Monoclonal Antibodies in Multiple Myeloma Offer Survival Hope
By Lynne Lederman, PhD
The reduction in the risk of disease progression and improved outcomes resulting from the addition of daratumumab in relapsed, refractory multiple myeloma (MM) “show the importance of targeting common antigens” in this hematologic malignancy, said ASCO president Julie M. Vose, MD, MBA at a plenary session of a late-breaking abstract presentation at ASCO 2016.
According to Paul G. Richardson, MD, Dana-Farber Cancer Institute, Boston, MA, who discussed the daratumumab study, it has been “well worth the wait for monoclonal antibodies in myeloma.”
Monoclonal antibodies (mAbs) approved or in development for MM are summarized in Table 1.
Daratumumab Effective in Combination Therapy
Daratumumab is a first-in-class anti-CD38 mAb that has been approved as a single agent in the US for the treatment of patients with MM who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).1
Daratumumab is also approved in Europe for relapsed and refractory MM previously treated with a PI and an IMiD, and that has progressed on the last therapy.2
Antonio Palumbo, MD, University of Torino, Italy, characterized CD38 as the most relevant antigen on myeloma cells today and presented the planned interim analysis of the CASTOR phase 3 study of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory MM.3
The CASTOR study randomly assigned patients (n=251) to daratumumab 16 mg/kg plus standard subcutaneous (SC) bortezomib plus low dose dexamethasone or to bortezomib plus dexamethasone (n=247).
Daratumumab was administered by intravenous (IV) infusion every week for cycles 1 to 3 and every 3 weeks for cycles 4 to 8, in 21-day cycles. Thereafter, daratumumab alone was administered every 4 weeks as maintenance therapy to the daratumumab group.
Median follow-up was 7.4 months, which is relatively short, because the trial was stopped when a difference in efficacy between arms was observed: Adding daratumumab to bortezomib and dexamethasone resulted in a 61% reduction in the risk of disease progression or death.
Efficacy results are summarized in Table 2.
The progression-free survival (PFS) benefit was seen for the daratumumab combination for all subgroups, including age, renal function, disease stage, lines of therapy, and prior stem cell transplant, although patients with early stage disease, who had received only 1 prior line of therapy, and/or had not received prior bortezomib, had a PFS advantage. Dr. Palumbo says these results support the use of daratumumab earlier in the disease course.
Infusion-related reactions resembled those seen with other mAbs used in cancer treatment; they were manageable and occurred primarily with the first infusion.
There has been a report that CD38 expression may be lost from MM tumor cells.4
During a recent American Society of Hematology (ASH)/Food and Drug Administration (FDA) update on daratumumab, we asked Dr. Richardson if CD38 disappearance was of concern. He replied that down-regulation of CD38 does not mean there is a failure to respond.
In addition, histone deacetylase inhibitors (HDACi) may upregulate the target, so in the case of low CD38 expression, he would consider using the combination of an anti-CD38 mAb with an HDACi. However, this is an unapproved combination and would need to be tested.
SC Administration of Daratumumab Under Investigation
SC formulations of therapeutic antibodies in combination with recombinant human hyaluronidase (rHuPh20) have been approved in Europe. Hareth Nahi, MD, PhD, Karolinska University Hospital, Huddinge, Sweden, described an open-label, dose-escalation phase 1b study of SC daratumumab with rHuPh20 in patients with relapsed or refractory MM who have received ≥2 prior therapies, and who have not received prior anti-CD38 antibodies, including daratumumab.5
The recommended SC dose will be selected in part 1. In part 2, approximately 128 patients will be randomly assigned either to SC daratumumab-rHuPh20 at the recommended dose (n=40) or to IV daratumumab 1200 mg (n=40) to evaluate the pharmacokinetics, safety, and efficacy of SC daratumumab.
Enrollment is ongoing, and the estimated completion date for the primary outcome measures is January 2017.
