Approved Combinations and Novel Agents Expand Therapy Options Across Multiple Myeloma Settings

Shaji Kumar, MD

Shaji Kumar, MD

The addition of novel agents and combinations to the treatment of multiple myeloma (MM), along with improvements in personalized therapy based on genetic profiles of individual patients, are propelling care forward with their potential for prolonging survival and deepening responses beyond those from the current standards of care.

Significant advances, most notably with the addition of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), in the management of MM have improved outcomes over the past 2 decades. In the last 5 years, the United States FDA has approved several new therapies for myeloma—daratumumab (Darzalex),1 ixazomib (Ninlaro),²elotuzumab (Empliciti),³and the selective inhibitor of nuclear export (SINE) compound selinexor (Xpovio).⁴

New regimens involving these agents are expected to build upon the therapeutic benefits obtained in recent decades and have the potential to change the standard of care.

The triplet regimen consisting of daratumumab with lenalidomide (Revlimid) and dexamethasone (DRd) was recently approved for the treatment of patients with newly diagnosed MM ineligible for autologous stem cell transplantation. The approval was based on data from the phase III MAIA trial that showed a 44% reduction in the risk of disease progression or death in newly diagnosed, transplant-ineligible patients compared with lenalidomide and dexamethasone (Rd) alone.^5,6Prior to these results, the current standard treatment in this patient population was Rd.^6,7

In addition, the accelerated approval of selinexor in combination with dexamethasone for the treatment of MM refractory to 5 of the most commonly used antimyeloma agents marks the first approved therapy regimen for this patient population, which is historically associated with poor prognoses and limited therapeutic options, and marks an important step forward in the treatment of the disease.^4,8

Paul G. Richardson, MD

Paul G. Richardson, MD

When discussing recent FDA approvals in an interview with Targeted Therapies in Oncology (TTO), Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center of Dana-Farber Cancer Institute and the RJ Corman Professor of Medicine at Harvard Medical School, both in Boston Massachusetts, said that in combination with other agents, selinexor “is particularly promising. I think it will have broad effect in patients with exquisite need, especially those with high-risk [disease]. There are a variety of settings in which it stands apart as being an excellent candidate agent in combination for improving outcomes. The approval of selinexor...opens the door to rational combinations thereafter.”

Treating Later-Stage Disease With Selinexor

The oral SINE compound selinexor inhibits exportin 1, a protein responsible for the nucleocytoplasmic shuttling of over 200 cargo proteins, including tumor suppressors, oncoproteins, and growth regulatory factors.⁹

In 2018, data from the phase IIb STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple-class refractory MM previously exposed to all 5 of the most commonly prescribed antimyeloma therapies currently available were reported at the American Society of Hematology (ASH) Annual Meeting in San Diego, California.^10,11Selinexor plus low-dose dexamethasone demonstrated a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of 8.6 months in patients with disease that was documented to be refractory to at least 1 PI, at least 1 IMiD, daratumumab, a glucocorticoid, and the patient’s last line of therapy.1¹Prior study results show the combination to be active in patients with high-risk cytogenetic features.¹²

“STORM Part 2 represents the largest, most heavily pretreated population with MM in a prospective clinical trial to date,” Ajai Chari, MD, director of clinical research, Multiple Myeloma Program, Mount Sinai School of Medicine in New York City, said during a presentation at the conference. “Patients received a median of 7 prior therapies over 6.6 years. These patients have no known available therapies with clinical benefit.”

