Anti-CD38 Antibodies on Horizon in Multiple Myeloma

Thomas Martin, MD, of the University of California, San Francisco

Anti-CD38 monoclonal antibodies continue to demonstrate promise and generate excitement that a new treatment paradigm could be on the horizon for patients with multiple myeloma.

Two studies spotlighted at the 2014 ASH Annual Meeting characterized the efficacy of these agents in the frontline setting and for patients with refractory disease. In a phase Ib trial, the human IgG1κ antibody daratumumab combined with standard frontline therapies induced a dramatic improvement in outcomes without additional toxicity for patients with multiple myeloma.¹Additionally, in a separate phase Ib study, nearly two-thirds of patients with heavily pretreated relapsed/refractory multiple myeloma responded to treatment with the humanized IgG1 monoclonal antibody SAR650984 in combination with lenalidomide and dexamethasone.²

"These therapies are going to be tested in the frontline, in the early relapsed patients, and in the multiple relapsed patients. These are some of the most exciting agents in multiple myeloma," said the lead study author of the SAR650984 trial Thomas Martin, MD, of the University of California, San Francisco. "These CD38 therapies are blockbuster drugs.”

In May 2013, single-agent daratumumab received a breakthrough therapy designation from the FDA as a treatment for patients with multiple myeloma following two lines of therapy. In combination with lenalidomide and dexamethasone, daratumumab demonstrated an overall response rate (ORR) of 75% across the entire study, which included a dose-escalation portion. In an expansion cohort of patients who received daratumumab at the maximum-tolerated dose of 16 mg/kg (n = 13), the ORR was 92.3%.³

In the frontline setting, the four-arm phase Ib study combined daratumumab with bortezomib and dexamethasone (VD); bortezomib, thalidomide, and dexamethasone (VTD); bortezomib, melphalan, and prednisone (VMP); or pomalidomide and dexamethasone (POM-D). Patients in the VD and VTD arms were untreated and transplant eligible, patients in the VMP arm were untreated but not candidates for transplant, and those in the POM-D arm were relapsed/refractory to at least two lines of therapy.

At the time of the analysis, twenty-four patients received treatment with daratumumab at 16 mg/kg plus the backbone therapy at a standard dose. In the VD (n = 6) and VTD arms (n = 6), patients were treated for eighteen 3-week cycles or until transplantation. In the VMP arm (n = 6), treatment continued for nine 6-week cycles. In the POM-D (n = 6) arm, patients received treatment in 4-week cycles until progression.

The ORR was 100% with VD, VTD, and VMP, and 50% with POM-D. Responses comprised very good partial responses and partial responses; no patients in the frontline arms achieved a complete response (CR). In the POM-D arm, the CR rate was 17% (n = 1). Most patients responded within 30 days of receiving treatment.

“We consider that the addition of 16 mg/kg [of] daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity,” study author María-Victoria Mateos, MD, from Hospital Universitario Salamanca, Spain, said during a press briefing. “Daratumumab was associated with high rates of response in combination with the different backbones.”

Infusion-related reactions were the only added toxicity seen with daratumumab when combined with a bortezomib-containing regimen. All infusion reactions were grade 1 and resolved with supportive care. Most other side effects reported in the study could be attributed to the backbone therapy, the authors of the study wrote.

“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” lead study author Philippe Moreau, MD, University Hospital of Nantes in France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”

In addition to daratumumab, findings for SAR650984 also support the dramatic efficacy of targeting CD38 in patients with multiple myeloma. In the phase Ib study, three separate dosages of SAR650984 (3, 5, and 10 mg/kg) were administered every 2 weeks in combination with lenalidomide and dexamethasone. A total of 24 patients with relapsed/refractory multiple myeloma received the 10 mg/kg dose. In the 28-day treatment cycle, lenalidomide was administered at 25 mg on days 1 to 21, which was adjusted to 10 mg in patients with baseline creatinine clearance ≤60 mL/min. Dexamethasone was administered at 40 mg on days 1, 8, 15, and 22.

Patients in the study had received a median of six prior therapies over the course of a median of 4.5 years following diagnosis. These treatments included prior immunomodulatory therapy with lenalidomide (94%) or pomalidomide (29%), bortezomib (94%), and carfilzomib (48%). Eighty-four percent of patients were relapsed and refractory to a least one prior immunomodulatory agent.

After a median follow-up of 9 months, the ORR across the entire population was 58%, with a clinical benefit rate of 65%, including a 6% stringent complete response rate. In patients receiving the 10-mg/kg dosage, the ORR was 63%.

After a 9-month follow-up, the median progression-free survival (PFS) was 6.2 months. The median PFS was not yet reached in patients who received fewer than three prior regimens before entering the study.

In patients who were relapsed and refractory to immunomodulatory therapy (n = 26), the ORR was 50%. In patients refractory to carfilzomib (n = 15), the ORR was 40%, and in those relapsed and refractory to pomalidomide (n = 9), the ORR was 33%.

“This combination was well tolerated, there were no unexpected toxicities, and in my mind had a fairly dramatic response, with two-thirds of patients having a response even though they were refractory to other agents,” said Martin. “I do think these anti-CD38 antibodies are the next blockbuster class of agents. These are the next agents that are really going to start showing some benefits for our myeloma patients.”

The most common treatment-related adverse events were fatigue (41.9%), nausea (38.7%), upper respiratory tract infection (38.7%), and diarrhea (35.5%). Two patients experienced grade 3 infusion-associated reactions, resulting in treatment discontinuation. Infusion reactions of all grades occurred in 38.7% of patients.

“These antibodies tend to be very well tolerated drugs, there tends to be some incidence of infusion reaction, which occurs about a third of the time,” Martin explained. “These are mostly mild, grade 1 and 2. We only had to stop the infusion in 3% of overall infusions. After the second cycle, there are no infusion reactions.”

Press briefing moderator, Brad S. Kahl, MD, from the University of Wisconsin School of Medicine, provided further insight into the CD38 antibodies, calling their development very exciting.

“Obviously it’s very early, probably too early to plant the victory flag in the ground. Having said that, the early data is very promising and totally justifies moving these therapies forward to the frontline,” explained Kahl.

Genmab is developing daratumumab in collaboration with Janssen Biotech, and Sanofi Oncology is developing SAR650984.

In addition to daratumumab and SAR650984, Celgene and MorphoSys are collaborating on the development of the CD38 antibody MOR202. This treatment is currently being investigated in a phase I/II study as a monotherapy and in combination with dexamethasone plus either lenalidomide or bortezomib for patients with relapsed/refractory multiple myeloma (NCT01421186).

"These therapies all bind to a different part of the CD38 receptor. Whether that makes any clinical difference, we certainly don’t know at this time," said Martin.

_References::

_{1. Moreau P, Mateos M-V, Bladé J, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 176.}

_{2. Martin III TG, Baz R, Benson Jr DM, et al. A Phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 83.}

_{3. Plesner T, Arkenau H-T, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 84.}