The treatment paradigm for multiple myeloma has changed dramatically in the past decade with the availability of several efficacious agents in various drug classes. At the National Comprehensive Cancer Network® (NCCN®) 13th Annual Congress: Hematologic Malignancies™, Shaji K. Kumar, MD, Professor of Hematology at the Mayo Clinic, Rochester, discussed evidence-based management strategies for patients with newly diagnosed multiple myeloma, including the role of autologous stem cell transplant.¹

Pharmacologic Options for Newly Diagnosed Disease

As Dr. Kumar reported, the ideal initial therapy for newly diagnosed multiple myeloma should rapidly and effectively control disease, reverse disease-related complications, decrease the risk of early death, be easily tolerated with minimal/manageable toxicity, and not interfere with stem cell collection if needed. According to Dr. Kumar, this is accomplished with the combination of a proteasome inhibitor and an immunomodulatory agent. The basis of this current approach comes from SWOG S0777, a randomized, open-label, phase III trial, which showed the addition of proteasome inhibitor bortezomib (Velcade) to the reference treatment lenalidomide (Revlimid) plus dexamethasone (VRD) resulted in significantly improved progression-free and overall survival, with an acceptable risk-benefit profile.² The triplet combination also yielded a deeper response, added Dr. Kumar, as indicated by the proportion of patients with a very good partial response or better.

Stem cell transplantation continues to have a very important role [in management of multiple myeloma] and should be considered early in all eligible patients.

— Shaji K. Kumar, MD

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“Based on these data, we strongly believe the combination of proteasome inhibitor and immunomodulatory drug should be the standard of care therapy for myeloma patients, but there are other regimens that can be used,” he said. “Not everyone in the world can use lenalidomide and bortezomib.”

A randomized trial conducted in France compared bortezomib/thalidomide (Thalomid)/dexamethasone (VTD) with bortezomib/cyclophosphamide/dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation.³ Although VCD was associated with significantly higher hematologic toxicity, peripheral neuropathy was more common in the VTD arm. More important, emphasized Dr. Kumar, the overall response rate, especially deeper response, was higher with the thalidomide combination. Clearly, there’s a balance between efficacy and toxicity that clinicians must consider when treating this disease, he observed.

Changing drugs within the proteasome inhibitor combination to achieve better outcomes may also help to reduce toxicity. Two phase II trials at the University of Chicago are exploring the addition of carfilzomib (Kyprolis) to lenalidomide/dexamethasone (KRd).⁴ Although not designed for a formal comparison, noted Dr. Kumar, the response with four cycles of this triplet combination was “significantly better than what we’ve historically seen with other combination regimens.” Nevertheless, he added, before this combination becomes standard-of-care therapy, data from ongoing phase III trials are needed.

Stopping Induction Therapy and the Role of Transplant

According to Dr. Kumar, determining when to stop induction therapy can be challenging, based on the paucity of data. It’s also unclear, he said, whether patients with a suboptimal response to initial therapy benefit from additional alternative therapy prior to stem cell transplant. A retrospective analysis of more than 539 myeloma patients who had an autologous stem cell transplantation after having achieved less than a partial response to first-line induction chemotherapy found no difference in progression-free or overall survival between people who went directly to transplant and those who switched therapy prior to transplant.⁵

Data regarding the impact of autologous stem cell transplantation, however, are more conclusive. A recent study by Attal et al demonstrated that patients receiving transplant had a much deeper response, with almost 14% higher minimal residual disease (MRD) negativity, than did those receiving consolidation therapy with VRD.⁶

“Stem cell transplantation continues to have a very important role and should be considered early in all eligible patients,” said Dr. Kumar.

Following transplant, trials have increasingly shown the benefit of maintenance therapy in this population. A meta-analysis published in the Journal of Clinical Oncology showed that patients who received lenalidomide maintenance therapy had better progression-free and overall survival than did those who did not.⁷ The only patients who did not benefit from maintenance therapy, said Dr. Kumar, were those with International Staging System stage III disease and those with high-risk disease.

“In our practice, we tend to use bortezomib maintenance for these high-risk patients,” said Dr. Kumar, who noted the role of double transplant is also being explored. A compilation of European phase III studies showed better outcomes with tandem autologous stem cell transplantation, especially in patients with del(17p) and t(4;14) cytogenetic abnormalities.

“These data are still early,” Dr. Kumar acknowledged, “but they suggest the need for a discussion with patients about tandem transplant, particularly in high-risk disease.”

Supportive Care Approaches

Finally, as nearly 30% of patients with myeloma present with some degree of renal dysfunction, reversing renal dysfunction has become an integral part of supportive care. In patients with light chain–induced acute renal failure, bortezomib-based regimens have been shown to induce a high rate of myeloma and renal responses.⁸ Use of bisphosphonates is also the current standard of care for at least the first 18 months, as studies have shown zoledronic acid prevents skeletal-related events and improves overall survival in the first 4 months of treatment.⁹

“I cannot stress enough the importance of supportive care,” shared Dr. Kumar, who also emphasized managing infections with the timely use of antibiotics.

Newer Treatments Under Study

Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, noted that monoclonal antibodies daratumumab (Darzalex) and elotuzumab (Empliciti) have shown exciting activity in the relapsed setting and may soon be tested as front-line therapy as well.

The monoclonal antibodies daratumumab and elotuzumab have shown exciting activity in the relapsed setting and may soon be tested as front-line therapy as well.

— Andrew D. Zelenetz, MD, PhD

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“Infusion reactions are very common with monoclonal antibodies, but the mechanism with daratumumab is slightly different because CD38 is expressed on the airway,” said Dr. Zelenetz. “This can lead to bronchospasm and other airway difficulties, so it’s critical to be aware of that first infusion reaction dose. Montelukast is quite effective in that setting and should be part of the premedication regimen.”

“Some of the other drugs being tested are simply new drugs in a class,” Dr. Zelenetz added. “Carfilzomib has a little less neurotoxicity, for example, but it’s still fundamentally a proteasome inhibitor. We know how to handle it, whereas the antibody really is different.” ■

DISCLOSURE: Drs. Kumar and Zelenetz reported no conflicts of interest.

REFERENCES

1. Kumar SK: Management of newly diagnosed multiple myeloma in those eligible for transplant. 2017 NCCN Hematologic Malignancies Congress. Presented October 7, 2017.

2. Durie BG, Hoering A, Abidi MH, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet 389:519-527, 2017.

3. Moreau P, Hulin C, Macro M, et al: VTD is superior to VCD prior to intensive therapy in multiple myeloma: Results of the prospective IFM2013-04 trial. Blood 127:2569-2574, 2016.

4. Dimopoulos MA, Stewart AK, Masszi T, et al: Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment. Blood Cancer J 7:e554, 2017.

5. Vij R, Kumar S, Zhang MJ, et al: Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma. Biol Blood Marrow Transplant 21:335-341, 2015.

6. 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.

7. McCarthy PL, Holstein SA, Petrucci MT, et al: Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol 35:3279-3289, 2017.

8. Ludwig H, Adam Z, Hajek R, et al: Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: Results of a phase II study. J Clin Oncol 28:4635-4641, 2010.

9. Morgan GJ, Davies FE, Gregory WM, et al: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial. Lancet 376:1989-1999, 2010.