By Jack Aiello, Myeloma Survivor Diagnosed 1995

This is my third time attending an International Myeloma Workshop (IMW) meeting which is held every 2 years. This 4-day meeting consists of 3200 attendees from 41 countries, mostly hematologists (70%) with smaller numbers of pharma reps (15%), researchers, and nurses who were there to present and learn from 620 submitted abstracts, each one focusing totally on myeloma! Like ASH, there are also exhibitors and posters but the focus is very much on the oral presentations. This 17th IMW meeting contrasts with the first one held in 1987 with 34 attendees (including Drs. Robert Kyle and Brian Durie).

Dr. Richardson shared his perspectives about the IMW meeting. I've included more details on individual sessions and topics below: 

Great Debates

Although this was one of the final sessions, I believe it to be quite illustrative of questions we have today about myeloma. For each debate, one myeloma expert takes “Yes” side and another argues for “No”, with each doctor presenting their arguments and then offering rebuttals. Before each debate, the audience is polled and polled again after the debate. I’ll report the questions below and the final debate results, with some discussion.

1) Should we treat Smoldering Myeloma outside of a clinical trial? Yes-38% No-62%

However, had this question been phrased as “High Risk” smoldering multiple myeloma, I believe the voting would have been reversed. Key unanswered questions include: 

• Do we treat high risk smoldering myeloma?
• Does age affect smoldering myeloma treatment?

2) Should Revlimid/Velcade/Dex (RVd) or Kyprolis/Revlimid/dex (KRd) be considered as standard front-line therapy? RVd-69% KRd-31%

The thinking was the KRd induction should be reserved for high risk multiple myeloma patients, whereas VRd should be given to the older population. Key unanswered questions include: 

• What’s the best induction for high risk multiple myeloma...VRd or KRd with/without Dara?

3) Should MRD negativity be used in clinical practice to guide treatment? Yes-38% No-62%

This is an important question being asked in clinical trials now (e.g. S1803) but we really don’t have data yet to tell us that we can stop treatment, even after years of being MRD negative. Using MRD negativity as a clinical trial endpoint was also discussed in the context of earlier FDA new drug approval. Key unanswered questions include: 

• Do we treat myeloma patients until they become MRD negative? 
• Do we continue treatment forever in MRD negative patients?
• Do we change treatment for MRD positive patients?
• Do we treat MRD negative patients that become MRD positive even if they have a stringent complete response? 

4) Is definitive duration or indefinite Revlimid the right choice for maintenance? Definitive – 51% Indefinite-49%

The primary arguments for limiting duration were an increase of secondary cancers after 2 years and that refractory Revlimid is difficult to treat.

5) Should monoclonal antibodies be included for induction in every multiple myeloma patient? Yes-59% No-41%

Up front daratumumab either as Dara/Rev/Dex (DRd) or Dara/Rev/Velcade/Dex) (DRVd) has shown benefit except in high risk myeloma. 

6) Will Autologous Stem Cell Transplant remain a standard of care in 5 years? Yes-52% No-48%

It was noted that while today it is standard of care today, newer treatment approaches like the Forte trial (KRd x 12 cycles) and quad induction therapies, more MRD negative patients might be seen after induction therapy (the preparatory treatment before transplant). And Dr. Richardson added that long-term MDS and acute myeloid leukemia are possible transplant outcomes. Dr. Bensinger theorized that a CAR-T followed by a RIC (Reduced Intensity Condition “Mini”) Allo might be a reasonable treatment plan.

Great Debate Additional Questions

• What’s a better definition of high risk multiple myeloma?
• Should fixed length induction or induction length be based on response to treatment?
• Who should consider consolidation therapy after transplant?
• What is the best consolidation therapy after transplant?
• What are the best options for frail and elderly patients?
• There’s an unmet need for relapsed/refractory myeloma patients who relapse within 1 year of an SCT
• What’s the best option for penta-refractory? (they are resistant to 5 different types of therapy)
• CAR-T therapy questions: 
  • What is the optimal dose?
  • What is optimal conditioning treatment (before the CAR T treatment is given)
  • What is the best patient population?
  • If a patient has Cytokine Release Syndrome, when do you start treatment (Tocilizumab)?
  • What treatment should be given after CAR T therapy?