Prior to the reporting of the data from this study, selinexor was granted orphan drug designation, fast track designation, and priority review for this patient population based on the trial results.¹³

In February 2019 at the FDA’s Oncologic Drugs Advisory Committee meeting about the new drug application (NDA), the committee voted 8 to 5 to recommend that the FDA wait for the results from the randomized, open-label, phase III BOSTON trial evaluating selinexor in combination with bortezomib (Velcade) and dexamethasone in patients with relapsed or refractory MM before making a final decision regarding approval. Subsequently, the target action date for the NDA was extended to July 6, 2019.¹⁴

Daratumumab in the Frontline Setting and Beyond

On July 3, 2019, the FDA granted accelerated approval to selinexor in combination with dexamethasone for adult patients with relapsed or refractory MM who received at least 4 prior therapies and whose disease is refractory to &ge;2 PIs, &ge;2 IMiDs, and an anti-CD38 monoclonal antibody. The designation was based on efficacy and safety data in a patient subgroup of 83 individuals that showed an overall response rate (ORR) of 25.3%, including 1 stringent complete response (sCR), 4 very good partial responses (VGPRs), and 16 partial responses (PRs). The FDA noted that the continued approval for this indication may be contingent upon verification and description of clinical benefit in the BOSTON confirmatory trial.⁴At a median follow-up of 28.0 months, MAIA study data, which served as the basis for the approval of the DRd combination, showed the median PFS had not been reached in the experimental arm versus 31.9 months with Rd alone (HR, 0.56; 95% CI, 0.43-0.73;P<.001). DRd also yielded deeper responses, including higher rates of complete response (CR) or better (47.6% vs 24.9%;P<.001). The ORR was also higher with the triplet regimen (92.9% with DRd vs 81.3% with Rd).⁶

&ldquo;Based on the MAIA trial, patients who are not being considered for transplant ,and who do not have high-risk disease, will be appropriate for the DRd induction,&rdquo; Shaji Kumar, MD, professor of medicine at Mayo Clinic College of Medicine in Rochester, Minnesota, said in an interview withTTO. &ldquo;The MRD [minimal residual disease] rate was clearly higher in the daratumumab group, nearly 3 to 4 times that in the control group, speaking to its efficacy.&rdquo;

Data regarding patient-reported outcomes from the MAIA study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, providing key insights into the patients&rsquo; perspective on their health-related quality of life (HRQoL) while on treatment. Questionnaire data were collected at baseline and every 3 months during treatment to assess treatment effects of DRd versus Rd alone. Although compliance rates were high and comparable at baseline (>90%) and through month 12 (>80%) for both groups, significantly greater improvement was observed at cycle 3 in patients in the DRd group and increasing improvements with the regimen occurred across all time points. Notably, meaningful differences were observed between the DRd and Rd groups in 2 subscale scores: pain symptoms and cognitive functioning. This led the presenters to conclude that faster and sustained improvement in HRQoL was observed in patients treated with DRd versus Rd alone.¹⁵

One consideration that came out of the MAIA trial is that patients with high-risk cytogenetics did not see as great a benefit with the addition of daratumumab compared with patients who had standard-risk features. &ldquo;We did not see this in the other trial, POLLUX (NCT02076009), which did the same comparison in another group of patients, those with relapsed disease,&rdquo; Kumar said. &ldquo;It is possible that this may be related to the difficulty in defining high-risk [features] in the relapsed patient population. Nevertheless, the lack of benefit for the high-risk patients seen in MAIA may reflect a rather short follow-up at this time, [and] with longer follow-up, it is possible that the benefit will emerge.&rdquo;

Another advancement for daratumumab includes the priority review that was granted to the anti-CD38 monoclonal antibody in combination with bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) for use in transplant-eligible patients with newly diagnosed MM, with a target action date of September 26, 2019.¹⁶

The supplemental biologics license application is based on data from the phase III CASSIOPEIA trial in which 1085 patients were randomized to daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd; n = 543) or VTd alone (n = 542). Data from this study were presented at the 2019 American Society of Clinical Oncology Annual Meeting and showed a sCR rate of 28.9% versus 20.3% in the D-VTd and VTd-alone arms, respectively. The rates of PFS at 18 months were 92.7% with daratumumab compared with 84.6% with VTd (HR, 0.47; 95% CI, 0.33-0.67;P<.0001). Although the median OS was not reached in either arm at the time of analysis, the OS rate at 24 months was 97% with D-VTd compared with 93% with VTd.17 The addition of daratumumab to this regimen was also found to be associated with significant increases in MRD-negativity rates post induction (34.6% vs 23.1% with VRd;P<.0001) and post consolidation (63.7% vs 43.5%;P<.0001).¹⁸