Other mAbs for MM
Elotuzumab has been approved in combination with lenalidomide and dexamethasone for treatment of MM previously treated with 1 to 3 prior therapies in the US;6 and in combination with lenalidomide and dexamethasone for the treatment of patients with MM who have received at least 1 prior therapy in Europe.7 Unlike daratumumab, elotuzumab, which targets SLAMF7, does not have significant single agent activity.
Sagar Lonial, MD, Winship Cancer Institute, Emory University, Atlanta, GA, presented the results of an extended follow-up of the ELOQUENT-2 trial, a phase 3, open-label, randomized, multicenter study, which showed a durable PFS with little incremental toxicity in patients with relapsed/refractory MM treated with elotuzumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone.
The trial results were previously published.8 In this extended 3-year follow-up, the PFS, duration of response, and OS benefits previously seen were consistent across key patient subsets for the elotuzumab combination, including age, type of prior therapies, risk category, and renal function.
Patients with high risk MM had a 37% reduction in the risk of progression or death with elotuzumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone (HR 0.63). The elotuzumab group had a relative improvement in median PFS of 105%.
Rates of adverse events were similar between groups, with the exception of infusion reactions which occurred in 10% of patients in the elotuzumab group, which were mild and manageable with premedication. Follow-up for OS is ongoing.
Joshua Richter, MD, Hackensack University Medical Center, Hackensack, NJ, reported results from a phase 2 dose-finding study of isatuximab in patients with relapsed/refractory MM that was double refractory to both a proteasome inhibitor (PI) and an IMiD, or after ≥3 prior lines of therapy.10 Like daratumumab, isatuximab targets CD38 and has single-agent activity.
In arm 1, (n=23), the dose was 3 mg/kg every 2 weeks; the overall response rate (ORR) was 9%, and this dose is not being pursued. Isatuximab doses and schedules tested and results for arms 2, 3, and 4 are summarized in Table 3.
Median OS was not reached in arms 2 and 4. Grade 3 and 4 toxicities for isatuximab doses of ≥10 mg/kg included anemia (97%), thrombocytopenia (57%), and neutropenia (42%). About half of patients had infusion-associated reactions, mostly with the first infusion. Dose-finding trials with isatuximab in combination therapies are in progress.
MOR202 is also an anti-CD38 mAb. Marc S. Raab, MD, Heidelberg University Hospital, Heidelberg, Germany, was first author of a poster presenting results of MOR202 alone and in combination with pomalidomide or lenalidomide in relapsed or refractory MM.11
In the interim analysis of this phase 1/2a study, the maximum tolerated dose of MOR202 alone and in combination was not reached. Administration by 2-hour IV infusion was well-tolerated, with a 14% incidence of infusion-related reactions primarily to the first infusion.
Although responses were seen, particularly to the pomalidomide combination, only 28 patients enrolled and 25 were evaluable. A dose of 16 mg/kg weekly was selected for further evaluation in combination both with lenalidomide and dexamethasone and with pomalidomide and dexamethasone.
Cost of Therapy Is Part of the Discussion
At the end of the plenary session, Deborah Schrag, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA,12 applied 5 currently available value frameworks in oncology13 to the therapeutic approaches discussed in the session.
Using the ASCO value framework,14 daratumumab for relapsed MM earns a high score for net health benefit, but that comes at a very high cost. Dr. Schrag predicts that it will be adopted in high income countries, where discounts will be sought; middle income countries will find the cost prohibitive.
During the post-plenary discussion, Dr. Palumbo acknowledged that when combining daratumumab or other mAbs with PIs and IMiDs, “the financial toxicity will be enormous, but beside this side effect from a scientific point of view certainly the idea of putting together the 3 major drugs with different MOAs is probably the future” of treatment, provided no major cumulative toxicity is detected.
Eric M. Maiese, PhD, Janssen Scientific Affairs, Horsham, PA, and colleagues presented a poster on the cost per median overall month of OS (mOS) in patients with MM who had received ≥3 lines of therapy or whose disease was double refractory to a PI and an IMiD.15 The study included costs for daratumumab, carfilzomib, and combination pomalidomide plus dexamethasone.
