Conference Update

Daratumumab combo– setting a new standard for refractory multiple myeloma?

Hematology
2 years ago, OP Editor

In just a week of time, a CD38 monoclonal antibody–daratumumab (Darzalex, Janssen)- has been reported twice to markedly reduce disease progression by more than 60% and to double the duration of remission in patients with relapsed or refractory multiple myeloma based on two independent clinical trials, when adding on to two different standard-of-care regimens. Presenting investigators of the trials believed that daratumumab-based regimens will become the new standard of care in relapsed/ refractory multiple myeloma (RRMM).

“Relapse of multiple myeloma [MM] after primary treatment is inevitable in almost all patients”, wrote Meletios A Dimopoulos MD, professor and chair of the Department of Clinical Therapeutics at the University of Athens, Greece, in his review article of RRMM. “Recurrence of MM is typically more aggressive with each relapse, leading to the development of treatment-refractory disease which is associated with shorter survival”, he pointed out.1

CD38 is overexpressed on multiple myeloma cells. “We’ve suspected for a long time that CD-38 is the major treatment target for multiple myeloma”, said Antonio Palumbo, MD, professor and chief of myeloma unit at the University of Torino, Italy.2 Daratumumab, a CD38 monoclonal antibody, is one of the first drugs with the ability to directly kill myeloma cells and at the same time stimulate the immune system response to attack the tumor. This direct effect explains the rapid tumor shrinkage, whereas the immune effect sustains the prolonged responses to treatment. The FDA and EMA have approved daratumumab as a monotherapy in RRMM settings under accelerated approval and conditional approval respectively in 2015 based on superior response data from a non-randomized phase II trial.

The new findings from the CASTOR study and the POLLUX study, in which daratumumab was combined with bortezomib (Velcade, Janssen)/ dexamethasone and lenalidomide (Revlimid, Calgene)/ dexamethasone respectively, may bring hope to patients with debilitating RRMM. Results of CASTOR were presented by lead investigator Professor Palumbo on 5-June during the plenary session at ASCO annual meeting 20163 while results of POLLUX were presented by principal investigator Professor Dimopoulos on 11 June during the presidential symposium at European Hematology Association Congress 2016.4

Study details

CASTOR and POLLUX were similarly designed open-label phase III RCTs recruiting RRMM patients who had received ≥1 previous line of therapy with PFS as primary endpoint.

For CASTOR, 498 patients were randomized to receive daratumumab injection 16mg/kg q1w for 9 weeks, q3w for 15 weeks and q4w until disease progression or no injection on top of standard 8 cycles (q3w) of bortezomib (1.3mg/m2 sc on days 1,4,8,11) plus dexamethasone (20 mg on days 1,2,4,5,8,9,11,12) (bortezomib/ dexamethasone).

For POLLUX, 569 patients were randomized to receive daratumumab injection 16 mg/kg q1w for 8 weeks, q2w for 16 weeks and q4w until disease progression or no injection on top of standard oral lenalidomide 25 mg for 21 days of each 28-day cycle plus dexamethasone 40 mg weekly (lenalidomide/ dexamethasone).4

Both studies were unblinded after the recommendation from the independent data monitoring committee based on the planned interim results described below.

Clear-cut efficacy over the standard regimens

In CASTOR, median PFS was not reached in the daratumumab add-on group compared to 7.16 months in bortezomib/ dexamethasone group (HR=0.39, p<0.001), with a mean follow-up of 7.4 months. “This 61% reduction in disease progression is unprecedented compared with other studies in refractory myeloma, and is translated into nearly doubled duration of remission”, Professor Palumbo highlighted. Response rate of at least very good partial response (VGPR) was 59% for daratumumab add-on compared with 29% for standard regimen (p<0.0001), complete response or better were 19% vs 9% (p=0.0012) and negativity for minimal residual disease (MRD) at the level of 10-4 were 14% vs 3%.3

In POLLUX, again, an unprecedented 63% reduction in the risk of disease progression or death was seen in daratumumab group compared with lenalidomide/ dexamethasone group (PFS: not reached vs 18.4 months; HR=0.37, 95%CI:0.27-0.52, p<0.0001), after a median follow-up of 13.5 months. More patients achieved deep and durable responses in daratumumab group, with higher rates of VGPR or better (76% vs 44%, p<0.0001) and more than doubling of CR or better (43% vs 19%, p<0.0001).4 The negativity of MRD at the level of 10-4 were 30% vs 8% (p<0.0001).

Consistent safety profile with individual components3,4

Both studies showed manageable safety profile consistent with known tolerability profiles of individual components. Specially, thrombocytopenia (45% vs 33%), anemia (14% vs 16%), neutropenia (13% vs 4%) were the most common serious treatment emergent adverse events (TEAE) when daratumumab added on to bortezomib/ dexamethasone, while pneumonia (8% vs 8%) was most common serious TEAE when daratumumab added on to lenalidomide/ dexamethasone. Treatment discontinuation due to TEAE was similar between groups in both studies, ranging from 7-9% with numerically lower rates in daratumumab-treated groups.

Infusion-related reactions (IRRs) associated with daratumumab were seen in 45-48% of patients (grade 3/4: 5-9%) in both studies. >92% of IRR events occurred during the first infusion.

“Safety is also good as addition of daratumumab does not increase the toxicity of the two-drug combo except infusion-related reaction”, mentioned Professor Palumbo.

Setting a new standard of care for refractory myeloma?

Both presenters of the trials were very positive regarding the use of daratumumab in the RRMM settings. “Daratumumab is a fast-acting drug – in many cases tumors shrank in just one month. As a result of shrinkage and slower tumor growth, patients had less pain and a better quality of life”, said Professor Palumbo.2 “These results are clinically important because signs and symptoms came into control”, Professor Dimopoulos emphasized. With continued therapy, “there was a continued improvement in response.”3 It’s clear now that “we’ll be moving to a three-drug regimen with daratumumab as the standard of care”, believed Professor Palumbo.3

Agreeing with the presenters, “this will become the new standard of care once approval are through”, said Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, in Boston, “Both CASTOR and POLLUX studies are game changers in my view”.

However, Professor Philip McCarthy, MD, director of BMT center, Rosewell Park Cancer Institute, New York, was a bit more cautious that “although these findings are impressive, it would have been better to have some forms of continued therapy for the control groups. We look forward to the upfront studies with this drug in combo with an immunomodulatory drug plus a proteasome inhibitor”.5

When discussing whether daratumumab combo could replace transplant, “ASCT remains the standard of care”, said Dr Richard Schilsky, MD, ASCO chief medical officer. “Another study presented in ASCO 2016 meeting showed that upfront transplantation reduced the risk of progression, compared with a bortezomib-based treatment in younger, fit patients6”, he continued, “However, this won’t settle the debate, mostly because there is a whole slew of newer agents that have been introduced since bortezomib that are even more effective. How those drugs, including daratumumab, are compared with transplant-based regimen remains to be seen”.5

“For now, ASCT is here to stay for younger patients who want to go that route”, said Dr Noopur Raje, MD, associate professor of medicine at Harvard Medical School and director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center in Boston, “Younger patients should have that option.” However, noticing more new and effective treatment are coming in, she, however, believed that “this is going to be evolving with new drugs”.5

Dr Peter F. Lebowitz, MD, PhD, Janssen’s global oncology head who develops daratumumab, is very optimistic about this drug and said in a press-release that “these twin studies [CASTOR and POLLUX] help pave the way for the future of daratumumab as a foundational therapy in combination with either of the 2 most widely used classes of therapy”.7

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