Major IMW Discussion Topics

Treatments for Smoldering Myeloma and Newly Diagnosed Patients

Dr. Kyle remarked “90% of MGUS patients will die of other causes” so treatment for smoldering myeloma patients is being investigated. The classic definition of smoldering myeloma is an M-protein > 3g/dL and no myeloma defining events. Dr. San Miguel noted “There are 51 clinical trials assessing early treatment in SMM.” Researchers are focusing on high-risk multiple myeloma where the definitions of high-risk vary.

Dr Rajkumar said “High risk smoldering myeloma is whatever factors result in a 50% progression to multiple myeloma within 2 years.” Some doctors look at M-protein and call it high-risk if it’s increasing by more than 10% within 6 mos. Others use the 20-2-20 definition of 20% plasma cell, 2% M-protein, and 20 free light chain (FLC) ratio. Genomic profiling may further improve the definition. Treatments being offered to high risk smoldering myeloma patients include “preventive” regimens such as Rev (+ dex) and “curative” regimens with trials.

IMW provided updates on newly diagnosed transplant eligible myeloma that included KCRd (Myeloma XI trial) and DaraVRd (Griffen trial) as well as added convenience with weekly Kyprolis and subQ Dara. And for patients who are not transplant eligible, RVd is better than Rd, which is better than Vd (except for high-risk patients).

Treatments for Previously Treated Myeloma

While there are many treatment options, choosing therapy should be guided by:

1. What is known about a patient’s myeloma (e.g. prior therapy & efficacy, cytogentics) and
2. What is known about the patient (e.g. age, other medical problems, side effects from past therapies, personal preferences.

At the IMW conference, updates and posters included:

• Empliciti (ERd) (Eloquent trial)
• Weekly Kyprolis (Arrow)
• Pomalidomide with Kyprolis (pooled studies) or Velcade (Optimismm)
• And selinexor (Xpovio) (approved with dex (Storm) but is in trial with other drugs).
• New drug updates were shown for Venetoclax + Vd (Bellini) (targeted for t(11;14)),
• Melflufen + dex (Horizon study) for extramedullary disease
• Phase I study of AMG176, an MCL-1 inhibitor

Immunotherapeutic Approaches

• Dr. Ken Anderson emphasized that using our own immune system to fight myeloma could be the best solution. These types of therapies fall into the categories of Monoclonal Antibodies, immunomodulators, checkpoint inhibitors, CAR-T, and vaccines.
• Isatuximab is a CD38 monoclonal antibody (similar to Dara) where in combination with Pom-dex showed benefit for relapsed/refractory myeloma patients, including high-risk (ICARIA-MM trial) and Isatuximab+KRd showed positive early results for 10 newly diagnosed high risk myeloma patients.
• While positive results for the BiTE AMG420 were updated, Amgen has decided to refocus their efforts on their extended half-life BiTE AMG701 because it is easier to administer to patients.
• The ADC GSK’916 (DREAMM study) continues to show promise.
• Iberdomide (CC220 “CelMoD”) is the newest immunomodulator from Celgene and can apparently overcome resistance to other IMIDs and is being testing in trials with Dara and Velcade.
• CAR-T therapy keeps moving forward, primarily targeting BCMA but also other targets (GPRC5D, NY-ESO-1) and is expanding to Allo CAR-T as well as CAR NK-cell therapy.

Guiding Treatment Decisions...Prognostic, Genetics, MRD, and Maintenance

Cytogenic/FISH tests are used to look at chromosomal changes but newer tests (GEP, NGS) can assess changes in the DNA and may well be the future, especially if results can be tied to treatment decisions. At IMW, the MMRF CoMMpass study is showing early results of a new high-risk subtype and predictors of early relapse.

MRD continues to be discussed and shown to be excellent for prognostic purposes but not used on any regular basis to guide therapy outside of clinical trials. However, I thought an interesting point was made that the role of maintenance is to sustain MRD-. And maintenance trials at IMW showed that either Revlimid or Velcade or even Kyprolis can be given as effective maintenance.

Summary

Beyond what I’ve written, even more was discussed, such as targeting mutations and pathways like RAS (KRAS, NRAS), BRAF, MEK, BCL2 (found in t(11;14) and treated with Venetoclax), and MCL-1. Some drugs already exist for these and are incorporated in the MMRF’s MyDRUG precision medicine trial.

PS. I try to be accurate with my note taking but material is presented quickly. If you have any questions, please feel free to email me jackaiello@comcast.net