The [daratumumab/KRd] combination is feasible, “but it is not yet ready for prime time.”

— Parameswaran Hari, MD

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THE ADDITION of daratumumab (Darzalex) to a triplet induction regimen led to good responses in newly diagnosed multiple myeloma, but not without toxicities. And in the treatment of myeloma bone disease, denosumab (Xgeva) in place of zoledronic acid preserved renal function and may be associated with longer progression-free survival. 

These were two cutting-edge approaches highlighted in a hematology session during Best of ASCO New Orleans. At the meeting, Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, discussed this year’s top selected abstracts in plasma cell dyscrasias, originally presented at this year’s ASCO Annual Meeting in Chicago.¹ 

New Agents in Newly Diagnosed Multiple Myeloma 

WITH THE INTRODUCTION of “ultra-novel” agents such as daratumumab and carfilzomib (Kyprolis), the treatment of multiple myeloma is changing, according to Dr. Hari. 

“If transplant is not possible upfront, but it appears the patient might improve later, it is important to collect and cryopreserve cells,” said Dr. Hari. He referenced one phase III study in which 4-year overall survival was 82% and 81% for deferred and upfront autologous stem cell transplant, respectively.² 

However, upfront transplant is vital in prolonging progression-free survival. “We know that the interval from diagnosis to first relapse usually represents 60% or more of the time a patient lives with myeloma—the first progression-free survival is usually the longest,” he said. “Unfortunately, myeloma remains an incurable disease, despite all the drugs we have.” 

But according to Dr. Hari, about 50% of multiple myeloma patients can survive to their second decade with myeloma, with “old-fashioned induction and transplant followed by maintenance.” So the question remains: What is the best induction strategy with the availability of ultra-novel agents? 

Quadruplet Therapy 

A PHASE IB STUDY presented at the ASCO Annual Meeting evaluated daratumumab in combination with carfilzomib, lenalidomide (Revlimid), and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma.³ Daratumumab has previously demonstrated efficacy and safety in combination with established standard-of-care regimens in relapsed or refractory multiple myeloma. 

The study enrolled 22 transplant-eligible or -ineligible patients, who were treated for at least 13 cycles or until elective treatment discontinuation or transplant. Primary endpoints were safety and tolerability. 

Median follow-up was 10.8 months, and the median number of treatment cycles was 11.5. The safety profile was consistent with previous studies of either daratumumab or KRd; serious adverse events occurred in nearly half of patients, and the most common grade 3 or 4 adverse events were lymphopenia (64%) and neutropenia (14%). All daratumumab-associated infusion reactions were mild, and the drug combination had no apparent adverse impact on cardiac function. 

Depth of response improved with duration of treatment. After four cycles, 100% of patients had at least a partial response, and a very good partial response was observed in 91% of patients. Treatment had no impact on the collection of stem cells, and stem cell yield was consistent with previous KRd studies. The investigators concluded that the addition of daratumumab to KRd resulted in deep and durable responses, and these data support further investigation of the drug combination as a front-line regimen. 

According to Dr. Hari, this drug combination is “feasible and probably safe” in newly diagnosed multiple myeloma, particularly due to its negligible impact on stem cell collection, “but it is not yet ready for prime time.” 

Is KRd for induction preferable to the commonly used regimen of bortezomib (Velcade), lenalidomide, and dexamethasone (VRD)? “The jury is still out,” said Dr. Hari. The superiority of bortezomib or carfilzomib in extending overall or progression-free survival in newly diagnosed multiple myeloma has not yet been established in a large study, but an investigation addressing this issue is currently recruiting.⁴ 

“And the jury hasn’t even been selected for [evaluating] upfront daratumumab,” he added. The ongoing GRIFFIN study⁵ is comparing VRD and daratumumab to VRD alone for 4 cycles, followed by transplant, consolidation to VRD and daratumumab or VRD alone for another 2 cycles, finally followed by maintenance with lenalidomide and daratumumab, or lenalidomide alone for 56 months. 

“The quest is to find a quadruplet—something akin to ‘R-CHOP’ in non-Hodgkin lymphoma—for myeloma, which would basically give us a cure in a significant proportion with or without transplant,” he said. “But the KRd data and the KRd-daratumumab data are similar at this early point, and since judging with limited data is fraught with error, I would advise against doing that.” 