In an interview withTTO, Phillipe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France, and primary investigator on the study, said, &ldquo;The study clearly showed that both before maintenance and after consolidation, the addition of daratumumab is increasing the response rate, the quality of the response, the depth of the response, and MRD negativity; this translates into a better PFS, a significant PFS benefit, with a hazard ratio less than 0.5 [compared with VTd alone].&rdquo;

The second phase of the CASSIOPEIA trial, which will randomize patients to receive either daratumumab maintenance or no maintenance, is currently ongoing.

The clinical efficacy of daratumumab plus VRd versus VRd alone is being evaluated in the randomized, open-label, parallel-assignment phase II GRIFFIN study. In data presented at the 2018 ASH Annual meeting, D-VRd was shown to induce at least a VGPR in all patients, with 63% (n = 16) achieving sCR or CR at the end of consolidation therapy.¹⁹Moreover, half of the patients achieved MRD negativity after consolidation in the safety run-in phase of the trial, according to Peter Voorhees, MD, associate professor of medicine at University of North Carolina Lineberger Comprehensive Cancer Center in Charlotte.

Vorhees also added that all 16 patients underwent successful stem cell mobilization with subsequent transplant, leading to the conclusion that &ldquo;adding daratumumab to a VRd backbone [does not] negatively impacts stem cell collection and engraftment.&rdquo;¹⁹

Topline data from the study reported in July 2019 showed a higher percentage of sCR in D-VRd—treated patients than those who received VRd alone (42.4% vs 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82,P= .1359), meeting the study&rsquo;s primary endpoint and exceeding statistical significance.²⁰

Additional data presented at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation indicated that daratumumab demonstrated an encouraging efficacy and acceptable toxicity profile when used as salvage therapy in patients with relapsed or refractory MM after allogenic stem cell transplantation. With a median follow-up of 14 months after the first administration, 20 of 22 patients were alive, for a 1-year OS rate of 90.9%, and the ORR was 68%—made up of 5 PRs, 8 VGPRs, and 2 CRs&mdash;with daratumumab therapy.²¹

Finally, a new subcutaneous form of daratumumab, which is coformulated with recombinant human hyaluronidase PH20, may soon be available based on data from the phase III COLUMBA study that were presented at the 2019 ASCO Annual Meeting and demonstrated noninferiority compared with the intravenous administration of daratumumab. The biologics license application submitted to the FDA is also supported by data from the nonrandomized phase II PLEIADES study, which is seeking a VGPR or better in patients treated with the subcutaneous formulation plus VRd.²²

Potential for Venetoclax in the Multiple Myeloma Space

The first-in-class selective inhibitor of the B-cell lymphoma-2 (B-CL2) protein venetoclax (Venclexta) that has indications in chronic lymphocytic leukemia, small lymphocytic lymphoma, and newly diagnosed acute myeloid leukemia is being investigated in certain patient subsets of MM.

Earlier this year, the FDA placed a partial clinical hold on all trials evaluating venetoclax in MM, following a review of data from the ongoing phase III BELLINI trial in relapsed or refractory MM.23 Although the median PFS was nearly doubled in the venetoclax arm compared with the placebo arm (22.4 vs 11.5 months; HR, 0.63;P= .01), a greater number of deaths due to infection in the experimental arm marred OS findings.²⁴

&ldquo;The BELLINI trial did show increased deaths in the venetoclax arm, mostly related to infections occurring in the context of disease relapse,&rdquo; said Kumar, who was also the lead study author. &ldquo;There are specific characteristics, such as the presence of high-risk [cytogenetics] and low expression of B-CL2, that put patients at risk of not responding to therapy as well increasing the risk of death. It is unclear what the role of the specific regimen is, but venetoclax is clearly active in patients with t(11;14) as a single agent and in all patients in a variety of combinations. Other combinations, such as those with daratumumab and carfilzomib, are currently ongoing.&rdquo;

