The latest strategies for managing newly diagnosed transplant-eligible patients with multiple myeloma

Adding a monoclonal antibody to standard three-drug induction therapy may offer a deeper response in newly diagnosed transplant-eligible patients with multiple myeloma, recent studies show. 

Antibody A protein made by immune system cells and released into the blood. Antibodies defend the body against foreign substances, such as bacteria.
Andrew Cowan, MD
Andrew J. Cowan, MD

The findings come at a time when research is rapidly changing the landscape of multiple myeloma treatment. In a recent presentation, Andrew Cowan, MD, of Seattle Cancer Care Alliance (SCCA) explained how multi-drug combinations for induction therapy are increasingly effective, leading to higher and deeper response rates.

“What we know is that the depth of response prior to transplant predicts patient outcomes,” says Dr. Cowan, SCCA's interim clinical director of myeloma. “And if a patient can achieve minimal residual disease status, they have a far superior prognosis.”

In addition to induction therapy, Dr. Cowan also provided updates on:

  • Autologous hematopoietic cell transplantation (HCT), including when to initiate transplant and whether doctors should use tandem transplants. 
  • Maintenance therapy, including the current standard and the use of multiple agents in high-risk patients. 

“The strides we’ve made in multiple myeloma treatment are very exciting,” says Dr. Cowan. “Groundbreaking research at SCCA, Fred Hutch, and UW Medicine is moving the standards of care forward. As this happens, we want oncologists in the community to be aware of what’s new in the field so they can optimize the care of their patients." 

Guided by the latest research, Dr. Cowan’s strategies for treating newly diagnosed patients now include:

  • Induction therapy: Three-drug combination of protease inhibitor (PI)-immunomodulatory drug (IMiD)-dexamethasone for standard risk patients or 4-drug combination, including a monoclonal antibody (Dara-RVd) for high-risk patients
  • Autologous HCT: As early as possible after cytoreductive induction therapy
  • Maintenance therapy: IMiD for standard risk patients or RVd for high-risk patients
  • Supportive care: Intravenous bisphosphonates or RANKL inhibitors to reduce the risk of fractures

Three-drug induction therapy provides the standard of care

The randomized SWOG S077 clinical trial compared lenalidomide, bortezomib, and dexamethasone (RVd) to lenalidomide and dexamethasone. It showed improved progression-free survival and overall survival, and led the widespread use of RVd induction as the standard of care for newly-diagnosed multiple myeloma. 

Preclinical data for carfilzomib showed it may be a more potent PI than bortezomib. However, a large intergroup study published in 2020 comparing RVd (bortezomib, lenalidomide and dexamethasone) and KRD (carfilzomib, lenalidomide and dexamethasone) found no difference in progression-free survival.

“Given these results, either RVd or KRd are still reasonable choices for newly diagnosed patients with multiple myeloma,” says Dr. Cowan. “But it might make sense to use KRd for a patient who has a pre-existing neuropathy.”

Four-drug induction therapy shows great promise, especially for high-risk patients

Four-drug induction therapy may be most beneficial for high-risk patients, according to two key studies. The studies investigated the addition of a CD38 monoclonal antibody (daratumumab) to the three-drug PI-IMiD-dexamethasone backbone for induction therapy. They are:

CASSIOPEIA Study

This phase 3 study conducted in Europe compared daratumumab-VTd with VTd. The primary endpoint was stringent complete response (sCR), which requires:

  • No clonal plasma cells found in bone marrow biopsy 
  • No monoclonal protein in the blood
  • Normal 24-hour urine
  • Normal serum-free light chains

The researchers found improved depth of response with the addition of daratumumab to VTd:  Nearly one-third more patients (29%) who received dara-VTd achieved sCR, up from 20% who received VTd. A remarkable 53% reduction in the risk of progression or death occurred in the dara-VTd treatment arm. 

While VTd is not an induction regimen that is widely used in the U.S., the results demonstrate a benefit with the addition of daratumumab, either in induction or maintenance. 