Although numerous other triplets are currently in phase III trials, and forthcoming data could hold promise for improving induction in upfront myeloma therapy, Dr. Hari maintains that VRD is the minimum standard and to “stick with that for now.” 

He advises waiting for data before subjecting patients to additional costs and toxicity, as well as employing an emerging strategy of “response-adapted therapy,” which involves identifying early nonresponders and switching them to a different regimen, as this can greatly reduce cost and toxicity. 

Denosumab to Preserve Renal Function 

BISPHOSPHONATES ARE BENEFICIAL in reducing skeletal-related events in multiple myeloma, and zoledronic acid, in particular, is associated with improved survival and a possible antitumor effect in these patients. But the drug is also associated with renal toxicity and possible accumulation in renal tubular cells, and there is some evidence for improvement of renal dysfunction when patients switch from zoledronic acid to denosumab, which has an established track record of safety and efficacy in bone metastases.

A randomized, double-blind phase III study presented at the ASCO Annual Meeting by Raje et al⁶ sought to determine the impact of denosumab compared to zoledronic acid on renal function in the treatment of myeloma bone disease. 

Eligible patients were randomized 1:1 to denosumab at 120 mg with placebo (n = 859) or zoledronic acid at 4 mg with placebo (n = 859) every 4 weeks, along with antimyeloma therapy. The primary endpoint was noninferiority of denosumab with respect to time to the first on-study skeletal-related event. 

The noninferiority endpoint was met, and the investigators concluded that denosumab and zoledronic acid were equally effective in protecting bone strength. Median time to the first skeletal-related event was 22.8 months in the denosumab arm, vs 23.9 months in the zoledronic acid arm (P = .01), and the mean number of events per patient was exactly the same in both arms (0.66). 

Practice-Changing Findings? 

THERE WAS NO DIFFERENCE in overall survival, but progression-free survival in the denosumab arm was superior to the zoledronic acid arm: 46 vs 35 months. “I will wait for the actual paper to be published before I make a decision to change practice on the basis of this finding, but it is very interesting,” noted Dr. Hari. “Zoledronic acid is the only bone agent so far that has had an impact on survival, but it looks like, in terms of progression-free survival, denosumab is even better. So we’ll have to analyze these data later, as more information about this study comes out.” 

The incidence of renal toxicity was significantly lower with denosumab compared to zoledronic acid (10% vs 17.1%), particularly in patients with baseline creatinine clearance ≤ 60 mL/min (12.9% vs 26.4%). However, there was no statistical difference between the two arms in the occurrence of osteonecrosis of the jaw, although there was a slightly higher trend with denosumab. 

“So, should we change from zoledronic acid to denosumab?” Dr. Hari posited. Although it was noninferior to zoledronic acid for the prevention of skeletal-related events, caused fewer toxicities, and may be associated with better progression-free survival, patient benefit should be the deciding factor. According to Dr. Hari, it would be a serious departure from known practice, and cost and reimbursement are issues. (Confirm reimbursement before using denosumab, he urged.) 

“But this is a major study that has some practical implications,” he added. “Strongly consider using denosumab in cases of renal frailty. There are enough data to suggest that the skeletal-protective effects are the same, and there may even be a slight increase in progression-free survival.” ■

DISCLOSURE: Dr. Hari has received consulting fees from Janssen, Amgen, Celgene, and Takeda and research support from Takeda, Amgen, and Celgene. 

REFERENCES 

1. Hari P: Hematologic malignancies: Plasma cell dyscrasia. Best of ASCO New Orleans. Presented July 28, 2017. 

2. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017. 

3. Jakubowiak A, Chari A, Lonial S, et al: Daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma (MMY1001). 2017 ASCO Annual Meeting. Abstract 8000. 

4. Bortezomib or Carfilzomib With Lenalidomide and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma. ClinicalTrials.gov identifier NCT01863550. 

5. Daratumumab in Combination With Lenalidomide and Dexamethasone in Relapsed and Relapsed-Refractory Multiple Myeloma. ClinicalTrials.gov identifier NCT01615029. 

6. Raje N, Roodman DG, Willenbacher W, et al: Impact of denosumab compared with zoledronic acid on renal function in the treatment of myeloma bone disease. 2017 ASCO Annual Meeting. Abstract 8005.