In June 2019, AbbVie announced that the FDA lifted the partial clinical hold placed on the phase III CANOVA study, evaluating venetoclax in combination with dexamethasone versus pomalidomide (Pomalyst) in combination with dexamethasone in patients with relapsed or refractory MM positive for t(11;14). The lift of the partial hold follows an agreement on revisions to the CANOVA study protocol, including new risk-mitigation measures, protocol-specified guidelines, and updated futility criteria.²⁵

Phase III Results in Relapsed/Refractory Disease

The primary analysis of the phase II ELOQUENT-3 study, which evaluated elotuzumab in combination with pomalidomide and dexamethasone (EPd) in the relapsed or refractory setting, were recently presented and showed the combination yielded sustained and clinically relevant PFS and OS benefits compared with pomalidomide and dexamethasone (Pd), with no new safety signals. Moreover, the initial ORR was 53% (95% CI, 40%-66%) in the EPd group compared with 26% (95% CI, 16%-40%) in the Pd group (OR, 3.25; 95% CI, 1.49-7.11;P= .0029). The rate of VGPR or better was 20% versus 9%, with and without elotuzumab, respectively.²⁶

&ldquo;These data point to the potential for this combination to become a new standard of care for patients with multiple myeloma that returned after or did not respond to prior therapies, including lenalidomide and a proteasome inhibitor,&rdquo; lead study author Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at Kapodistrian University of Athens School of Medicine, said during a presentation of the data at the 2019 European Hematology Association Congress.

Another biologics license application has been accepted by the FDA for isatuximab, a novel anti-CD38 monoclonal antibody, in combination with Pd for the treatment of patients with relapsed or refractory MM.²⁷The combination was evaluated in the phase III ICARIA-MM trial in patients who received &ge;2 prior lines of therapy, including lenalidomide and a PI, and were refractory to their last therapy. Data from this trial were presented at the 2019 ASCO Annual Meeting and showed that the isatuximab combination significantly improved median PFS (11.5 vs 6.5 months; HR, 0.596; 95% CI, 0.44-0.81;P= .001) and ORR (60.4% vs 35.3%,P<.0001) compared with Pd alone.²⁸The FDA has a scheduled decision date of April 30, 2020.

Potential for CAR T-Cell Therapy

Promising data are also emerging for chimeric antigen receptor (CAR) T-cell therapies targeting the B-cell maturation antigen (BCMA) in MM. Earlier this year, the FDA granted an orphan drug designation to the autologous CAR T-cell therapy P-BCMA-101 for the treatment of patients with relapsed or refractory MM.²⁹

The designation was based on the results of a phase I study that demonstrated tolerability and responses with P-BCMA-101 in this patient population. Patients enrolled in the study were heavily pretreated (3-9 prior therapies); all had failed IMiDs, PIs, and daratumumab; and 64% had high-risk cytogenetics. In the evaluable patients, the ORR was reported to be 83% (5/6), despite 1 patient experiencing cytokine release syndrome. None of the patients required treatment with tocilizumab (Actemra) or safety switch activation. No patient deaths, neurotoxicity, or unexpected/off-target toxicities related to treatment were reported. The infusions were reported to be generally well tolerated, with cytopenias, including transfusion-requiring cytopenias and febrile neutropenia, being the most common grade &ge;3 adverse events.³⁰