GRIFFIN Study 

This phase 2 study conducted in the U.S. compared dara-RVd with RVd, using a primary endpoint of sCR. As in the CASSIOPEIA study, patients receiving daratumumab had much deeper responses: 42.4% vs 32.0% achieved sCR in the dara-RVd and RVd arms, respectively. 

The benefits of dara-RVd also continued after consolidation and 12 months of maintenance therapy. These included:

  • Depth of response: More than 60 percent (63.6%) in the dara-RVd arm achieved sCR. This contrasts with 47.4% in the RVD arm.  
  • Minimal residual disease (MRD): More than 60 percent (62.5%) in the dara-RVd arm had no MRD. This represents an increase from 27.2% in the RVD arm.

The GRIFFIN study, whose control arm most closely matches standard of care in the U.S., did not show a benefit with respect to progression-free survival with the addition of daratumumab. Although it met its primary endpoint, progression-free survival has not yet been shown. 

Autologous HCT remains a cornerstone therapy for multiple myeloma

The issue of whether transplants should still be part of therapy in patients with newly diagnosed multiple myeloma comes up frequently, says Dr. Cowan. Current research supports the use of transplants and shows that:

  • Autologous HCT significantly improves progression-free survival 
  • Early transplant may be beneficial than late transplant.
  • Tandem autologous transplants (two transplants within six months) may be beneficial for patients with high-risk cytogenetics, especially those with del(17p), but the evidence is still weak. 

Maintenance therapy approaches vary by risk level

Over the past decade, the results of many studies established lenalidomide as the standard of care for maintenance therapy. A study published in 2012 found a median progression-free survival of 46 months with lenalidomide maintenance compared with 27 months of placebo. The three-year overall survival was 88% with lenalidomide, up from 80% with placebo. 

“It’s important to note how powerful maintenance therapy is,” says Dr. Cowan. “It consistently shows a benefit in progression-free survival, and at least one study also found improvement in overall survival.” 

Bortezomib is also a possible choice for maintenance. A 2012 study comparing bortezomib vs. thalidomide maintenance therapy found superior rates of complete response with bortezomib (49% vs. 34%). In addition, subgroup analysis of high-risk patients found improved progression-free survival and overall survival with bortezomib. This study and others have provided the basis for using bortezomib as maintenance therapy in patients with high-risk cytogenetics. 

But bortezomib alone is not Dr. Cowan’s treatment protocol for high-risk patients. The SWOG 1211 study and others showed the utility of three-drug RVd as maintenance therapy. Dr. Cowan’s approach for these patients is RVd consolidation for two to three years, followed by ongoing maintenance with lenalidomide or bortezomib. 

Multiple myeloma treatment at SCCA 

SCCA is internationally-recognized for pioneering bone marrow transplant. As a leading treatment center for multiple myeloma, SCCA offers patients exceptional transplant outcomes and access to the latest advances in care.

SCCA physicians also provide consultations for community oncologists to discuss patient cases and therapy options. 

For patient referrals contact: 

Antibody A protein made by immune system cells and released into the blood. Antibodies defend the body against foreign substances, such as bacteria. Biopsy The removal of a sample of tissue or fluid that is examined to see whether cancer is present. This may be done with a large needle or through surgical removal of tissue or fluids. Bone marrow The soft, spongy material in the center of your bones that produces all your blood cells, such as white blood cells, red blood cells and platelets. Bone marrow transplant The process of treating disease with high doses of chemotherapy, radiation therapy or both. Bone marrow or peripheral blood stem cells are given after treatment to help the body make more blood cells. The process of treating disease with high doses of chemotherapy, radiation therapy or both. Because this treatment destroys the bone marrow’s ability to produce blood cells, bone marrow or peripheral blood stem cells are given after treatment to help the body make more blood cells. Clinical trial A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis or treatment of a disease. Neuropathy A numbness, tingling or pain from nerve damage caused by a tumor or by treatment. Prognosis A statement about the likely outcome of a disease in a patient. Progression In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body. Standard care A treatment or other intervention currently being used and considered to be of proven effectiveness based on past studies. Standard treatment A treatment or other intervention currently being used and considered to be of proven effectiveness based on past studies.