New Treatments, Drugs, Approaches Benefit Myeloma Patients

Three decades after the establishment of the

UAMS Myeloma Center, its focus remains on the future by striving to cure more patients.

“Our treatment approach, which comprises an induction, transplant, consolidation and maintenance phase has now been widely adopted in myeloma care,” said Frits van Rhee, M.D., Ph.D., clinical director of the Myeloma Center. “Using this approach and incorporating novel drugs into treatment has yielded a significant improvement in outcomes over the years.”

“We estimate that 40% of patients with standard-risk myeloma can enjoy long-term, disease-free survival. Many of these patients will not relapse and we consider them functionally cured,” he said. “The challenge remains in patients with high-risk myeloma and those with low risk who have an early relapse.” He said other treatment centers face the same challenge.

Total Therapy 7, a clinical trial open to highrisk patients, focuses on doing just that. TT-7 launched in August 2017 has 45 patients enrolled. Early results suggest that it leads to higher complete remission rates than in previous clinical trials for high-risk patients.

“We believe it is critically important to improve our maintenance strategy because historically, the high-risk patients tend to relapse in their maintenance phase,” van Rhee said.

The Total Therapy 7 protocol calls for a different approach in maintenance, giving the monoclonal antibody daratumumab (DARZALEX) together with carfilzomib (KRYPROLIS), a second-generation proteasome inhibitor, in a three-month block, then switching to a combination of lenalidomide (REVLIMID), daratumumab and dexamethasone for the next three months, alternating between the two combinations every three months for a period of three years. Daratumumab uses the patient’s immune system to kill myeloma cells.

“The hope is that, used in this way, daratumumab synergizes and enhances the effects of carfilzomib and lenalidomide,” van Rhee said. “In essence we are trying to incorporate an immunological approach by using daratumumab rather than adding yet another chemotherapy drug. The hope is that maintenance will be more tolerable, and the patient will be more compliant with it.”

He said that overall, the development of immunological approaches such as monoclonal antibodies, bi-specific antibodies and CAR-T cells will likely improve the outcome of patient groups that are presently difficult to treat.

“Furthermore, the emergence of new drugs such as venetoclax allows for the development of more effective and more targeted therapy for certain patient groups. This increasing therapeutic arsenal will allow us to both use the immune system to combat myeloma as well as develop more effective strategies using a precision medicine type of approach. I think this is a very exciting time for myeloma patients with so many new treatment methods becoming available,” van Rhee said.

“We have already established, through our longterm follow-up care data that myeloma patients can be cured,” he said. “And we anticipate that our percentages of patients with excellent long-term outcomes will increase in the future. We’ve made a lot of progress in the treatment of myeloma in the past 30 years, but I think the future looks bright. The next 30 years holds great promise for myeloma patients.”

The Challenge - High-Risk Patients

100%

80%

60%

5-Year Events / N Estimate TT2 - Thal 19 / 20 10% (0,20) TT2 + Thal 23 / 26 19% (5,33) TT3a 33 / 40 25% (12, 38) Logrank P-value = .10

40%

20%

0% 0 5 10 15 20 25 Years After Enrollment

The name for the Total Therapy protocols came from the work that was being done at St. Jude Children’s Research Hospital with newly diagnosed ALL patients, called the “Total” protocols.

TT4

TT2 TT3

Bortezomib Low Risk TT5A/B

High Risk, Bortezomib (A), Carfilzomib (B) TT6

Previously Treated TT7

High Risk, Daratumumab

TT1

Induction, Tandem transplant, consolidation, maintenance Thalidomide • Incorporate novel drugs upfront • Address complicated mutational spectrum • Overcome drug resistance • Optimize the response • Prevent clonal evolution and disease escape • Eradicate the disease

Total Therapy 7 for High-Risk Myeloma

Diagnosis Transplant #1

Melphalan

Induction then Stem Cell Collection Immunotherapy + Chemo: Carfilzomib Thalidomide Dexamethasone Daratumumab Platinum Adriamycin Cytoxan Etoposide

Stem cell collection

Transplant #2

Melphalan

Maintenance Immunotherapy + Chemo: Dara (monthly) + carfilzomib, dexamethasone alternating Dara (monthly) + Revlimid, dexamethasone

Consolidation #1 Immunotherapy: Daratumumab starts 28 days after stem cell infusion, given for 4 weeks Immunotherapy + Chemo: Daratumumab + carfilzomib for 8 weeks

Consolidation #2 Immunotherapy:

Daratumumab starts 28 days after second stem cell infusion, given for 8 weeks “The challenge remains in patients with high-risk myeloma and those with low risk who have an early relapse.”