalidomide maintenance (vs placebo) on overall survival from 30.8 months for the intent-to-treat analysis (hazard ratio = 0.61; 95% CI = 0.47–0.81) to 40.1 months (hazard ratio = 0.52; 95% CI = 0.36–0.73) for the rank-preserving structural failure time model analysis and 38.8 months (hazard ratio = 0.52; 95% CI = 0.37–0.74) for the iterative parameter estimation analysis. Results were consistent across the two methods.
Clinical Implications: Once investigators adjusted for crossover, there was an additional improvement in overall survival. Previously, a preplanned, pooled meta-analysis of 3 studies that included CALGB/Alliance7 indicated that the overall survival gain was 2.5 years; however, these data from the CALGB study alone show that lenalidomide maintenance may provide a survival benefit of more than 3 years.
In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this type of analysis. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of lenalidomide maintenance therapy after auto-HCT and support guideline recommendations.
Clinically Relevant Biologic Finding
Abstract 749: The role of clonal hematopoiesis of indeterminate potential in multiple myeloma: Immunomodulator maintenance after auto-HCT predicts better outcome8
Key Findings: The Dana-Farber Cancer Institute cohort had a median patient age of 58 years (range = 24–83 years) at the time of auto-HCT and a median follow-up of 8 years (range = 0.1–14.5 years) after auto-HCT. About 204 patients (32%) in the Dana-Farber Cancer Institute cohort had clonal hematopoiesis of indeterminate potential at the time of auto-HCT by targeted next-generation sequencing using a 224-gene panel. The most commonly detected mutated genes were DNMT3A, TET2, TP53, ASXL1, and PPM1D. About 24 patients (3.8%) developed a second hematologic malignancy at a median of 4 years (range = 1–10 years) posttransplant, half of whom had clonal hematopoiesis of indeterminate potential.
Around 48% of the Dana-Farber Cancer Institute cohort received immunomodulatory drugs as part of induction therapy. Different induction regimens had no effect on clonal hematopoiesis of indeterminate potential prevalence at the time of auto-HCT. Around 56% of the Dana-Farber Cancer Institute cohort received immunomodulatory drug maintenance, 22% of which received maintenance for at least 3 years (range = 0.06–12.8 years).
Among those who did not receive immunomodulatory drug maintenance, patients with clonal hematopoiesis of indeterminate potential had worse progression-free survival (P < .001) and overall survival (P = .005). In patients receiving immunomodulatory drug maintenance, having clonal hematopoiesis of indeterminate potential had no effect on progression-free or overall survival.
On the other hand, the Multiple Myeloma Research Foundation (MMRF) cohort had a median patient age of 63 years (range = 27–93 years) and a median follow-up of 3.03 years (range = 0–5.9 years) from the time of diagnosis. Similarly, when studying the genomic results of 139 of 1,144 patients from MMRF, as well as the 205 patients from the Broad Institute data set, the investigators detected clonal hematopoiesis of indeterminate potential in 25.6% of them, and the top 5 most commonly mutated genes were similar to those of our cohort.
Clinical Implications: Clonal hematopoiesis of indeterminate potential is a common entity among patients with multiple myeloma, reaching a prevalence of up to 25% to 32% (by next-generation sequencing), which predicts a worse progression-free and overall survival in those who do not receive immunomodulatory drug maintenance therapy after auto-HCT. In patients with clonal hematopoiesis of indeterminate potential, the use of immunomodulatory drug abrogated the deleterious effect imposed by clonal hematopoiesis of indeterminate potential to a point that the outcome is identical to that of patients without clonal hematopoiesis of indeterminate potential. This study suggests that patients with clonal hematopoiesis of indeterminate potential are more likely to be predisposed to secondary malignancies after high-dose chemotherapy and autologous rescue, and testing for clonal hematopoiesis of indeterminate potential may be an important consideration, especially in transplant-eligible candidates. ■
Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; and Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Anderson is Program Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics; and Kraft Family Professor of Medicine, Harvard Medical School, Boston.
DISCLOSURE: Dr. Abutalib has served on an advisory board for Millennium Takeda. Dr. Anderson has served as an advisor to Celgene, Millennium Takeda, Gilead, Bristol-Myers Squibb, and Janssen.
REFERENCES
1. Facon T, Kumar SK, Plesner T, et al: Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma ineligible for transplant (MAIA). 2018 ASH Annual Meeting & Exposition. Abstract LBA-2. Presented December 4, 2018.
2. Mateos MV, Dimopoulos MA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518-528, 2018.
3. Gay F, Cerrato C, Scalabrini DR, et al: Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant-Krd consolidation vs Krd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-Kcd consolidation: Analysis of the randomized Forte trial in newly diagnosed multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 121. Presented December 1, 2018.
4. Landgren O, Siegel DS, Auclair D, et al: Carfilzomib-lenalidomide-dexamethasone versus bortezomib-lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma: Results from the prospective, longitudinal, observational Commpass study. 2018 ASH Annual Meeting & Exposition. Abstract 799. Presented December 3, 2018.
5. Dimopoulos MA, Gay F, Schjesvold FH, et al: Maintenance therapy with the oral proteasome inhibitor ixazomib significantly prolongs progression-free survival following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Phase 3 Tourmaline-MM3 trial. 2018 ASH Annual Meeting & Exposition. Abstract 301. Presented December 2, 2018.
6. McCarthy PL, Richardson P, Suman V, et al: Survival analysis from the CALGB study of lenalidomide maintenance therapy in newly diagnosed multiple myeloma post-autologous stem cell transplantation adjusted for crossover (Alliance 100104). 2018 ASH Annual Meeting & Exposition. Abstract 4737. Presented December 3, 2018.
7. McCarthy PL, Holstein SA, Petrucci MT, et al: Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol 35:3279-3289, 2017.
8. Mouhieddine TH, Park J, Redd RA, et al: The role of clonal hematopoiesis of indeterminate potential in multiple myeloma: Immunomodulator maintenance post autologous stem cell transplant predicts better outcome. 2018 ASH Annual Meeting & Exposition. Abstract 749. Presented December 3, 2018.