Costs included pre- and post-medication, administration, monitoring, auxiliary, and adverse events (AE) costs. Drug costs were based on Redbook Wholesale Acquisition Costs; monitoring, auxiliary, and AE costs were based on Medicare fee schedules and publications; treatment duration was based on median PFS; dosing was based on FDA-approved labeling.
In this analysis, the average cost per mOS for daratumumab was lowest at $4,261, and highest for pomalidomide plus dexamethasone at $5,160; carfilzomib costs were intermediate. Although this analysis does not take into account the cost of salvage therapy or pricing discounts, it may contribute to cost-benefit analyses of MM therapies.
As always, the results of the early phase trials and those with short follow-up times will need to be confirmed. Mikkael Sekeres, MD, Cleveland Clinic, Cleveland, Ohio, who moderated the ASH/FDA update on daratumumab, commented, “Those of us treating other hematologic malignancies are green with envy” over the increase in treatment options that have been or will soon be approved for patients with MM.
The era of novel agents for MM has brought increased survival, and this is expected to continue as newer agents and immunotherapies are developed.
- Darzalex (daratumumab) injection, for intravenous use. Prescribing Information. Janssen Biotech, Inc. Horsham, Pennsylvania. November 2015.
- Darzalex (daratumumab) EPAR Summary for the public. EMA/257672/2016.
- Palumbo, A, Chanan-Khan A, Weisel K, et al. Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. LBA4, ASCO Annual Meeting Plenary Session, 2016.
- Ise M, Matsubayashi K, Tsujimura H, et al. Loss of CD38 expression in relapsed refractory multiple myeloma. Clinical Lymphoma, Myeloma & Leukemia. 206;16:e590e64.
- Nahi H, Hellemans P, Masterson TJ, et al. An open-label, dose-escalation phase 1b study of subcutaneous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO). J Clin Oncol 34, 2016 (suppl; abstr TPS8071).
- Empliciti (elotuzumab) for injection, for intravenous use. Prescribing information. Bristol-Myers Squibb Company, Princeton, New Jersey. November, 2015.
- Empliciti (elotuzumab) initial authorization. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003967/WC500200340.pdf. Accessed June 27, 2016.
- Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. New Engl J Med. 2015;373:621-31.
- Lonial S, Richardson P, Mateos M-V, et al. ELOQUENT-2 update: phase 3 study of elotuzumab plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone in relapsed/refractory multiple myeloma—identifying responders by subset analysis. J Clin Oncol 34, 2016 (suppl; abstr 8037).
- Richter JR, Martin TG, Vij R, et al. Updated data from a phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38 mAb) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 34, 2016 (suppl; abstr 8005).
- Raab MS, Goldschmidt H, Agis H, et al. A phase I/IIa study of the human anti-CD38 antibody MOR202 (MOR03087) in relapsed or refractory multiple myeloma (rrMM). J Clin Oncol 33, 2015 (suppl; abstr 8574).
- Schrag D. Value frameworks in oncology. ASCO Annual Meeting Plenary Session, 2016.
- Lederman, L. Value tools at ASCO 2016: building a framework for prime time. OBRgreen ASCO 2016 special edition. June 2016, vol. 11, issue 6. Available at: http://obroncology.com/obrgreen/article/Value-Tools-at-ASCO-2016-Building-a-Framework-for-Prime-Time. Accessed June 27, 2016.
- Schnipper LE, Davidson NE, Wollins DS, et al. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received. J Clin Oncol. Published online before print May 31, 2016, doi: 10.1200/JCO.2016.68.2518.
- Maiese EM, Dimova M, Baio G, Makin C. Cost per median overall month of survival in multiple myeloma patients with ≥3 lines of therapy or were double refractory. J Clin Oncol. 2016;34 (suppl; Abstract 8057).