References

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13. Karyopharm initiates rolling submission of new drug application to US Food and Drug Administration for selinexor as a treatment for patients with penta-refractory multiple myeloma [news release]. Newton, MA: Karyopharm Therapeutics Inc; July 18, 2018. bit.ly/2ymIIVC. Accessed July 29, 2019.
14. Karyopharm reports first quarter 2019 financial results and highlights recent company progress [news release]. Newton, MA: Karyopharm Therapeutics Inc; May 9, 2019. bit.ly/2Zkw8Sr. Accessed July 29, 2019.
15. Perrot A, Facon T, Plesner T, et al. Faster and sustained improvement in health-related quality of life (HRQoL) for newly diagnosed multiple myeloma (NDMM) patients ineligible for transplant treated with daratumumab, lenalidomide, and dexamethasone (D-Rd) versus Rd alone: MAIA.J Clin Oncol. 2019;37(suppl 15;abstr 8016). doi: 10.1200/JCO.2019.37.15_suppl.8016.
16. U.S. FDA grants priority review for daratumumab in combination with bortezomib, thalidomide and dexamethasone in frontline multiple myeloma [news release]. Copenhagen, Denmark: Genmab A/S; May 30, 2019. bit.ly/2JOv996. Accessed July 29, 2019.
17. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA part 1 results.J Clin Oncol. 2019;37(suppl 15;abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003.
18. Avet-Loiseau H, Moreau P, Attal M, et al. Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: analysis of the CASSIOPEIA trial.J Clin Oncol. 2019;37(suppl 15;abstr 8017). doi: 10.1200/JCO.2019.37.15_suppl.8017.
19. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara‐Vrd) vs. vrd in patients (pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT).Blood. 2018;132(suppl 1):151-151. doi: 10.1182/blood-2018-151.
20. Genmab announces positive topline results in the phase II GRIFFIN study of transplant eligible, newly diagnosed patients with multiple myeloma treated with daratumumab in combination with lenalidomide, bortezomib, and dexamethasone [news release]. Copenhagen, Denmark: Genmab A/S; July 8, 2019. bit.ly/2xFVspY. Accessed July 30, 2019.
21. Essmann S, von Pein U-M, Klyuchnikov E, et al. Daratumumab as salvage therapy in relapsed/Refractory multiple myeloma patients after allogenic stem cell transplantation.Bone Marrow Transplant. 2019;54(suppl 1;abstr 545). doi: 10.1038/s41409-019-0559-4.
22. Janssen submits application to U.S. FDA seeking approval of new DARZALEX (daratumumab) subcutaneous formulation. Raritan, NJ: Janssen Pharmaceutical Companies of Johnson & Johnson; July 12, 2019. bit.ly/2XGEHKC. Accessed July 28, 2019.
23. AbbVie provides update on VENCLEXTA/VENCLYXTO (venetoclax) multiple myeloma program [press release]. North Chicago, IL: AbbVie; March 19, 2019. bit.ly/2Ogtt7M. Accessed July 30, 2019.
24. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relpased/refractory multiple myeloma&nbsp;Presented at: 2019 European Hematology Association Congress; Amsterdam, The Netherlands; June 13-16, 2019. Abstract LB2601. bit.ly/2YrOsYJ.
25. AbbVie announces US FDA lifts partial clinical hold on phase 3 study of venetoclax in patients with multiple myeloma positive for the t(11;14) genetic abnormality [press release]. North Chicago, IL: AbbVie; June 24, 2019. bit.ly/2x9UZvJ. Accessed July 30, 2019.
26. Dimopoulos M, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: efficacy results after additional follow-up of the phase 2, randomized ELOQUENT-2 study. Presented at: 2019 European Hematology Association Congress; Amsterdam, The Netherlands; June 13-16, 2019. Abstract PS1370. bit.ly/2YvTAiu.
27. Sanofi: FDA to review isatuximab as a potential treatment for relapsed/refractory multiple myeloma [press release]. Paris, France: Sanofi; July 10, 2019. bit.ly/2JrKs63. Accessed July 30, 2019.
28. Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).J Clin Oncol. 2019;37(suppl 15;abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004.
29. Poseida Therapeutics receives US FDA orphan drug designation for P-BCMA-101 for the treatment of multiple myeloma [press release]. San Diego, CA: Poseida Therapeutics Inc; May 13, 2019. bit.ly/2YjCMHM. Accessed July 30, 2019.
30. Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM).Blood. 2018;132(suppl 1;abstr 1012). doi: 10.1182/blood-2018-99-111419.